bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023‒12‒24
fifty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Prognostic risk signature in patients with acute myeloid leukemia treated with hypomethylating agents and venetoclax.
  2. Preleukemic single-cell landscapes reveal mutation-specific mechanisms and gene programs predictive of AML patient outcomes.
  3. Distinct roles of hematopoietic cytokines in the regulation of leukemia stem cells in murine MLL-AF9 leukemia.
  4. Multi-gene measurable residual disease assessed by digital polymerase chain reaction has clinical and biological utility in acute myeloid leukemia patients receiving venetoclax/azacitidine.
  5. Preclinical characterization and clinical trial of CFI-400945, a polo-like kinase 4 inhibitor, in patients with relapsed/refractory acute myeloid leukemia and higher-risk myelodysplastic neoplasms.
  6. Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth.
  7. DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML.
  8. Quantifying measurable residual disease correctly.
  9. Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.
  10. The ncBAF complex regulates transcription in AML through H3K27ac sensing by BRD9.
  11. FLT3 targeting in the modern era: from clonal selection to combination therapies.
  12. AML alters bone marrow stromal cell osteogenic commitment via Notch signaling.
  13. Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study.
  14. Age-related micro-environmental changes as drivers of clonal hematopoiesis.
  15. The SNP rs460089 in the gene promoter of the drug transporter OCTN1 has prognostic value for treatment-free remission in chronic myeloid leukemia patients treated with imatinib.
  16. Hyperactive Natural Killer cells in Rag2 knockout mice inhibit the development of acute myeloid leukemia.
  17. Interleukin-15 and -21-activated, donor-derived NK cell infusion after haploidentical HCT in high-risk AML and MDS-a cohort analysis.
  18. Real-World Effectiveness of Dasatinib Versus Imatinib in Newly Diagnosed Patients With Chronic Myeloid Leukemia.
  19. Lymphopenia confers poorer prognosis in Myelodysplastic Syndromes with very low and low IPSS-M.
  20. Toward an improved understanding of hypomethylating agent and venetoclax therapies.
  21. A traffic light for TFR by lineage-specific MRD.
  22. Predicting cytopenias, progression, and survival in patients with clonal cytopenia of undetermined significance: a prospective cohort study.
  23. BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state.
  24. USP47 stabilizes YBX1 to promote the progression of acute myeloid leukemia.
  25. Diagnostic capabilities, clinical features, and longitudinal UBA1 clonal dynamics of a nationwide VEXAS cohort.
  26. Single-cell time series analysis reveals the dynamics of HSPC response to inflammation.
  27. Targeting S100A9 protein affects mTOR-ER stress signaling and increases venetoclax sensitivity in Acute Myeloid Leukemia.
  28. NIH natural history study of FPDMM patients.
  29. The Clinical Utility of FLT3 Mutation Testing in Acute Leukemia: A Canadian Consensus.
  30. Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms.
  31. Chronic Myelomonocytic Leukemia Patients With Lysozyme Nephropathy and Renal Infiltration Display Markers of Severe Disease.
  32. Allogeneic hematopoietic cell transplantation for patients with acute myeloid leukemia not in remission.
  33. Galectin-3 predicts acute GvHD and overall mortality post reduced intensity allo-HCT: a BMT-CTN biorepository study.
  34. Backtracking to the future: unraveling the origins of childhood leukemia.
  35. Myeloid neoplasm occurrence during stable molecular remission of NPM1-mutated AML: are we facing secondary disease or AML relapse?
  36. Seeding the future: the natural history of RUNX1 deficiency.
  37. Sociodemographic associations with uptake of novel therapies for acute myeloid leukemia.
  38. Inhibition of RIP1 improves immune reconstitution and reduces GVHD mortality while preserving graft-versus-leukemia effects.
  39. A newly identified 45-kDa JAK2 variant with an altered kinase domain structure represents a novel mode of JAK2 kinase inhibitor resistance.
