bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024–03–10
forty-five papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Oral decitabine and cedazuridine plus venetoclax for older or unfit patients with acute myeloid leukaemia: a phase 2 study.
  2. Myelodysplastic neoplasms dissected into indolent, leukaemic and unfavourable subtypes by computational clustering of haematopoietic stem and progenitor cells.
  3. Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis: A retrospective analysis of the DRST and GREM registries.
  4. TET2 mutation as prototypic clonal hematopoiesis lesion.
  5. Functional characterization of cooperating MGA mutations in RUNX1::RUNX1T1 acute myeloid leukemia.
  6. BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor.
  7. Epigenetic control over cell-intrinsic immune response antagonizes self-renewal in acute myeloid leukemia.
  8. Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells.
  9. Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
  10. In vivo ablation of NFκB cascade effectors alleviates disease burden in myeloproliferative neoplasms.
  11. Correction: Mitochondrial regulation of GPX4 inhibition-mediated ferroptosis in acute myeloid leukemia.
  12. SHP2 inhibition displays efficacy as a monotherapy and in combination with JAK2 inhibition in preclinical models of myeloproliferative neoplasms.
  13. Outcomes and prognosis of haploidentical haematopoietic stem cell transplantation in children with FLT3-ITD mutated acute myeloid leukaemia.
  14. Targeting CCL2/CCR2 signaling overcomes MEK inhibitor resistance in Acute Myeloid Leukemia.
  15. Therapeutic Targeting of TIM-4-L With Engineered T Cells for Acute Myeloid Leukemia.
  16. 5G2 mutant mice model loss of a commonly deleted segment of chromosome 7q22 in myeloid malignancies.
  17. Ex vivo expansion potential of murine hematopoietic stem cells is a rare property only partially predicted by phenotype.
  18. Bahcc1 is critical for the aberrant epigenetic program in a mouse model of MLL-ENL-mediated leukemia.
  19. CD155/PVR determines Acute Myeloid Leukemia targeting by Delta One T cells.
  20. Chronic myelomonocytic leukemia: 2024 update on diagnosis, risk stratification and management.
  21. IDH Mutant Myeloid Neoplasms are Associated with Seronegative Rheumatoid Arthritis and Innate Immune Activation.
  22. The dark side of stemness - the role of hematopoietic stem cells in development of blood malignancies.
  23. Regulation of HOX gene expression in AML.
  24. Acquired Multidrug Resistance in AML Is Caused by Low Apoptotic Priming in Relapsed Myeloblasts.
  25. The MYC-NFATC2 axis maintains the cell cycle and mitochondrial function in acute myeloid leukaemia cells.
  26. Clinical outcomes of patients with acute myeloid leukemia and cardiovascular disease.
  27. The multi-CDK inhibitor dinaciclib reverses bromo- and extra-terminal domain (BET) inhibitor resistance in acute myeloid leukemia via inhibition of Wnt/β-catenin signaling.
  28. Clinical features and management of germline CEBPA-mutated carriers.
  29. Clonal hematopoiesis.
  30. Prognostic impact of SF3B1 mutation and multilineage dysplasia in myelodysplastic syndromes with ring sideroblasts: a Mayo Clinic study of 170 informative cases.
  31. Incidence and outcome of central nervous system relapse after hematopoietic stem cell transplantation in patients suffering from acute myeloid leukemia and acute lymphoblastic leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
  32. Asparaginase completion among adults including older patients with acute lymphoblastic leukemia treated with a modified DFCI protocol.
  33. Nilotinib with or without cytarabine for Philadelphia positive acute lymphoblastic leukemia.
  34. Plasma Proteomic Signature Predicts Myeloid Neoplasm Risk.
  35. Mutations in myeloid transcription factors and activated signaling genes predict chronic myeloid leukemia outcomes.
  36. Treatment outcomes of venetoclax-combination regimens for relapsed/refractory myeloid malignancies after anti-CD47-directed therapy.
  37. A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
  38. Cell-free DNA from nail clippings as source of normal control for genomic studies in hematologic malignancies.
  39. Clonal hematopoiesis of indeterminate potential is associated with acute kidney injury.
  40. Differential Effects of JAK1 vs. JAK2 Inhibition in Mouse Models of Hemophagocytic Lymphohistiocytosis.
  41. Harmonizing definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism in allogeneic hematopoietic cell transplantation: a report on behalf of the EBMT, ASTCT, CIBMTR, and APBMT.
  42. Treatment-free remission in CML patients with additional chromosome abnormalities in the Philadelphia-positive clone or variant Philadelphia translocations.
  43. Increased donor inhibitory KIR are associated with reduced GVHD and improved survival following HLA-matched unrelated donor HCT in paediatric acute leukaemia.
  44. Alloengraftment without significant toxicity or GVHD in CD45 antibody-drug conjugate conditioned Fanconi anemia mice.
  45. Circulating Hematopoietic Stem/Progenitor Cells subsets contribute to human hematopoietic homeostasis.
  1. Lancet Haematol. 2024 Mar 04. pii: S2352-3026(24)00033-4. [Epub ahead of print]
    Oral decitabine and cedazuridine plus venetoclax for older or unfit patients with acute myeloid leukaemia: a phase 2 study.
    Alexandre Bazinet, Guillermo Garcia-Manero, Nicholas Short, Yesid Alvarado, Alex Bataller, Tareq Abuasab, Rabiul Islam, Kathryn Montalbano, Ghayas Issa, Abhishek Maiti, Musa Yilmaz, Nitin Jain, Lucia Masarova, Steven Kornblau, Elias Jabbour, Guillermo Montalban-Bravo, Caitlin R Rausch, Sherry Pierce, Courtney D DiNardo, Tapan Kadia, Naval Daver, Marina Konopleva, Xuelin Huang, Hagop Kantarjian, Farhad Ravandi.
       BACKGROUND: Hypomethylating agents combined with venetoclax are effective regimens in patients with acute myeloid leukaemia who are ineligible for intensive chemotherapy. Decitabine and cedazuridine (ASTX727) is an oral formulation of decitabine that achieves equivalent area-under-curve exposure to intravenous decitabine. We performed a single centre phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax.
    METHODS: This study enrolled patients with newly diagnosed (frontline treatment group) acute myeloid leukaemia who were ineligible for intensive chemotherapy (aged ≥75 years, an Eastern Cooperative Oncology Group [ECOG] performance status of 2-3, or major comorbidities) or relapsed or refractory acute myeloid leukaemia. Being aged 18 years or older and having an ECOG performance status of 2 or less were requirements for the relapsed or refractory disease treatment cohort, without any limits in the number of previous lines of therapy. Treatment consisted of ASTX727 (cedazuridine 100 mg and decitabine 35 mg) orally for 5 days and venetoclax 400 mg orally for 21-28 days in 28-day cycles. The primary outcome was overall response rate of ASTX727 plus venetoclax. Living patients who have not completed cycle one were not evaluable for response. Safety was analysed in all patients who started treatment. This study was registered on ClinicalTrials.gov (NCT04746235) and is ongoing. The data cutoff date for this analysis was Sept 22, 2023.
    FINDINGS: Between March 16, 2021, and Sept 18, 2023, 62 patients were enrolled (49 frontline and 13 relapsed or refractory) with a median age of 78 years (IQR 73-82). 36 (58%) were male; 53 (85%) were White, 4 (6%) Black, 2 (3%) Asian and 3 (5%) other or did not answer. 48 (77%) of 62 patients were European LeukemiaNet 2022 adverse risk, 24 (39%) had antecedent myelodysplastic syndromes, 12 (19%) had previously failed a hypomethylating agent, ten (16%) had therapy-related acute myeloid leukaemia, and 11 (18%) had TP53 mutations. The median follow-up time was 18·3 months (IQR 8·8-23·3). The overall response rate was 30 (64%) of 47 patients (95% CI 49-77) in frontline cohort and six (46%) of 13 patients (19-75) in relapsed or refractory cohort. The most common grade 3 or worse treatment-emergent adverse events were febrile neutropenia in 11 (18%) of 62 patients, pneumonia in eight (13%), respiratory failure in five (8%), bacteraemia in four (6%), and sepsis in four (6%). Three deaths occurred in patients in remission (one sepsis, one gastrointestinal haemorrhage, and one respiratory failure) and were potentially treatment related.
    INTERPRETATION: ASTX727 plus venetoclax is an active fully oral regimen and safe in most older or unfit patients with acute myeloid leukaemia. Our findings should be confirmed in larger multicentric studies.
    FUNDING: MD Anderson Cancer Center Support Grant, Myelodysplastic Syndrome/Acute Myeloid Leukaemia Moon Shot, Leukemia SPORE, Taiho Oncology, and Astex Pharmaceuticals.
    DOI:  https://doi.org/10.1016/S2352-3026(24)00033-4
  2. Leukemia. 2024 Mar 08.
    Myelodysplastic neoplasms dissected into indolent, leukaemic and unfavourable subtypes by computational clustering of haematopoietic stem and progenitor cells.
    Margot F van Spronsen, Sofie Van Gassen, Carolien Duetz, Theresia M Westers, Yvan Saeys, Arjan A van de Loosdrecht.
      Myelodysplastic neoplasms (MDS) encompass haematological malignancies, which are characterised by dysplasia, ineffective haematopoiesis and the risk of progression towards acute myeloid leukaemia (AML). Myelodysplastic neoplasms are notorious for their heterogeneity: clinical outcomes range from a near-normal life expectancy to leukaemic transformation or premature death due to cytopenia. The Molecular International Prognostic Scoring System made progress in the dissection of MDS by clinical outcomes. To contribute to the risk stratification of MDS by immunophenotypic profiles, this study performed computational clustering of flow cytometry data of CD34+ cells in 67 MDS, 67 AML patients and 49 controls. Our data revealed heterogeneity also within the MDS-derived CD34+ compartment. In MDS, maintenance of lymphoid progenitors and megakaryocytic-erythroid progenitors predicted favourable outcomes, whereas expansion of granulocyte-monocyte progenitors increased the risk of leukaemic transformation. The proliferation of haematopoietic stem cells and common myeloid progenitors with downregulated CD44 expression, suggestive of impaired haematopoietic differentiation, characterised a distinct MDS subtype with a poor overall survival. This exploratory study demonstrates the prognostic value of known and previously unexplored CD34+ populations and suggests the feasibility of dissecting MDS into a more indolent, a leukaemic and another unfavourable subtype.
    DOI:  https://doi.org/10.1038/s41375-024-02203-z
  3. Leukemia. 2024 Mar 06.
    Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis: A retrospective analysis of the DRST and GREM registries.