  40. Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A.
  41. NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy.
  42. Chemical genetic control of cytokine signaling in CAR-T cells using lenalidomide-controlled membrane-bound degradable IL-7.
  43. STAT5a and SH2B3 novel mutations display malignancy roles in a triple-negative primary myelofibrosis patient.
  44. An Overview on Lipid Droplets Accumulation as Novel Target for Acute Myeloid Leukemia Therapy.
  45. Home time among older adults with acute myeloid leukemia by therapy intensity.
  46. Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells.
  47. CHIP-JAK2V617F, Chronic Inflammation, Abnormal Megakaryocyte Morphology, Organ Failure, and Multimorbidties.
  48. Vacuoles in circulating immature myeloid cells in VEXAS syndrome and comparison with UBA1-wild type patients.
  49. Intensive Care Risk and Long-Term Outcomes in Pediatric Allogeneic Hematopoietic Cell Transplant Recipients.
  50. Cord blood transplantation for adult lymphoid neoplasms in Europe and Japan.
  51. Clinical, Histopathological and Molecular Spectrum of Cutaneous Lesions in Myelodysplastic Syndrome and Myeloproliferative Neoplasms (MDS/MPN): An Integrative Review.
  52. The impact of thrombosis on probabilities of death and disease progression in polycythemia vera: a multistate transition analysis of 1,545 patients.
  1. Blood Adv. 2023 Dec 19. pii: bloodadvances.2023011757. [Epub ahead of print]
    Prognostic risk signature in patients with acute myeloid leukemia treated with hypomethylating agents and venetoclax.
    Alex Bataller, Alexandre Bazinet, Courtney D DiNardo, Abhishek Maiti, Gautam Borthakur, Naval G Daver, Nicholas J Short, Elias J Jabbour, Ghayas C Issa, Naveen Pemmaraju, Musa Yilmaz, Guillermo Montalban-Bravo, Koichi Takahashi, Sanam Loghavi, Guillermo Garcia-Manero, Farhad Ravandi, Hagop M Kantarjian, Tapan M Kadia.
      Hypomethylating agents (HMAs) and venetoclax (Ven) represent the standard of care for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. However, the European LeukemiaNet (ELN) risk classifications have been validated in patients treated with intensive therapy. In this study we validate a recently proposed new molecular prognostic risk signature (mPRS) for patients with AML treated with HMAs and Ven. This classification allocated patients to favorable, intermediate (N/KRAS or FLT3-internal tandem duplication mutations) and lower (TP53 mutations) benefit groups. We retrospectively analyzed 159 patients treated with HMA and Ven. The mPRS classification allocated 74 (47%), 31 (19%), and 54 (34%) patients to the higher, intermediate, and lower benefit groups, respectively. The overall response rate was 71% (86%, 54%, and 59% in the higher, intermediate, and lower benefit groups, respectively). The median OS and EFS times were 30 and 19 months, respectively, in the higher benefit group; 12 and 8 months, respectively, in the intermediate benefit group; and 5 and 4 months, respectively, in the lower benefit group (p < .001). The C-index for OS and EFS was higher when stratifying patients according to mPRS classification, compared with the ELN 2022 classification. The 2-year cumulative incidence of relapse was 35%, 70%, and 60% in the higher, intermediate, and lower benefit groups, respectively (p = .005). The mPRS classification accurately segregated groups of AML patients treated with HMA plus Ven. In these patients, N/KRAS and TP53 mutations appear to negatively impact outcomes and therefore new treatment approaches are warranted.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011757
  2. Cell Genom. 2023 Dec 13. 3(12): 100426
    Preleukemic single-cell landscapes reveal mutation-specific mechanisms and gene programs predictive of AML patient outcomes.