    Johannes Lübke, Deborah Christen, Juliana Schwaab, Anne Kaiser, Nicole Naumann, Khalid Shoumariyeh, Madlen Jentzsch, Katja Sockel, Judith Schaffrath, Francis A Ayuk, Matthias Stelljes, Inken Hilgendorf, Elisa Sala, Jennifer Kaivers, Stefan Schönland, Christoph Wittke, Bernd Hertenstein, Markus Radsak, Ulrich Kaiser, Valeska Brückl, Nicolaus Kröger, Tim H Brümmendorf, Wolf-Karsten Hofmann, Stefan Klein, Edgar Jost, Andreas Reiter, Jens Panse.
      We identified 71 patients with AdvSM (aggressive SM [ASM], SM with an associated hematologic neoplasm [SM-AHN, e.g., acute myeloid leukemia, SM-AML], mast cell leukemia [MCL]) in two national registries (DRST/GREM) who received an allogeneic hematopoietic cell transplantation (alloHCT) performed in Germany from 1999-2021. Median overall survival (OS) of ASM/SM-AHN (n = 30, 45%), SM-AML (n = 28, 39%) and MCL ± AHN (n = 13, 19%) was 9.0, 3.3 and 0.9 years (P = 0.007). Improved median OS was associated with response of SM (17/41, 41%; HR 0.4 [0.2-0.9], P = 0.035) and/or of AHN (26/43, 60%, HR 0.3 [0.1-0.7], P = 0.004) prior to alloHCT. Adverse predictors for OS included absence of KIT D816V (10/61, 16%, HR 2.9 [1.2-6.5], P < 0.001) and a complex karyotype (9/60, 15%, HR 4.2 [1.8-10.0], P = 0.016). HLA-match, conditioning type or transplantation at centers reporting above-average alloHCTs (≥7) had no impact on OS. Taking into account competing events at years 1, 3 and 5, relapse-related mortality and non-relapse mortality rate were 15%/23%, 20%/30% and 23%/35%, respectively. Irrespective of subtype, subsequent treatment response was achieved in 13/30 (43%) patients and was highest on midostaurin/avapritinib (7/9, 78%). We conclude that outcome of alloHCT in AdvSM is more affected by disease phenotype and treatment response prior to transplant than by transplant characteristics.
    DOI:  https://doi.org/10.1038/s41375-024-02186-x
  4. Semin Hematol. 2024 Feb 02. pii: S0037-1963(24)00013-1. [Epub ahead of print]
    TET2 mutation as prototypic clonal hematopoiesis lesion.
    Luca Guarnera, Babal K Jha.
      Loss of function TET2 mutation (TET2MT) is one of the most frequently observed lesions in clonal hematopoiesis (CH). TET2 a member TET-dioxygenase family of enzymes that along with TET1 and TET3, progressively oxidize 5-methyl cytosine (mC) resulting in regulated demethylation of promoter, enhancer and silencer elements of the genome. This process is critical for efficient transcription that determine cell lineage fate, proliferation and survival and the maintenance of the genomic fidelity with aging of the organism. Partial or complete loss-of-function TET2 mutations create regional and contextual DNA hypermethylation leading to gene silencing or activation that result in skewed myeloid differentiation and clonal expansion. In addition to myeloid skewing, loss of TET2 creates differentiation block and provides proliferative advantage to hematopoietic stem and progenitor cells (HSPCs). TET2MT is a prototypical lesion in CH, since the mutant clones dominate during stress hematopoiesis and often associates with evolution of myeloid malignancies. TET2MT clones has unique privilege to create and persist in pro-inflammatory milieu. Despite extensive knowledge regarding biochemical mechanisms underlying distorted myeloid differentiation, and enhanced self-replication of TET2MT HSPC, the mechanistic link of various pathogenesis associated with TET2 loss in CHIP is less understood. Here we review the recent development in TET2 biology and its probable mechanistic link in CH with aging and inflammation. We also explored the therapeutic strategies of targeting TET2MT associated CHIP and the utility of targeting TET2 in normal hematopoiesis and somatic cell reprograming. We explore the biochemical mechanisms and candidate therapies that emerged in last decade of research.
    Keywords:  Aging; CHIP; Epigenetics; Inflammation; TET2; Targeting; Therapeutic development
    DOI:  https://doi.org/10.1053/j.seminhematol.2024.01.013
  5. Leukemia. 2024 Mar 07.
    Functional characterization of cooperating MGA mutations in RUNX1::RUNX1T1 acute myeloid leukemia.
    Melvin E Thomas, Wenqing Qi, Michael P Walsh, Jing Ma, Tamara Westover, Sherif Abdelhamed, Lauren J Ezzell, Chandra Rolle, Emily Xiong, Wojciech Rosikiewicz, Beisi Xu, Allister J Loughran, Shondra M Pruett-Miller, Laura J Janke, Jeffery M Klco.
      MGA (Max-gene associated) is a dual-specificity transcription factor that negatively regulates MYC-target genes to inhibit proliferation and promote differentiation. Loss-of-function mutations in MGA have been commonly identified in several hematological neoplasms, including acute myeloid leukemia (AML) with RUNX1::RUNX1T1, however, very little is known about the impact of these MGA alterations on normal hematopoiesis or disease progression. We show that representative MGA mutations identified in patient samples abolish protein-protein interactions and transcriptional activity. Using a series of human and mouse model systems, including a newly developed conditional knock-out mouse strain, we demonstrate that loss of MGA results in upregulation of MYC and E2F targets, cell cycle genes, mTOR signaling, and oxidative phosphorylation in normal hematopoietic cells, leading to enhanced proliferation. The loss of MGA induces an open chromatin state at promoters of genes involved in cell cycle and proliferation. RUNX1::RUNX1T1 expression in Mga-deficient murine hematopoietic cells leads to a more aggressive AML with a significantly shortened latency. These data show that MGA regulates multiple pro-proliferative pathways in hematopoietic cells and cooperates with the RUNX1::RUNX1T1 fusion oncoprotein to enhance leukemogenesis.
    DOI:  https://doi.org/10.1038/s41375-024-02193-y
  6. Blood. 2024 Feb 16. pii: blood.2023022832. [Epub ahead of print]
    BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor.
    Warren Fiskus, Jessica Piel, Michael P Collins, Murphy Hentemann, Branko Cuglievan, Christopher P Mill, Christine Birdwell, Kaberi Das, John A Davis, Hanxi Hou, Antrix Jain, Anna Malovannaya, Tapan M Kadia, Naval G Daver, Koji Sasaki, Koichi Takahashi, Danielle Hammond, Patrick K Reville, Jian Wang, Sanam Loghavi, Rwik Sen, Xinjia Ruan, Xiaoping Su, Lauren Flores, Courtney D DiNardo, Kapil N Bhalla.
      BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/co-factors to access enhancers/promoter and modulate gene-expressions responsible for cell growth and differentiation of AML stem/progenitor cells. In AML with MLL1r (MLL1 rearrangement) or mutant (mt) NPM1, although Menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring Menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1 and CDK4/6. Co-treatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In patient-derived xenograft (PDX) models of AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared to each drug, co-treatment with FHD-286 and BETi, MI, decitabine or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with MLL1r or mtNPM1.
    DOI:  https://doi.org/10.1182/blood.2023022832
  7. Blood. 2024 Mar 08. pii: blood.2023021640. [Epub ahead of print]
    Epigenetic control over cell-intrinsic immune response antagonizes self-renewal in acute myeloid leukemia.
    Eloisa Felipe Fumero, Carolin Walter, Joris Maximillian Frenz, Franca Carlotta Seifert, Vijay Alla, Thorben Hennig, Linus Angenendt, Wolfgang Hartmann, Sebastian Wolf, Hubert Serve, Thomas Oellerich, Georg Lenz, Carsten Müller-Tidow, Christoph Schliemann, Otmar Huber, Martin Dugas, Matthias Mann, Ashok Kumar Jayavelu, Jan-Henrik Mikesch, Maria Francisca Arteaga.
      Epigenetic modulation of the cell-intrinsic immune response holds promise as a therapeutic approach for leukemia. However, current strategies designed for transcriptional activation of endogenous transposons and subsequent interferon type-I (IFN-I) response, show limited clinical efficacy. Histone lysine methylation is an epigenetic signature in IFN-I response associated with suppression of IFN-I and IFN stimulated genes, suggesting histone demethylation as key mechanism of reactivation. In this study, we unveil the histone demethylase PHF8 as a direct initiator and regulator of cell-intrinsic immune response in acute myeloid leukemia (AML). Site-specific phosphorylation of PHF8 orchestrates epigenetic changes that upregulate cytosolic RNA sensors, particularly the TRIM25-RIG-I-IFIT5 axis, thereby triggering the cellular IFN-I response-differentiation-apoptosis network. This signaling cascade largely counteracts differentiation block and growth of human AML cells across various disease subtypes in vitro and in vivo. Through proteome analysis of over 200 primary AML bone marrow samples, we identify a distinct PHF8/IFN-I signature in half of the patient population, without significant associations with known clinically or genetically defined AML subgroups. This profile was absent in healthy CD34-positive hematopoietic progenitor cells, suggesting therapeutic applicability in a large fraction of AML patients. Pharmacological support of PHF8 phosphorylation significantly impairs growth of primary AML patient samples. These findings provide novel opportunities for harnessing the cell-intrinsic immune response in the development of immunotherapeutic strategies against AML.
    DOI:  https://doi.org/10.1182/blood.2023021640
  8. Hemasphere. 2024 Feb;8(2): e45
    Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells.
    Talia Velasco-Hernandez, Juan L Trincado, Meritxell Vinyoles, Adria Closa, Alba Martínez-Moreno, Francisco Gutiérrez-Agüera, Oscar Molina, Virginia C Rodríguez-Cortez, Pau Ximeno-Parpal, Narcís Fernández-Fuentes, Paolo Petazzi, Sergi Beneyto-Calabuig, Lars Velten, Paola Romecin, Raquel Casquero, Fernando Abollo-Jiménez, Rafael D de la Guardia, Patricia Lorden, Alex Bataller, Hélène Lapillonne, Ronald W Stam, Susana Vives, Montserrat Torrebadell, Jose L Fuster, Clara Bueno, Jean-Emmanuel Sarry, Eduardo Eyras, Holger Heyn, Pablo Menéndez.
      Relapse remains a major challenge in the clinical management of acute myeloid leukemia (AML) and is driven by rare therapy-resistant leukemia stem cells (LSCs) that reside in specific bone marrow niches. Hypoxia signaling maintains cells in a quiescent and metabolically relaxed state, desensitizing them to chemotherapy. This suggests the hypothesis that hypoxia contributes to the chemoresistance of AML-LSCs and may represent a therapeutic target to sensitize AML-LSCs to chemotherapy. Here, we identify HIFhigh and HIFlow specific AML subgroups (inv(16)/t(8;21) and MLLr, respectively) and provide a comprehensive single-cell expression atlas of 119,000 AML cells and AML-LSCs in paired diagnostic-relapse samples from these molecular subgroups. The HIF/hypoxia pathway signature is attenuated in AML-LSCs compared with more differentiated AML cells but is more expressed than in healthy hematopoietic cells. Importantly, chemical inhibition of HIF cooperates with standard-of-care chemotherapy to impair AML growth and to substantially eliminate AML-LSCs in vitro and in vivo. These findings support the HIF pathway in the stem cell-driven drug resistance of AML and unravel avenues for combinatorial targeted and chemotherapy-based approaches to specifically eliminate AML-LSCs.