    Tomoya Isobe, Iwo Kucinski, Melania Barile, Xiaonan Wang, Rebecca Hannah, Hugo P Bastos, Shirom Chabra, M S Vijayabaskar, Katherine H M Sturgess, Matthew J Williams, George Giotopoulos, Ludovica Marando, Juan Li, Justyna Rak, Malgorzata Gozdecka, Daniel Prins, Mairi S Shepherd, Sam Watcham, Anthony R Green, David G Kent, George S Vassiliou, Brian J P Huntly, Nicola K Wilson, Berthold Göttgens.
      Acute myeloid leukemia (AML) and myeloid neoplasms develop through acquisition of somatic mutations that confer mutation-specific fitness advantages to hematopoietic stem and progenitor cells. However, our understanding of mutational effects remains limited to the resolution attainable within immunophenotypically and clinically accessible bulk cell populations. To decipher heterogeneous cellular fitness to preleukemic mutational perturbations, we performed single-cell RNA sequencing of eight different mouse models with driver mutations of myeloid malignancies, generating 269,048 single-cell profiles. Our analysis infers mutation-driven perturbations in cell abundance, cellular lineage fate, cellular metabolism, and gene expression at the continuous resolution, pinpointing cell populations with transcriptional alterations associated with differentiation bias. We further develop an 11-gene scoring system (Stem11) on the basis of preleukemic transcriptional signatures that predicts AML patient outcomes. Our results demonstrate that a single-cell-resolution deep characterization of preleukemic biology has the potential to enhance our understanding of AML heterogeneity and inform more effective risk stratification strategies.
    Keywords:  acute myeloid leukemia; hematopoiesis; myeloid malignancies; preleukemia; single-cell RNA-seq
    DOI:  https://doi.org/10.1016/j.xgen.2023.100426
  3. Stem Cell Reports. 2023 Dec 06. pii: S2213-6711(23)00452-6. [Epub ahead of print]
    Distinct roles of hematopoietic cytokines in the regulation of leukemia stem cells in murine MLL-AF9 leukemia.
    Yanchun Li, Christopher S Seet, Ryan Mack, Kanak Joshi, Austin P Runde, Patrick A Hagen, Kevin Barton, Peter Breslin, Ameet Kini, Hong-Long Ji, Jiwang Zhang.
      Lymphoid-primed multipotent progenitor (LMPP)-like and granulocyte-monocyte progenitor (GMP)-like leukemia stem cells (LSCs) co-exist in the blood of most patients with acute myeloid leukemia (AML). Complete elimination of both types of LSCs is required to cure AML. Using an MLL-AF9-induced murine AML model, we studied the role of hematopoietic cytokines in the survival of LMPP- and GMP-like LSCs. We found that SCF or FLT3L promotes the survival of LMPP-like LSCs by stimulating Stat5-mediated Mcl1 expression, whereas interleukin-3 (IL-3) or IL-6 induces the survival of GMP-like LSCs by stimulating Stat3/nuclear factor κB (NF-κB)-mediated Bcl2 expression. Functional study demonstrated that, compared to AML cells cultured in IL-3 and IL-6 medium, AML cells in SCF- or Flt3L-only culture are highly clonogenic in in vitro culture and are highly leukemogenic in vivo. Our study suggests that co-inhibition of both STAT5-MCL1 and STAT3/NF-κB-BCL2 signaling might represent an improved treatment strategy against AML, specifically AML cases with a monocytic phenotype and/or FLT3 mutations.
    Keywords:  AML; Bcl2; Mcl1; hematopoietic cytokines; leukemia stem cells; survival signaling
    DOI:  https://doi.org/10.1016/j.stemcr.2023.11.003
  4. Haematologica. 2023 Dec 14.
    Multi-gene measurable residual disease assessed by digital polymerase chain reaction has clinical and biological utility in acute myeloid leukemia patients receiving venetoclax/azacitidine.