    DOI:  https://doi.org/10.1002/hem3.45
  9. Nat Commun. 2024 Mar 02. 15(1): 1931
    Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
    Martha M Zarou, Kevin M Rattigan, Daniele Sarnello, Engy Shokry, Amy Dawson, Angela Ianniciello, Karen Dunn, Mhairi Copland, David Sumpton, Alexei Vazquez, G Vignir Helgason.
      Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-46114-0
  10. Blood. 2024 Mar 08. pii: blood.2023022804. [Epub ahead of print]
    In vivo ablation of NFκB cascade effectors alleviates disease burden in myeloproliferative neoplasms.
    Angelo Brunelli Albertoni Laranjeira, Tim Kong, Steven C Snyder, Mary C Fulbright, Daniel A C Fisher, Daniel T Starczynowski, Stephen T Oh.
      Hyperactivation of the NFκB cascade propagates oncogenic signaling and pro-inflammation, which together augments disease burden in myeloproliferative neoplasms (MPNs). Here, we systematically ablate NFκB signaling effectors to identify core dependencies using a series of primary samples and syngeneic and patient-derived xenograft (PDX) mouse models. Conditional knockout of Rela attenuated Jak2V617F and MPLW515L-driven onset of polycythemia vera and myelofibrosis disease hallmarks, respectively. In PDXs, RELA-knockout diminished leukemic engraftment and bone marrow fibrosis while extending survival. Knock-out of upstream effector Myd88 also alleviated disease burden; conversely, perturbation of negative regulator miR-146a microRNA induced earlier lethality and exacerbated disease. Perturbation of NFκB effectors further skewed the abundance and distribution of hematopoietic multipotent progenitors. Finally, pharmacological targeting of interleukin-1 receptor-associated kinase 4 (IRAK4) with inhibitor CA-4948 suppressed disease burden and inflammatory cytokines specifically in MPN without inducing toxicity in non-diseased models. These findings highlight vulnerabilities in MPN that are exploitable with emerging therapeutic approaches.
    DOI:  https://doi.org/10.1182/blood.2023022804
  11. Leukemia. 2024 Mar 08.
    Correction: Mitochondrial regulation of GPX4 inhibition-mediated ferroptosis in acute myeloid leukemia.
    Hiroki Akiyama, Ran Zhao, Lauren B Ostermann, Ziyi Li, Matthew Tcheng, Samar J Yazdani, Arman Moayed, Malcolm L Pryor, Sandeep Slngh, Natalia Baran, Edward Ayoub, Yuki Nishida, Po Yee Mak, Vivian R Ruvolo, Bing Z Carter, Aaron D Schimmer, Michael Andreeff, Jo Ishizawa.
      
    DOI:  https://doi.org/10.1038/s41375-024-02202-0
  12. Am J Hematol. 2024 Mar 05.
    SHP2 inhibition displays efficacy as a monotherapy and in combination with JAK2 inhibition in preclinical models of myeloproliferative neoplasms.
    Garima Pandey, Lucia Mazzacurati, Tegan M Rowsell, Nathan P Horvat, Narmin E Amin, Guolin Zhang, Afua A Akuffo, Christelle M Colin-Leitzinger, Eric B Haura, Andrew T Kuykendall, Ling Zhang, Pearlie K Epling-Burnette, Gary W Reuther.
      Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocytosis, and primary myelofibrosis, are clonal hematopoietic neoplasms driven by mutationally activated signaling by the JAK2 tyrosine kinase. Although JAK2 inhibitors can improve MPN patients' quality of life, they do not induce complete remission as disease-driving cells persistently survive therapy. ERK activation has been highlighted as contributing to JAK2 inhibitor persistent cell survival. As ERK is a component of signaling by activated RAS proteins and by JAK2 activation, we sought to inhibit RAS activation to enhance responses to JAK2 inhibition in preclinical MPN models. We found the SHP2 inhibitor RMC-4550 significantly enhanced growth inhibition of MPN cell lines in combination with the JAK2 inhibitor ruxolitinib, effectively preventing ruxolitinib persistent growth, and the growth and viability of established ruxolitinib persistent cells remained sensitive to SHP2 inhibition. Both SHP2 and JAK2 inhibition diminished cellular RAS-GTP levels, and their concomitant inhibition enhanced ERK inactivation and increased apoptosis. Inhibition of SHP2 inhibited the neoplastic growth of MPN patient hematopoietic progenitor cells and exhibited synergy with ruxolitinib. RMC-4550 antagonized MPN phenotypes and increased survival of an MPN mouse model driven by MPL-W515L. The combination of RMC-4550 and ruxolitinib, which was safe and tolerated in healthy mice, further inhibited disease compared to ruxolitinib monotherapy, including extending survival. Given SHP2 inhibitors are undergoing clinical evaluation in patients with solid tumors, our preclinical findings suggest that SHP2 is a candidate therapeutic target with potential for rapid translation to clinical assessment to improve current targeted therapies for MPN patients.
    DOI:  https://doi.org/10.1002/ajh.27282
  13. Bone Marrow Transplant. 2024 Mar 05.
    Outcomes and prognosis of haploidentical haematopoietic stem cell transplantation in children with FLT3-ITD mutated acute myeloid leukaemia.
    Qianwen Shang, Lu Bai, Yifei Cheng, Pan Suo, Guanhua Hu, Chenhua Yan, Yu Wang, Xiaohui Zhang, Lanping Xu, Kaiyan Liu, Xiaojun Huang.
      The presence of internal tandem duplication mutations in the FMS-like tyrosine kinase 3 receptor (FLT3-ITD) is a poor prognostic predictor in paediatric patients with acute myeloid leukaemia (AML). We evaluated the treatment outcomes and prognostic factors of 45 paediatric patients with FLT3-ITD AML who achieved complete remission before haploidentical haematopoietic stem cell transplantation (haplo-HSCT) at our institution from 2012 to 2021. Among the 45 patients, the overall survival (OS), event‑free survival (EFS), and cumulative incidence of relapse (CIR) rates were 74.9% ± 6.6%, 64.1% ± 7.2%, and 31.4% ± 7.1%, respectively, with 48.8 months of median follow-up. Univariate and multivariate analyses associated positive minimal residual disease (MRD) at pre-HSCT and non-remission (NR) after introduce 1 with inferior long-term survival. The 100-day cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 35.6% ± 5.2%, and that of grade III-IV aGVHD was 15.6% ± 3.0% The overall 4-year cumulative incidence of chronic graft-versus-host disease after transplantation was 35.7% ± 9.8%, respectively. In conclusion, haplo-HSCT may be a feasible strategy for paediatric patients with FLT3-ITD AML, and pre-HSCT MRD status and NR after introduce 1 significantly affected the outcomes.
    DOI:  https://doi.org/10.1038/s41409-024-02214-5
  14. Clin Cancer Res. 2024 Mar 07.
    Targeting CCL2/CCR2 signaling overcomes MEK inhibitor resistance in Acute Myeloid Leukemia.
    Rucha V Modak, Katia G de Oliveira Rebola, John McClatchy, Mona Mohammadhosseini, Alisa Damnernsawad, Stephen E Kurtz, Christopher A Eide, Guanming Wu, Ted Laderas, Tamilla Nechiporuk, Marina A Gritsenko, Joshua R Hansen, Chelsea Hutchinson, Sara J C Gosline, Paul Piehowski, Daniel Bottomly, Nicholas Short, Karin Rodland, Shannon K McWeeney, Jeffrey W Tyner, Anupriya Agarwal.
       PURPOSE: Emerging evidence underscores the critical role of extrinsic factors within the microenvironment in protecting leukemia cells from therapeutic interventions, driving disease progression, and promoting drug resistance in acute myeloid leukemia (AML). This emphasizes the need for the identification of targeted therapies that inhibit intrinsic and extrinsic signaling to overcome drug resistance in AML.
    EXPERIMENTAL DESIGN: We performed a comprehensive analysis utilizing a cohort of ~300 AML patient samples. This analysis encompassed the evaluation of secreted cytokines/growth factors, gene expression, and ex vivo drug sensitivity to small molecules. Our investigation pinpointed a notable association between elevated levels of CCL2 and diminished sensitivity to the MEK inhibitors. We validated this association through loss-of-function and pharmacological inhibition studies. Further, we deployed global phosphoproteomics and CRISPR/Cas9 screening to identify the mechanism of CCR2-mediated MEKi resistance in AML.
    RESULTS: Our multifaceted analysis unveiled that CCL2 activates multiple pro-survival pathways, including MAPK and cell cycle regulation in MEKi-resistant cells. Employing combination strategies to simultaneously target these pathways heightened growth inhibition in AML cells. Both genetic and pharmacological inhibition of CCR2 sensitized AML cells to trametinib, suppressing proliferation while enhancing apoptosis. These findings underscore a new role for CCL2 in MEKi resistance, offering combination therapies as an avenue to circumvent this resistance.
    CONCLUSIONS: Our study demonstrates a compelling rationale for translating CCL2/CCR2 axis inhibitors in combination with MEK pathway-targeting therapies, as a potent strategy for combating drug resistance in AML. This approach has the potential to enhance the efficacy of treatments to improve AML patient outcomes.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-2654
  15. Clin Cancer Res. 2024 Mar 07.
    Therapeutic Targeting of TIM-4-L With Engineered T Cells for Acute Myeloid Leukemia.
    Brandon Cieniewicz, Edson Oliveira, Mike Saxton, Damoun Torabi, Ankit Bhatta, Phanidhar Kukutla, Alexander Arballo, Zhuo Yang, Bi Yu, Maria Fate, Hongxiu Ning, Lawrence Corey, Abhishek Maiti, Daniel Corey.
       PURPOSE: Disruption of lipid bilayer asymmetry is a common feature observed in cancer cells and offers novel routes for therapeutic targeting. We utilized the natural immune receptor TIM-4 to interrogate for loss of plasma membrane phospholipid polarity in primary acute myelogenous leukemia (AML) samples and evaluated the anti-leukemic activity of TIM-4-L-directed T cell therapy in preclinical AML models.
    METHODS: We performed FACs analysis on 33 primary AML bone marrow specimens and correlated TIM-4-L expression frequency and intensity with molecular disease characteristics. Using Kasumi-1 and MV-4-11 AML cell lines, we further tested the anti-leukemic effects of TIM-4-L-directed engineered T cells in vitro and in vivo.
    RESULTS: 86% of untreated AML blasts displayed upregulation of cell surface TIM-4-L. These observations were agnostic to AML genetic classification, as samples with mutations in TP53, ASXL1, and RUNX1 displayed TIM-4-L upregulation similar to that seen in favorable and intermediate subtypes. TIM-4-L dysregulation was also stably present in AML cell lines. To evaluate the potential of targeting upregulated TIM-4-L with adoptive T cell therapy (ACT), we constructed TIM-4-L-directed engineered T cells, which demonstrated potent anti-leukemic effects, effectively eliminating AML cell lines with a range of endogenous TIM-4-L expression levels both in vitro and in vivo.
    CONCLUSIONS: These results highlight TIM-4-L as a highly prevalent target on AML across a range of genetic classifications and novel target for T cell-based therapy in AML. Further investigations into the role of TIM-4-L in AML pathogenesis and its potential as an anti-leukemic target for clinical development are warranted.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-3044
  16. Leukemia. 2024 Mar 05.
    5G2 mutant mice model loss of a commonly deleted segment of chromosome 7q22 in myeloid malignancies.
    Jasmine C Wong, Kelley M Weinfurtner, Tamara Westover, Jangkyung Kim, Eric J Lebish, Maria Del Pilar Alzamora, Benjamin J Huang, Michael Walsh, Sherif Abdelhamed, Jing Ma, Jeffery M Klco, Kevin Shannon.
      Monosomy 7 and del(7q) are among the most common and poorly understood genetic alterations in myelodysplastic neoplasms and acute myeloid leukemia. Chromosome band 7q22 is a minimally deleted segment in myeloid malignancies with a del(7q). However, the rarity of "second hit" mutations supports the idea that del(7q22) represents a contiguous gene syndrome. We generated mice harboring a 1.5 Mb germline deletion of chromosome band 5G2 syntenic to human 7q22 that removes Cux1 and 27 additional genes. Hematopoiesis is perturbed in 5G2+/del mice but they do not spontaneously develop hematologic disease. Whereas alkylator exposure modestly accelerated tumor development, the 5G2 deletion did not cooperate with KrasG12D, NrasG12D, or the MOL4070LTR retrovirus in leukemogenesis. 5G2+/del mice are a novel platform for interrogating the role of hemopoietic stem cell attrition/stress, cooperating mutations, genotoxins, and inflammation in myeloid malignancies characterized by monosomy 7/del(7q).
    DOI:  https://doi.org/10.1038/s41375-024-02205-x
  17. Elife. 2024 Mar 06. pii: RP91826. [Epub ahead of print]12
    Ex vivo expansion potential of murine hematopoietic stem cells is a rare property only partially predicted by phenotype.
    Qinyu Zhang, Rasmus Olofzon, Anna Konturek-Ciesla, Ouyang Yuan, David Bryder.
      The scarcity of hematopoietic stem cells (HSCs) restricts their use in both clinical settings and experimental research. Here, we examined a recently developed method for expanding rigorously purified murine HSCs ex vivo. After 3 weeks of culture, only 0.1% of cells exhibited the input HSC phenotype, but these accounted for almost all functional long-term HSC activity. Input HSCs displayed varying potential for ex vivo self-renewal, with alternative outcomes revealed by single-cell multimodal RNA and ATAC sequencing profiling. While most HSC progeny offered only transient in vivo reconstitution, these cells efficiently rescued mice from lethal myeloablation. The amplification of functional HSC activity allowed for long-term multilineage engraftment in unconditioned hosts that associated with a return of HSCs to quiescence. Thereby, our findings identify several key considerations for ex vivo HSC expansion, with major implications also for assessment of normal HSC activity.
    Keywords:  ex vivo expansion; hematopoietic stem cell; mouse; regenerative medicine; stem cells; transplantation
    DOI:  https://doi.org/10.7554/eLife.91826
  18. Blood Adv. 2024 Mar 07. pii: bloodadvances.2023011320. [Epub ahead of print]
    Bahcc1 is critical for the aberrant epigenetic program in a mouse model of MLL-ENL-mediated leukemia.
    Ryoichi Ono, Akihide Nakamura, Masahiro Masuya, Makoto Shinmei, Isao Tawara, Tetsuya Nosaka.
      In leukemogenesis, genotoxic stress in hematopoietic stem and progenitor cells (HSPCs) drives individual context-dependent programs of malignant transformation. In light of the various differentiation stages of HSPCs based on a recently revised definition using CD150/CD48, our analyses showed that a subpopulation of long-term-repopulating HSCs was most susceptible to MLL-ENL-mediated transformation. An analysis of the molecular mechanism identified Bromo-adjacent homology domain and coiled-coil containing 1 (Bahcc1), which encodes a reader molecule of trimethylated histone H3 lysine 27 (H3K27me3), as a candidate gene involved in distinct susceptibility to leukemic transformation. Interestingly, Bahcc1 was previously reported to be highly expressed in acute myeloid leukemia (AML) with an unfavorable prognosis, including some cases of MLL-rearranged AML. We found that MLL-ENL upregulated Bahcc1 through binding to its promoter, and that Bahcc1 was involved in MLL-ENL-mediated immortalization at least partly through repression of H3K27me3-marked Cdkn1c. Analyses using bone marrow transplantation in mice showed that depletion of Bahcc1 suppressed the leukemogenic activity of MLL-ENL. In a public database, high BAHCC1 expression was associated with a poor prognosis in pediatric AML, in which BAHCC1 expression was significantly lower in MLL-AF9-AML than in other MLL-fusion-AML. These findings shed light on the distinct immortalization potential of HSPCs and suggest a novel MLL-fusion-Bahcc1 axis, which may lead to development of molecular targeted therapy against MLL-fusion-mediated leukemia.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011320
  19. Blood. 2024 Feb 16. pii: blood.2023022992. [Epub ahead of print]
    CD155/PVR determines Acute Myeloid Leukemia targeting by Delta One T cells.
    Sofia Mensurado, Ana Carolina Condeço, Diego Sánchez-Martínez, Sara Shirley, Rui M L Coelho, Néstor Tirado, Meritxell Vinyoles, Rafael Blanco-Domínguez, Leandro Barros, Beatriz Galvão, Noélia Custódio, Maria Gomes da Silva, Pablo Menendez, Bruno Silva-Santos.
      Relapsed or refractory Acute Myeloid Leukemia (AML) remains a major therapeutic challenge. We have recently developed a V1+  T-cell-based product for adoptive immunotherapy, named Delta One T (DOT) cells, and demonstrated their cytolytic capacity to eliminate AML cell lines and primary blasts in vitro and in vivo. However, the molecular mechanisms responsible for the broad DOT-cell recognition of AML cells remain poorly understood. Here we dissected the role of NK-cell receptor ligands in AML cell recognition by DOT-cells. Screening of multiple AML cell lines highlighted a strong upregulation of the DNAM-1 ligands, CD155/PVR and CD112/Nectin-2, as well as the NKp30 ligand, B7-H6, in contrast with NKG2D ligands. CRISPR-mediated ablation revealed key non-redundant and synergistic contributions of PVR and B7-H6, but not Nectin-2, to DOT-cell targeting of AML cells. We further demonstrate that PVR and B7-H6 are critical for the formation of robust immunological synapses between AML and DOT-cells. Importantly, PVR but not B7-H6 expression in primary AML samples predicted their elimination by DOT-cells. These data provide new mechanistic insight into tumor-targeting by DOT cells and suggest that assessing PVR expression levels may be highly relevant to DOT-cell-based clinical trials.
    DOI:  https://doi.org/10.1182/blood.2023022992
  20. Am J Hematol. 2024 Mar 07.
    Chronic myelomonocytic leukemia: 2024 update on diagnosis, risk stratification and management.
    Mrinal M Patnaik, Ayalew Tefferi.
       DISEASE OVERVIEW: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, characterized by prominent monocytosis and an inherent risk for leukemic transformation (~15%-20% over 3-5 years).
    DIAGNOSIS: Newly revised diagnostic criteria include sustained (>3 months) peripheral blood (PB) monocytosis (≥0.5 × 109 /L; monocytes ≥10% of leukocyte count), consistent bone marrow (BM) morphology, <20% BM or PB blasts (including promonocytes), and cytogenetic or molecular evidence of clonality. Cytogenetic abnormalities occur in ~30% of patients, while >95% harbor somatic mutations: TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), RAS pathway (~30%), and others. The presence of ASXL1 and DNMT3A mutations and absence of TET2 mutations negatively impact overall survival (ASXL1WT /TET2MT genotype being favorable).
    RISK STRATIFICATION: Several risk models serve similar purposes in identifying high-risk patients that are considered for allogeneic stem cell transplant (ASCT) earlier than later. Risk factors in the Mayo Molecular Model (MMM) include presence of truncating ASXL1 mutations, absolute monocyte count >10 × 109 /L, hemoglobin <10 g/dL, platelet count <100 × 109 /L, and the presence of circulating immature myeloid cells; the resulting 4-tiered risk categorization includes high (≥3 risk factors), intermediate-2 (2 risk factors), intermediate-1 (1 risk factor), and low (no risk factors); the corresponding median survivals were 16, 31, 59, and 97 months. CMML is also classified as being "myeloproliferative (MP-CMML)" or "myelodysplastic (MD-CMML)," based on the presence or absence of leukocyte count of ≥13 × 109 /L.
    TREATMENT: ASCT is the only treatment modality that secures cure or long-term survival and is appropriate for MMM high/intermediate-2 risk disease. Drug therapy is currently not disease-modifying and includes hydroxyurea and hypomethylating agents; a recent phase-3 study (DACOTA) comparing hydroxyurea and decitabine, in high-risk MP-CMML, showed similar overall survival at 23.1 versus 18.4 months, respectively, despite response rates being higher for decitabine (56% vs. 31%).
    UNIQUE DISEASE ASSOCIATIONS: These include systemic inflammatory autoimmune diseases, leukemia cutis and lysozyme-induced nephropathy; the latter requires close monitoring of renal function during leukocytosis and is a potential indication for cytoreductive therapy.
    DOI:  https://doi.org/10.1002/ajh.27271
  21. Blood. 2024 Mar 08. pii: blood.2023023593. [Epub ahead of print]
    IDH Mutant Myeloid Neoplasms are Associated with Seronegative Rheumatoid Arthritis and Innate Immune Activation.
    Lih En Hong, Mihir D Wechalekar, Monika M Kutyna, Annabelle Small, Kelly Lim, Chloe Al Thompson-Peach, Joule J Li, Rakchha Chhetri, Hamish S Scott, Anna L Brown, Christopher N Hahn, David T Yeung, Salvia Sajid, Nirmal Robinson, Ranjeny Thomas, Susan Branford, Richard J J D'Andrea, Saumya E E Samaraweera, Mrinal M Patnaik, Susanna Proudman, Daniel Thomas, Chung Hoow Kok, Mithun Vinod Shah, Devendra K Hiwase.
      High prevalence of IDH-mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity and pro-inflammatory microenvironment, suggests causative association between IDH-mutations and seronegative RA. Our findings merit investigation of IDH-inhibitors as therapeutics for seronegative IDH-mutated RA.
    DOI:  https://doi.org/10.1182/blood.2023023593
  22. Front Oncol. 2024 ;14 1308709
    The dark side of stemness - the role of hematopoietic stem cells in development of blood malignancies.
    Jadwiga Filipek-Gorzała, Patrycja Kwiecińska, Agata Szade, Krzysztof Szade.
      Hematopoietic stem cells (HSCs) produce all blood cells throughout the life of the organism. However, the high self-renewal and longevity of HSCs predispose them to accumulate mutations. The acquired mutations drive preleukemic clonal hematopoiesis, which is frequent among elderly people. The preleukemic state, although often asymptomatic, increases the risk of blood cancers. Nevertheless, the direct role of preleukemic HSCs is well-evidenced in adult myeloid leukemia (AML), while their contribution to other hematopoietic malignancies remains less understood. Here, we review the evidence supporting the role of preleukemic HSCs in different types of blood cancers, as well as present the alternative models of malignant evolution. Finally, we discuss the clinical importance of preleukemic HSCs in choosing the therapeutic strategies and provide the perspective on further studies on biology of preleukemic HSCs.
    Keywords:  acute lymphoblastic leukemia; acute myeloid leukemia; chronic lymphocytic leukemia; chronic myeloid leukemia; clonal hematopoiesis; hematopoietic stem cell; mature cell neoplasm; preleukemic state
    DOI:  https://doi.org/10.3389/fonc.2024.1308709
  23. Blood Cancer J. 2024 Mar 07. 14(1): 42
    Regulation of HOX gene expression in AML.
    Irum Khan, Mohammed A Amin, Elizabeth A Eklund, Andrei L Gartel.
      As key developmental regulators, HOX cluster genes have varied and context-specific roles in normal and malignant hematopoiesis. A complex interaction of transcription factors, epigenetic regulators, long non-coding RNAs and chromatin structural changes orchestrate HOX expression in leukemia cells. In this review we summarize molecular mechanisms underlying HOX regulation in clinical subsets of AML, with a focus on NPM1 mutated (NPM1mut) AML comprising a third of all AML patients. While the leukemia initiating function of the NPM1 mutation is clearly dependent on HOX activity, the favorable treatment responses in these patients with upregulation of HOX cluster genes is a poorly understood paradoxical observation. Recent data confirm FOXM1 as a suppressor of HOX activity and a well-known binding partner of NPM suggesting that FOXM1 inactivation may mediate the effect of cytoplasmic NPM on HOX upregulation. Conversely the residual nuclear fraction of mutant NPM has also been recently shown to have chromatin modifying effects permissive to HOX expression. Recent identification of the menin-MLL interaction as a critical vulnerability of HOX-dependent AML has fueled the development of menin inhibitors that are clinically active in NPM1 and MLL rearranged AML despite inconsistent suppression of the HOX locus. Insights into context-specific regulation of HOX in AML may provide a solid foundation for targeting this common vulnerability across several major AML subtypes.
    DOI:  https://doi.org/10.1038/s41408-024-01004-y
  24. Blood Cancer Discov. 2024 Mar 04. OF1-OF22
    Acquired Multidrug Resistance in AML Is Caused by Low Apoptotic Priming in Relapsed Myeloblasts.
    Elyse A Olesinski, Karanpreet Singh Bhatia, Chuqi Wang, Marissa S Pioso, Xiao Xian Lin, Ahmed M Mamdouh, Shu Xuan Ng, Vedant Sandhu, Shaista Shabbir Jasdanwala, Binyam Yilma, Stephan Bohl, Jeremy A Ryan, Disha Malani, Marlise R Luskin, Olli Kallioniemi, Kimmo Porkka, Sophia Adamia, Wee Joo Chng, Motomi Osato, David M Weinstock, Jacqueline S Garcia, Anthony Letai, Shruti Bhatt.
      In many cancers, mortality is associated with the emergence of relapse with multidrug resistance (MDR). Thus far, the investigation of cancer relapse mechanisms has largely focused on acquired genetic mutations. Using acute myeloid leukemia (AML) patient-derived xenografts (PDX), we systematically elucidated a basis of MDR and identified drug sensitivity in relapsed AML. We derived pharmacologic sensitivity for 22 AML PDX models using dynamic BH3 profiling (DBP), together with genomics and transcriptomics. Using in vivo acquired resistant PDXs, we found that resistance to unrelated, narrowly targeted agents in distinct PDXs was accompanied by broad resistance to drugs with disparate mechanisms. Moreover, baseline mitochondrial apoptotic priming was consistently reduced regardless of the class of drug-inducing selection. By applying DBP, we identified drugs showing effective in vivo activity in resistant models. This study implies evasion of apoptosis drives drug resistance and demonstrates the feasibility of the DBP approach to identify active drugs for patients with relapsed AML.
    SIGNIFICANCE: Acquired resistance to targeted therapy remains challenging in AML. We found that reduction in mitochondrial priming and common transcriptomic signatures was a conserved mechanism of acquired resistance across different drug classes in vivo. Drugs active in vivo can be identified even in the multidrug resistant state by DBP.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-24-0001
  25. Mol Oncol. 2024 Mar 08.
    The MYC-NFATC2 axis maintains the cell cycle and mitochondrial function in acute myeloid leukaemia cells.
    Shaun D Patterson, Matthew E Massett, Xu Huang, Heather G Jørgensen, Alison M Michie.
      Acute myeloid leukaemia (AML) is a clonal haematological malignancy affecting the myeloid lineage, with generally poor patient outcomes owing to the lack of targeted therapies. The histone lysine demethylase 4A (KDM4A) has been established as a novel therapeutic target in AML, due to its selective oncogenic role within leukaemic cells. We identify that the transcription factor nuclear factor of activated T cells 2 (NFATC2) is a novel binding and transcriptional target of KDM4A in the human AML THP-1 cell line. Furthermore, cytogenetically diverse AML cell lines, including THP-1, were dependent on NFATC2 for colony formation in vitro, highlighting a putative novel mechanism of AML oncogenesis. Our study demonstrates that NFATC2 maintenance of cell cycle progression in human AML cells was driven primarily by CCND1. Through RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq), NFATc2 was shown to bind to the promoter region of genes involved in oxidative phosphorylation and subsequently regulate their gene expression in THP-1 cells. Furthermore, our data show that NFATC2 shares transcriptional targets with the transcription factor c-MYC, with MYC knockdown phenocopying NFATC2 knockdown. These data suggest a newly identified co-ordinated role for NFATC2 and MYC in the maintenance of THP-1 cell function, indicative of a potential means of therapeutic targeting in human AML.
    Keywords:  AML; CCND1; NFATC2; metabolic function
    DOI:  https://doi.org/10.1002/1878-0261.13630
  26. Leuk Res. 2024 Feb 20. pii: S0145-2126(24)00022-5. [Epub ahead of print]138 107456
    Clinical outcomes of patients with acute myeloid leukemia and cardiovascular disease.
    Gabriela Sanchez-Petitto, Olga G Goloubeva, Jack Masur, James Childress, Tahreem Iqbal, Max An, Safwan Muhammad, Justin Lawson, Grace Li, Brian Barr, Ashkan Emadi, Jennie Y Law, Seung Tae Lee, Vu H Duong, Maria R Baer, Sandrine Niyongere.
      Incidence of both acute myeloid leukemia (AML) and cardiovascular disease (CVD) increases with age. We evaluated whether pre-existing CVD impacts clinical outcomes in AML. We retrospectively evaluated 291 consecutive adult AML patients treated at our institution, 2014-2020. Pretreatment comorbidities were identified by chart review. Outcomes included complete remission (CR) and CR with incomplete count recovery (CRi) rates, disease-free survival (DFS), overall survival (OS) and incidence of cardiovascular adverse events. CVD was present in 34% of patients at AML diagnosis. CVD patients had worse performance status (p=0.03) and more commonly had secondary AML (p=0.03) and received hypomethylating (HMA) agent-based therapy (72% vs 38%, p< 0.001). CVD (0.45 vs 0.71, p<0.001) and diabetes mellitus (HR= 0.24, 95% CI: 0.08 - 0.8, p= 0.01) were associated with lower probability of achieving CR/CRi. Accounting for age, performance status (PS), complex karyotype, secondary disease and treatment, CVD patients had shorter OS (HR=1.5, 95% CI: 1.1-2.2, p=0.002), with 1- and 3-year OS 44% vs 67% and 25% vs 40%, respectively, but there was no difference in cumulative incidence of relapse between patients with vs without CVD. Thus, CVD is an independent risk factor for lower response rate and shorter survival in AML patients.
    Keywords:  Acute Myeloid Leukemia; Cardiovascular Disease
    DOI:  https://doi.org/10.1016/j.leukres.2024.107456
  27. Exp Hematol Oncol. 2024 Mar 04. 13(1): 27
    The multi-CDK inhibitor dinaciclib reverses bromo- and extra-terminal domain (BET) inhibitor resistance in acute myeloid leukemia via inhibition of Wnt/β-catenin signaling.
    Alexander R Marr, Madeline Halpin, Dominique L Corbin, Yerdanos Asemelash, Steven Sher, Britten K Gordon, Ethan C Whipp, Shaneice Mitchell, Bonnie K Harrington, Shelley Orwick, Samon Benrashid, Virginia M Goettl, Vedat Yildiz, Andrew D Mitchell, Olivia Cahn, Alice S Mims, Karilyn T M Larkin, Meixao Long, James Blachly, Jennifer A Woyach, Rosa Lapalombella, Nicole R Grieselhuber.
      Acute myeloid leukemia (AML) is a highly aggressive hematologic cancer with poor survival across a broad range of molecular subtypes. Development of efficacious and well-tolerable therapies encompassing the range of mutations that can arise in AML remains an unmet need. The bromo- and extra-terminal domain (BET) family of proteins represents an attractive therapeutic target in AML due to their crucial roles in many cellular functions, regardless of any specific mutation. Many BET inhibitors (BETi) are currently in pre-clinical and early clinical development, but acquisition of resistance continues to remain an obstacle for the drug class. Novel methods to circumvent this development of resistance could be instrumental for the future use of BET inhibitors in AML, both as monotherapy and in combination. To date, many investigations into possible drug combinations of BETi with CDK inhibitors have focused on CDK9, which has a known physical and functional interaction with the BET protein BRD4. Therefore, we wished to investigate possible synergy and additive effects between inhibitors of these targets in AML. Here, we describe combination therapy with the multi-CDK inhibitor dinaciclib and the BETi PLX51107 in pre-clinical models of AML. Dinaciclib and PLX51107 demonstrate additive effects in AML cell lines, primary AML samples, and in vivo. Further, we demonstrate novel activity of dinaciclib through inhibition of the canonical/β-catenin dependent Wnt signaling pathway, a known resistance mechanism to BETi in AML. We show dinaciclib inhibits Wnt signaling at multiple levels, including downregulation of β-catenin, the Wnt co-receptor LRP6, as well as many Wnt pathway components and targets. Moreover, dinaciclib sensitivity remains unaffected in a setting of BET resistance, demonstrating similar inhibitory effects on Wnt signaling when compared to BET-sensitive cells. Ultimately, our results demonstrate rationale for combination CDKi and BETi in AML. In addition, our novel finding of Wnt signaling inhibition could have potential implications in other cancers where Wnt signaling is dysregulated and demonstrates one possible approach to circumvent development of BET resistance in AML.
    Keywords:  AML; Combination therapy; Dinaciclib; PLX51107; Resistance; Wnt signaling; β-catenin
    DOI:  https://doi.org/10.1186/s40164-024-00483-w
  28. Leuk Res. 2024 Feb 03. pii: S0145-2126(24)00019-5. [Epub ahead of print]138 107453
    Clinical features and management of germline CEBPA-mutated carriers.
    Lili Pan, Yining Li, Huiying Gao, Xiaolin Lai, Yuanhua Cai, Zhixiang Chen, Xiaofan Li, Shao-Yuan Wang.
      Familial acute myeloid leukemia (AML) pedigrees with germline CCAAT/enhancer-binding protein-α (CEBPA) mutation have been rarely reported due to insufficient knowledge of their clinical features. Here, we report two Chinese families with multiple AML cases carrying germline CEBPA mutations, one of which had 11 cases spanning four consecutive generations. Additionally, we collected clinical data of 57 AML patients from 22 families with germline CEBPA mutations, with 58.3% of them harboring double CEBPA mutations. The first mutation frequently occurred at the N-terminal of CEBP/α (78.6%), resulting in an exclusive expression of p30 of CEBPA (CEBPAp30). The second mutation was mostly found at the C-terminal of CEBP/α (CEBPAothers). Germline CEBPAp30 carriers had higher incidences of AML (80.36% vs. 42.86%) and earlier onset of AML (18 vs. 38.5 years old) compared to germline CEBPAothers carriers. Despite the high rates of relapse, most familial AML cases exhibited favorable overall survival (OS), with germline CEBPAp30 carriers having better survival outcomes (>25 years vs. 11 years for CEBPAothers carriers). Among the 27 healthy germline CEBPA-mutated carriers, we detected a pre-leukemia clone harboring a pathogenic IDH2 variant (R140Q)in one individual. These findings should aid in the genetic counseling and management of AML patients and healthy carriers with germline CEBPA mutations.
    Keywords:  AML; CEBPA; Familial AML
    DOI:  https://doi.org/10.1016/j.leukres.2024.107453
  29. Semin Hematol. 2024 Feb 02. pii: S0037-1963(24)00014-3. [Epub ahead of print]
    Clonal hematopoiesis.
    Jaroslaw P Maciejewski.
      
    DOI:  https://doi.org/10.1053/j.seminhematol.2024.01.014
  30. Haematologica. 2024 Mar 07.
    Prognostic impact of SF3B1 mutation and multilineage dysplasia in myelodysplastic syndromes with ring sideroblasts: a Mayo Clinic study of 170 informative cases.
    Faiqa Farrukh, Maymona Abdelmagid, Abhishek Mangaonkar, Mrinal Patnaik, Aref Al-Kali, Michelle A Elliott, Kebede H Begna, Christopher C Hook, William J Hogan, Animesh Pardanani, Mark R Litzow, Rhett P Ketterling, Naseema Gangat, Daniel A Arber, Attilio Orazi, Rong He, Kaaren Reichard, Ayalew Tefferi.
      The revised 4th edition of the World Health Organization (WHO4R) classification lists myelodysplastic syndromes with ring sideroblasts (MDS-RS) as a separate entity with single lineage (MDS-RS-SLD) or multilineage (MDS-RS-MLD) dysplasia. The more recent International Consensus Classification (ICC) distinguishes between MDS with SF3B1 mutation (MDS-SF3B1) and MDS-RS without SF3B1 mutation; the latter is instead included under the category of MDS not otherwise specified. The current study includes 170 Mayo Clinic patients with WHO4R-defined MDS-RS, including MDS-RS-SLD (N=83) and MDS-RS-MLD (N=87); a subset of 145 patients were also evaluable for the presence of SF3B1 and other mutations, including 126 with (87%) and 19 (13%) without SF3B1 mutation. Median overall survival for all 170 patients was 6.6 years with 5- and 10-year survival rates of 59% and 25%, respectively. A significant difference in overall survival was apparent between MDS-RS-MLD and MDS-RS-SLD (p<0.01) but not between MDS-RS with and without SF3B1 mutation (p=0.36). Multivariable analysis confirmed the independent prognostic contribution of MLD (HR 1.8, 95% CI 1.1-2.8; p=0.01) and also identified age (p<0.01), transfusion need at diagnosis (p<0.01), and abnormal karyotype (p<0.01), as additional risk factors; the impact from SF3B1 or other mutations was not significant. Leukemia-free survival was independently affected by abnormal karyotype (p<0.01), RUNX1 (0.02) and IDH1 (p=0.01) mutations, but not by MLD or SF3B1 mutation. Exclusion of patients not meeting ICC-criteria for MDSSF3B1 did not change the observations on overall survival. MLD-based, as opposed to SF3B1 mutationbased, disease classification for MDS-RS might be prognostically more relevant.
    DOI:  https://doi.org/10.3324/haematol.2023.284719
  31. Haematologica. 2024 Mar 07.
    Incidence and outcome of central nervous system relapse after hematopoietic stem cell transplantation in patients suffering from acute myeloid leukemia and acute lymphoblastic leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
    Sabine Blum, Yves Chalandon, Myriam Labopin, Jürgen Finke, Tobias Gedde-Dahl, Tarek Ben Othman, Jan J Cornelissen, Pavel Jindra, Hélène Labussière-Wallet, Matthew Collin, Stig Lenhoff, Guido Kobbe, Norma C Gutiérrez, Arnon Nagler, Mohamad Mohty.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2023.284858
  32. Leukemia. 2024 Mar 02.
    Asparaginase completion among adults including older patients with acute lymphoblastic leukemia treated with a modified DFCI protocol.
    Maria Agustina Perusini, Claire Andrews, Atenafu G Eshetu, Vikas Gupta, Dawn Maze, Karen W L Yee, Aniket Bankar, Marta B Davidson, Guillaume Richard-Carpentier, Steven M Chan, Aaron D Schimmer, Jad Sibai, Salman Alharbi, Josephine A Lucero, Swe Mar Linn, Mark D Minden, Andre C Schuh, Hassan Sibai.
      
    DOI:  https://doi.org/10.1038/s41375-024-02201-1
  33. Blood. 2024 Mar 07. pii: blood.2023023502. [Epub ahead of print]
    Nilotinib with or without cytarabine for Philadelphia positive acute lymphoblastic leukemia.
    Yves Chalandon, Philippe Rousselot, Sylvie Chevret, Jean-Michel Cayuela, Rathana Kim, Françoise Huguet, Patrice Chevallier, Carlos Graux, Anne Thiebaut-Bertrand, Sylvain P Chantepie, Xavier Thomas, Laure Vincent, Celine Berthon, Yosr Hicheri, Emmanuel Raffoux, Martine Escoffre-Barbe, Isabelle Plantier, Magalie Joris, Pascal Turlure, Florence Pasquier, Amine Belhabri, Gabrielle Roth Guepin, Sabine Blum, Michael Gregor, Marina Lafage-Pochitaloff, Julie Quessada, Veronique Lheritier, Emmanuelle Clappier, Nicolas Boissel, Hervé Dombret.
      We previously demonstrated that a reduced-intensity chemotherapy schedule can safely replace Hyper-CVAD cycle 1 when combined with imatinib in adults with Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). In the present randomized GRAAPH-2014 trial, we used nilotinib and addressed the omission of cytarabine (Ara-C) in consolidation. The primary objective was the major molecular response (MMR) rate measured by BCR::ABL1 quantification after cycle 4 (end of consolidation). All patients were eligible for allogeneic stem cell transplant (SCT), whereas those in MMR could receive autologous SCT, followed by 2-year imatinib maintenance in both cases. After the enrollment of 156 out of 265 planed patients, the data and safety monitoring board decided to hold the randomization due to an excess of relapse in the investigational arm. Among the 155 evaluable patients, 77 received Ara-C during consolidation (arm A) and 78 did not (arm B). Overall, 133 (85%) patients underwent SCT, 93 allogeneic, 40 autologous. The non-inferiority endpoint regarding MMR was reached with 71.1% (arm A) and 77.2% (arm B) of patients reaching MMR. However, the 4-year cumulative incidence of relapse was higher in arm B as compared to arm A (31.3% [95% CI, 21.1-41.9%] versus 13.2% [95% CI, 6.7-21.9%]; p=0.017), which translated in a lower relapse-free survival. With a median follow-up of 3.8 years, 4-year overall survival (OS) was 79.0% (95% CI, 70.6-89.3%) in arm A versus 73.4% (95% CI, 63.9-84.4%) in arm B (p=0.35). Despite a non-inferior rate of MMR, more relapses were observed when ARA-C was omitted without impact on survival. ClinicalTrials.gov ID, NCT02611492.
    DOI:  https://doi.org/10.1182/blood.2023023502
  34. Clin Cancer Res. 2024 Mar 06.
    Plasma Proteomic Signature Predicts Myeloid Neoplasm Risk.
    Duc Tran, J Scott Beeler, Jie Liu, Brian Wiley, Irenaeus C C Chan, Zilan Xin, Michael H Kramer, Armel L Batchi-Bouyou, Xiaoyu Zong, Matthew J Walter, Giulia E M Petrone, Sarantis Chlamydas, Francesca Ferraro, Stephen T Oh, Daniel C Link, Ben Busby, Yin Cao, Kelly L Bolton.
       PURPOSE: Clonal hematopoiesis (CH) is thought to be the origin of myeloid neoplasms (MN). Yet our understanding of the mechanisms driving CH progression to MN and clinical risk prediction of MN remains limited. The human proteome reflects complex interactions between genetic and epigenetic regulation of biological systems. We hypothesized that the plasma proteome might predict MN risk and inform our understanding of the mechanisms promoting MN development.
    EXPERIMENTAL DESIGN: We jointly characterized CH and plasma proteomic profiles of 46,237 individuals in the UK Biobank at baseline study entry. During 500,036 person-years of follow-up, 115 individuals developed MN. Cox proportional hazard regression was used to test for an association between plasma protein levels and MN risk.
    RESULTS: We identified 115 proteins associated with MN risk of which 30% (N=34) were also associated with CH. These were enriched for known regulators of the innate and adaptive immune system. Plasma proteomics improved the prediction of MN risk (AUC=0.85, p=5×10-9) beyond clinical factors and CH (AUC=0.80). In an independent group (N=381,485), we used inherited polygenic risk scores (PRS) for plasma protein levels to validate the relevance of these proteins to MN development. PRS analyses suggest that most MN-associated proteins we identified are not directly causally linked to MN risk, but rather represent downstream markers of pathways regulating the progression of CH to MN.
    CONCLUSIONS: These data highlight the role of immune cell regulation in the progression of CH to MN and the promise of leveraging multi-omic characterization of CH to improve MN risk stratification.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-3468
  35. Blood Adv. 2024 Mar 06. pii: bloodadvances.2023012127. [Epub ahead of print]
    Mutations in myeloid transcription factors and activated signaling genes predict chronic myeloid leukemia outcomes.
    Maria Agustina Perusini, Daniela Zackova, TaeHyung Kim, Katia B B Pagnano, Carolina Pavlovsky, Ivana Jeziskova, Anežka Kvetková, Tomas Jurcek, Jaeyoon John Kim, Young Seok Yoo, Seongyoon Yi, Hyewon Lee, Kyoung Ha Kim, Myunghee Chang, Jose-Mario Capo-Chichi, Jessie Medeiros, Andrea Arruda, Mark D Minden, Zhaolei Zhang, Sagi Abelson, Jiri Mayer, Dennis Dong Hwan Kim.
      Advancements in genomics are transforming the clinical management of chronic myeloid leukemia (CML) towards precision medicine. The impact of somatic mutations on treatment outcomes is still under debate. We studied the association of somatic mutations in epigenetic modifiers genes and activated signaling/myeloid transcription factor (AS/MTF), with disease progression and treatment failure in CML patients following tyrosine kinase inhibitor (TKI) therapy. A total of 394 CML samples were sequenced, including 254 samples collected at initial diagnosis, and 140 samples taken during follow-up. Single-molecule molecular inversion probe (smMIP)-based next-generation sequencing (NGS) was conducted targeting recurrently mutated loci in 40 genes with a limit of detection of 0.2%. A total of 70 mutations were detected in 57 (22.4%) diagnostic samples, while 64 mutations were detected in 39 (27.9%) of the follow-up samples. Carrying any mutation at initial diagnosis was associated with worse outcomes following TKI therapy, particularly in AS/MTF genes. Patients having these mutations at initial diagnosis and treated with Imatinib showed higher risks of treatment failure (HR 2.53, 95% CI [1.13-5.66], p=0.0239). The adverse prognostic impact of the mutations was not clear for patients treated with second-generation TKIs (2G-TKI). The multivariate analysis affirmed that mutations in AS/MTF genes independently serve as adverse prognostic factors for molecular response, failure-free survival (FFS), and progression risk. Additionally, there was an observable non-significant trend indicating a heightened risk of progression to advanced disease and worse overall survival (OS). Conclusion: Mutations in the AS/MTF genes using smMIP-based NGS can help identify patients with a potential risk of both treatment failure and progression, even from initial diagnosis, and may help upfront TKI selection.
    DOI:  https://doi.org/10.1182/bloodadvances.2023012127
  36. Leuk Lymphoma. 2024 Mar 05. 1-4
    Treatment outcomes of venetoclax-combination regimens for relapsed/refractory myeloid malignancies after anti-CD47-directed therapy.
    Rafael Madero-Marroquin, Emily Dworkin, Howard Weiner, Caner Saygin, Mariam T Nawas, Michael W Drazer, Adam S DuVall, Satyajit Kosuri, Michael J Thirman, Olatoyosi Odenike, Wendy Stock, Richard A Larson, Anand A Patel.
      
    Keywords:  AML; MDS; Venetoclax; magrolimab; myeloid
    DOI:  https://doi.org/10.1080/10428194.2024.2324991
  37. Cell Stem Cell. 2024 Mar 07. pii: S1934-5909(24)00047-X. [Epub ahead of print]31(3): 359-377.e10
    A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
    Massimo Bonora, Claudia Morganti, Nick van Gastel, Kyoko Ito, Enrica Calura, Ilaria Zanolla, Letizia Ferroni, Yang Zhang, Yookyung Jung, Gabriele Sales, Paolo Martini, Takahisa Nakamura, Francesco Massimo Lasorsa, Toren Finkel, Charles P Lin, Barbara Zavan, Paolo Pinton, Irene Georgakoudi, Chiara Romualdi, David T Scadden, Keisuke Ito.
      Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self-renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO-generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC self-renewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non-stochastic nature of HSC fate determination.
    Keywords:  HSC self-renewal; NADPH; cholesterol; exosomes; extracellular vesicles; fate determination; fatty acid oxidation; hematopoietic stem cell; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.stem.2024.02.004
  38. Haematologica. 2024 Mar 07.
    Cell-free DNA from nail clippings as source of normal control for genomic studies in hematologic malignancies.
    Melissa Krystel-Whittemore, Kseniya Petrova-Drus, Ryan N Ptashkin, Mark D Ewalt, JinJuan Yao, Ying Liu, Menglei Zhu, Jamal Benhamida, Benjamin Durham, Jyoti Kumar, Khedoudja Nafa, Iwona Kiecka, Anita S Bowman, Erika Gedvilaite, Jacklyn Casanova, Yun-Te Lin, Abhinita S Mohanty, Satshil Rana, Anoop Balakrishnan Rema, Ivelise Rijo, Nelio Chaves, Paulo Salazar, Anita Yun, Sean Lachhander, Wei Wang, Mohammad S Haque, Wenbin Xiao, Mikhail Roshal, Sergio Giralt, Gilles Salles, Raajit Rampal, Eytan M Stein, Miguel-Angel Perales, Steven Horwitz, Ann Jakubowski, Doris Ponce, Alina Markova, Ozge Birsoy, Diana Mandelker, Simon Mantha, Ahmet Dogan, Ryma Benayed, Marc Ladanyi, Michael F Berger, A Rose Brannon, Ahmet Zehir, Chad Vanderbilt, Maria E Arcila.
      Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patient management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs. In contrast to solid tumors, conventional sources of normal control (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we find nail cfDNA is a robust source of germline control for paired genomic studies. In a subset of patients, nail DNA may have tumor DNA contamination, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1482) compared to lymphoid diseases (5.4%; 61/1128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. For nails collected after allogeneic stem-cell transplantation, donor DNA was identified in 22% (11/50). In this cohort, an association with recent history of graft-vs-host disease was identified. These findings should be considered as a potential limitation for the use of nail as normal control but could also provide important diagnostic information regarding the disease process.
    DOI:  https://doi.org/10.3324/haematol.2024.285054
  39. Nat Med. 2024 Mar 07.
    Clonal hematopoiesis of indeterminate potential is associated with acute kidney injury.
    Caitlyn Vlasschaert, Cassianne Robinson-Cohen, Jianchun Chen, Elvis Akwo, Alyssa C Parker, Samuel A Silver, Pavan K Bhatraju, Hannah Poisner, Shirong Cao, Ming Jiang, Yinqiu Wang, Aolei Niu, Edward Siew, Joseph C Van Amburg, Holly J Kramer, Anna Kottgen, Nora Franceschini, Bruce M Psaty, Russell P Tracy, Alvaro Alonso, Dan E Arking, Josef Coresh, Christie M Ballantyne, Eric Boerwinkle, Morgan Grams, Ming-Zhi Zhang, Bryan Kestenbaum, Matthew B Lanktree, Michael J Rauh, Raymond C Harris, Alexander G Bick.
      Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown. Clonal hematopoiesis of indeterminate potential (CHIP) confers increased risk for several chronic diseases associated with aging. Here we sought to test whether CHIP increases the risk of AKI. In three population-based epidemiology cohorts, we found that CHIP was associated with a greater risk of incident AKI, which was more pronounced in patients with AKI requiring dialysis and in individuals with somatic mutations in genes other than DNMT3A, including mutations in TET2 and JAK2. Mendelian randomization analyses supported a causal role for CHIP in promoting AKI. Non-DNMT3A-CHIP was also associated with a nonresolving pattern of injury in patients with AKI. To gain mechanistic insight, we evaluated the role of Tet2-CHIP and Jak2V617F-CHIP in two mouse models of AKI. In both models, CHIP was associated with more severe AKI, greater renal proinflammatory macrophage infiltration and greater post-AKI kidney fibrosis. In summary, this work establishes CHIP as a genetic mechanism conferring impaired kidney function recovery after AKI via an aberrant inflammatory response mediated by renal macrophages.
    DOI:  https://doi.org/10.1038/s41591-024-02854-6
  40. Blood. 2024 Mar 06. pii: blood.2023021046. [Epub ahead of print]
    Differential Effects of JAK1 vs. JAK2 Inhibition in Mouse Models of Hemophagocytic Lymphohistiocytosis.
    Camille Keenan, Sabrin Albeituni, Ninad Oak, Alexa N Stroh, Heather Tillman, Yingzhe Wang, Burgess B Freeman, Silvia Alemán-Arteaga, Lauren K Meyer, Rolanda Woods, Katherine C Verbist, Yinmei Zhou, Cheng Cheng, Kim E Nichols.
      Hemophagocytic lymphohistiocytosis (HLH) comprises a severe hyperinflammatory phenotype driven by the overproduction of cytokines, many of which signal via the JAK/STAT pathway. Indeed, the JAK1/2 inhibitor ruxolitinib has demonstrated efficacy in pre-clinical studies and early-phase clinical trials in HLH. Nevertheless, concerns remain for ruxolitinib-induced cytopenias, which are postulated to result from the blockade of JAK2-dependent hematopoietic growth factors. To explore the therapeutic effects of selective JAK inhibition in mouse models of HLH, we carried out studies incorporating the JAK1 inhibitor itacitinib, the JAK2 inhibitor fedratinib and the JAK1/2 inhibitor ruxolitinib. All three drugs were well-tolerated and at the doses tested, they suppressed interferon-gamma (IFNg)-induced STAT1 phosphorylation in vitro and in vivo. Itacitinib, but not fedratinib, significantly improved survival and clinical scores in CpG-induced secondary HLH. Conversely, in primary HLH, where perforin-deficient (Prf1-/-) mice are infected with lymphocytic choriomeningitis virus (LCMV), itacitinib and fedratinib performed suboptimally. Ruxolitinib demonstrated excellent clinical efficacy in both HLH models. RNA-sequencing of splenocytes from LCMV-infected Prf1-/- mice revealed that itacitinib targeted inflammatory and metabolic pathway genes in CD8 T cells, while fedratinib targeted genes regulating cell proliferation and metabolism. In monocytes, neither drug conferred major transcriptional impacts. Consistent with its superior clinical effects, ruxolitinib exerted the greatest transcriptional changes in CD8 T cells and monocytes, targeting more genes across several biologic pathways, most notably JAK-dependent pro-inflammatory signaling. We conclude that JAK1 inhibition is sufficient to curtail CpG-induced disease, but combined inhibition of JAK1 and JAK2 is needed to best control LCMV-induced immunopathology.
    DOI:  https://doi.org/10.1182/blood.2023021046
  41. Bone Marrow Transplant. 2024 Mar 05.
    Harmonizing definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism in allogeneic hematopoietic cell transplantation: a report on behalf of the EBMT, ASTCT, CIBMTR, and APBMT.
    Anna Sureda, Paul A Carpenter, Andrea Bacigalupo, Vijaya Raj Bhatt, Josu de la Fuente, Aloysius Ho, Leslie Kean, Jong Wook Lee, Isabel Sánchez-Ortega, Bipin N Savani, Johannes Schetelig, Edward A Stadtmauer, Yoshiyuki Takahashi, Yoshiko Atsuta, John Koreth, Nicolaus Kröger, Per Ljungman, Shinichiro Okamoto, Uday Popat, Robert Soiffer, Heather E Stefanski, Mohamed A Kharfan-Dabaja.
      Despite emergence of novel therapies to treat hematologic malignancies, allogeneic hematopoietic cell transplantation (allo-HCT) remains an essential treatment modality capable of curing these diseases. Allo-HCT has been also shown to be curative in benign hematologic disorders such as aplastic anemia, sickle cell disease, and thalassemia, among others. Recently, the American Society for Transplantation and Cellular Therapy (ASTCT) published standardized definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism. To attempt broader international consensus, a panel of adult and pediatric physician transplant experts was assembled from European Society for Blood and Marrow Transplantation (EBMT), ASTCT, the Center for International Blood and Marrow Transplant Research (CIBMTR), and Asia-Pacific Blood and Marrow Transplantation (APBMT). Consensus was defined as ≥70% of voting members strongly agreeing or somewhat agreeing with a definition. With few exceptions, there was a consensus to endorse the prior ASTCT definitions. Importantly, we revised existing EBMT and CIBMTR data collection forms to align with these harmonized definitions that will facilitate research and international collaboration among transplant researchers and across transplant registries.
    DOI:  https://doi.org/10.1038/s41409-024-02251-0
  42. Am J Hematol. 2024 Mar 04.
    Treatment-free remission in CML patients with additional chromosome abnormalities in the Philadelphia-positive clone or variant Philadelphia translocations.
    Simone Claudiani, Lynette Chee, Fiona Fernando, Loretta Brown, Udayakumar M Achandira, Afzal Khan, Kate Rothwell, Chloe Hayden, Ioannis Koutsavlis, Guy Hannah, Andrew Innes, Jane F Apperley, Dragana Milojkovic.
      Probability of treatment-free remission (TFR) in CML patients with additional chromosomal abnormalities (ACA) in the Philadelphia-positive clone or variant Philadelphia translocations (ACA/Var-Ph group, blue panel), in those with no cytogenetic abnormality other than the classical Philadelphia translocation (c-Ph group, green panel) and in the subgroups of CML patients with high-risk ACA (HR-ACA, yellow panel) and Var-Ph (red panel).
    DOI:  https://doi.org/10.1002/ajh.27278
  43. Br J Haematol. 2024 Mar 05.
    Increased donor inhibitory KIR are associated with reduced GVHD and improved survival following HLA-matched unrelated donor HCT in paediatric acute leukaemia.
    Elizabeth Krieger, Rehan Qayyum, Amir Toor.
      Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated effects after haematopoietic stem cell transplantation (HCT). Previous work has shown that accounting for known KIR-KIRL interactions may identify donors with optimal NK cell-mediated alloreactivity in the adult transplant setting. Paediatric acute leukaemia patients were retrospectively analysed, and KIR-KIRL combinations and maximal inhibitory KIR ligand (IM-KIR) scores were determined. Clinical outcomes were examined using a series of graphs depicting clinical events and endpoints. The graph methodology demonstrated that prognostic variables significant in the occurrence of specific clinical endpoints remained significant for relevant downstream events. KIR-KIRL combinations were significantly predictive for reduced grade 3-4 aGVHD likelihood, in patients transplanted with increased inhibitory KIR gene content and IM-KIR = 5 scores. Improvements were also observed in associated outcomes for both ALL and AML patients, including relapse-free survival, GRFS and overall survival. This study demonstrates that NK cell KIR HLA interactions may be relevant to the paediatric acute leukaemia transplant setting. Reduction in aGVHD suggests KIR effects may extend beyond NK cells. Moving forward clinical trials utilizing donors with a higher iKIR should be considered for URD HCT in paediatric recipients with acute leukaemia to optimize clinical outcomes.
    Keywords:  acute lymphoid leukaemia (ALL); acute myeloid leukaemia (AML); graft versus host disease (GVHD); graphs; killer immunoglobin-like receptors (KIR)
    DOI:  https://doi.org/10.1111/bjh.19356
  44. Blood. 2024 Mar 06. pii: blood.2023023549. [Epub ahead of print]
    Alloengraftment without significant toxicity or GVHD in CD45 antibody-drug conjugate conditioned Fanconi anemia mice.
    Asim Saha, Rahul Palchaudhuri, Leanne Lanieri, Sharon Hyzy, Megan J Riddle, Jamie Panthera, Cindy Eide, Jakub Tolar, Angela Panoskaltsis-Mortari, Lev Gorfinkel, Victor Tkachev, Ulrike Gerdemann, Francesca Alvarez-Calderon, Elisa Rojas Palato, Margaret L MacMillan, John E Wagner, Leslie S Kean, Mark Osborn, Hans-Peter Kiem, David T Scadden, Lisa M Olson, Bruce R Blazar.
      Fanconi anemia (FA) is an inherited DNA repair disorder characterized by bone marrow (BM) failure, developmental abnormalities, myelodysplasia, and leukemia and solid tumor predisposition. Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a mainstay treatment, is limited by conditioning regimen-related toxicity and graft-versus-host disease (GVHD). Antibody-drug-conjugates (ADCs) targeting hematopoietic stem cells (HSCs) can open marrow niches permitting donor stem cell alloengraftment. Here, we report that single dose anti-mouse CD45-targeted-ADC (CD45-ADC) facilitated stable, multilineage chimerism in 3 distinct FA mouse models representing 90% of FA complementation groups. CD45-ADC profoundly depleted host stem cell enriched LineageSca1+cKit+ cells within 48 hours. Fanca-/- recipients of minor-mismatched BM and single dose CD45-ADC had peripheral blood (PB) mean donor chimerism >90%; donor HSCs alloengraftment was verified in secondary recipients. In Fancc-/- and Fancg-/- recipients of fully allogeneic grafts, PB mean donor chimerism was 60-80% and 70-80%, respectively. The mean percent donor chimerism in BM and spleen mirrored PB results. CD45-ADC conditioned mice did not have clinical toxicity. A transient <2.5-fold increase in hepatocellular enzymes and mild-to-moderate histopathological changes were seen. Under GVHD allo-HSCT conditions, wildtype and Fanca-/- recipients of CD45-ADC had markedly reduced GVHD lethality compared to lethal irradiation. Moreover, single dose anti-human CD45-ADC given to rhesus macaque nonhuman primates on days -6 or -10 was at least as myeloablative as lethal irradiation. These data suggest that CD45-ADC can potently promote donor alloengraftment and hematopoiesis without significant toxicity or severe GVHD, as seen with lethal irradiation, providing strong support for clinical trial considerations in highly vulnerable FA patients.
    DOI:  https://doi.org/10.1182/blood.2023023549
  45. Blood. 2024 Mar 06. pii: blood.2023022666. [Epub ahead of print]
    Circulating Hematopoietic Stem/Progenitor Cells subsets contribute to human hematopoietic homeostasis.
    Pamela Quaranta, Luca Basso-Ricci, Raisa Jofra Jofra Hernández, Guido Pacini, Matteo Maria Naldini, Matteo Barcella, Luca Seffin, Giulia Pais, Giulio Spinozzi, Fabrizio Benedicenti, Carlo Pietrasanta, Jin-Gyu Cheong, Andrea Ronchi, Lorenza Pugni, Francesca Dionisio, Ilaria Monti, Stefania Giannelli, Silvia Darin, Federico Fraschetta, Graziano Barera, Francesca Ferrua, Valeria Calbi, Marco Ometti, Raffaella Di Micco, Fabio Mosca, Steven Zvi Josefowicz, Eugenio Montini, Andrea Calabria, Maria Ester Bernardo, Maria Pia Cicalese, Bernhard Gentner, Ivan Merelli, Alessandro Aiuti, Serena Scala.
      In physiological conditions, few circulating hematopoietic stem/progenitor cells (cHSPC) are present in the peripheral blood but their contribution to hematopoietic homeostasis in humans remain unsolved. By integrating advanced immunophenotyping, cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), functional single-cell assays and integration site (IS) clonal tracking, we unveiled the phenotypic composition, the transcriptional features and the biological role of human cHSPC subpopulations in relationship to their bone marrow (BM) counterpart. We found that cHSPC progressively reduced in cell count over aging and are enriched for primitive, lymphoid and erythroid subpopulations, showing pre-activated transcriptional and functional state. Moreover, cHSPC have low expression of multiple BM-retention molecules, but maintain their homing potential after xenotransplantation. By generating a comprehensive Human Organ-Resident HSPC (HuOR) dataset based on scRNAseq data, we detected organ-specific seeding properties of the distinct trafficking HSPC subpopulations. Of note, circulating multi-lymphoid progenitors (MLP) are primed for seeding the thymus and actively contribute to T-cell production at steady state in patients treated with HSPC-gene therapy (GT). Human clonal tracking data from GT patients also showed that cHSPC connect distant BM niches and participate to steady-state hematopoietic production, with primitive cHSPC having the highest re-circulation capability to travel in and out the BM. Finally, in case of hematopoietic impairment, cHSPC composition reflects the BM-HSPC content and might represent a biomarker of the BM state for clinical and research purposes. Overall, our comprehensive work unveiled fundamental insights into the in vivo dynamics of human HSPC trafficking and its role in sustaining hematopoietic homeostasis.
    DOI:  https://doi.org/10.1182/blood.2023022666
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