    Amanda C Winters, Mohd Minhajuddin, Brett M Stevens, Ajay Major, Grace Bosma, Diana Abbott, Nicholas Miltgen, Ji Yuan, Amy L Treece, Bradford J Siegele, Mark D Ewalt, Jonathan A Gutman, Craig T Jordan, Daniel A Pollyea.
      Venetoclax with azacitidine (ven/aza) is a lower-intensity therapeutic regimen that has been shown to improve outcomes in elderly patients with acute myeloid leukemia (AML). Measurable residual disease (MRD) using flow cytometry is a valuable tool for the prediction of relapse in AML using conventional therapies and ven/aza; however, the prognostic value for broad-scale molecular MRD after ven/aza treatment is less clear. We aimed to determine the utility of retrospective assessment using multi-gene molecular MRD by droplet digital PCR (ddPCR). We found this approach correlates with outcomes in a cohort of patients receiving frontline ven/aza for AML. The predictive value of ddPCR MRD persisted when NPM1 mutations were removed from analysis, as well as after adjustment for the impact of stem cell transplant (SCT) on outcomes. Late achievement of MRD negativity, including after SCT, was still associated with superior outcomes compared to persistently detectable MRD. We further explored the impact of ven/aza on the burden of different classes of mutations, and identified the persistence of splicing factor mutations, commonly associated with MDS, as a consistent finding after ven/aza treatment. These data add to our understanding of the effects of ven/aza on AML disease biology and provide details on molecular depth of remission that can guide prospective trials in the future.
    DOI:  https://doi.org/10.3324/haematol.2023.283790
  5. Leukemia. 2023 Dec 19.
    Preclinical characterization and clinical trial of CFI-400945, a polo-like kinase 4 inhibitor, in patients with relapsed/refractory acute myeloid leukemia and higher-risk myelodysplastic neoplasms.
    Tracy Murphy, Jacqueline M Mason, Brian Leber, Mark R Bray, Steven M Chan, Vikas Gupta, Dina Khalaf, Dawn Maze, Caroline J McNamara, Aaron D Schimmer, Andre C Schuh, Hassan Sibai, Michael Trus, Debbie Valiquette, Kylie Martin, Linh Nguyen, Xuan Li, Tak W Mak, Mark D Minden, Karen W L Yee.
      CFI-400945 is a selective oral polo-like kinase 4 (PLK4) inhibitor that regulates centriole duplication. PLK4 is aberrantly expressed in patients with acute myeloid leukemia (AML). Preclinical studies indicate that CFI-400945 has potent in vivo efficacy in hematological malignancies and xenograft models, with activity in cells harboring TP53 mutations. In this phase 1 study in very high-risk patients with relapsed/refractory AML and myelodysplastic syndrome (MDS) (NCT03187288), 13 patients were treated with CFI-400945 continuously in dose escalation from 64 mg/day to 128 mg/day. Three of the 9 efficacy evaluable AML patients achieved complete remission (CR). Two of 4 AML patients (50%) with TP53 mutations and complex monosomal karyotype achieved a CR with 1 patient proceeding to allogenic stem cell transplant. A third patient with TP53 mutated AML had a significant reduction in marrow blasts by > 50% with an improvement in neutrophil and platelet counts. Responses were observed after 1 cycle of therapy. Dose-limiting toxicity was enteritis/colitis. A monotherapy and combination therapy study with a newer crystal form of CFI-400945 in patients with AML, MDS and chronic myelomonocytic leukemia (CMML) is ongoing (NCT04730258).
    DOI:  https://doi.org/10.1038/s41375-023-02110-9
  6. Cell Rep. 2023 Dec 15. pii: S2211-1247(23)01580-2. [Epub ahead of print]42(12): 113568
    Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth.
    Daniel J L Coleman, Peter Keane, Rosario Luque-Martin, Paulynn S Chin, Helen Blair, Luke Ames, Sophie G Kellaway, James Griffin, Elizabeth Holmes, Sandeep Potluri, Salam A Assi, John Bushweller, Olaf Heidenreich, Peter N Cockerill, Constanze Bonifer.
      Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.
    Keywords:  CP: Cancer; FLT3-ITD acute myeloid leukemia; RUNX1 dependency; gene regulatory networks; shRNA drop-out screen; transcription factor regulatory modules
    DOI:  https://doi.org/10.1016/j.celrep.2023.113568
  7. Leukemia. 2023 Dec 15.
    DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML.
    Jean-François Spinella, Jalila Chagraoui, Céline Moison, Vincent P Lavallée, Isabel Boivin, Deanne Gracias, Sylvie Lavallée, Guillaume Richard Carpentier, François Beliveau, Josée Hébert, Guy Sauvageau.
      Monosomy 5 and deletions of the chromosome 5q (-5/del(5q)) are recurrent events in de novo adult acute myeloid leukemia (AML), reaching up to 40% of cases in secondary AML. These chromosome anomalies are associated with TP53 mutations and with very poor prognosis. Using the large Leucegene genomic and transcriptomic dataset composed of 48 -5/del(5q) patient specimens and 367 control AML, we identified DELE1 - located in the common deleted region - as the most consistently downregulated gene in these leukemias. DELE1 encodes a mitochondrial protein recently characterized as the relay of mitochondrial stress to the cytosol through a newly defined OMA1-DELE1-HRI pathway which ultimately leads to the activation of ATF4, the master transcription factor of the integrated stress response. Here, we showed that the partial loss of DELE1 expression observed in -5/del(5q) patients was sufficient to significantly reduce the sensitivity to mitochondrial stress in AML cells. Overall, our results suggest that DELE1 haploinsufficiency could represent a new driver mechanism in -5/del(5q) AML.
    DOI:  https://doi.org/10.1038/s41375-023-02107-4
  8. Leukemia. 2023 Dec 18.
    Quantifying measurable residual disease correctly.
    Alexander A Morley.
      
    DOI:  https://doi.org/10.1038/s41375-023-02106-5
  9. Cancers (Basel). 2023 Dec 15. pii: 5866. [Epub ahead of print]15(24):
    Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.
    Johnson Ung, Su-Fern Tan, Todd E Fox, Jeremy J P Shaw, Maansi Taori, Bethany J Horton, Upendarrao Golla, Arati Sharma, Zdzislaw M Szulc, Hong-Gang Wang, Charles E Chalfant, Myles C Cabot, David F Claxton, Thomas P Loughran, David J Feith.
      Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug LCL-805 across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 μM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 μM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.
    Keywords:  Akt; C6-ceramide nanoliposome; LCL-805; acid ceramidase; acute myeloid leukemia; ceramide; dimethylglycine-B-13 prodrug; iron chelation; sphingolipids
    DOI:  https://doi.org/10.3390/cancers15245866
  10. Cancer Res Commun. 2023 Dec 21.
    The ncBAF complex regulates transcription in AML through H3K27ac sensing by BRD9.
    David C Klein, Santana M Lardo, Sarah J Hainer.
      The non-canonical BAF complex (ncBAF) subunit BRD9 is essential for acute myeloid leukemia (AML) cell viability but has an unclear role in leukemogenesis. Because BRD9 is required for ncBAF complex assembly through its DUF3512 domain, precise bromodomain inhibition is necessary to parse the role of BRD9 as a transcriptional regulator from that of a scaffolding protein. To understand the role of BRD9 bromodomain function in regulating AML, we selected a panel of five AML cell lines with distinct driver mutations, disease classifications, and genomic aberrations and subjected these cells to short-term BRD9 bromodomain inhibition. We examined the bromodomain-dependent growth of these cell lines, identifying a dependency in AML cell lines but not HEK293T cells. To define a mechanism through which BRD9 maintains AML cell survival, we examined nascent transcription, chromatin accessibility, and ncBAF complex binding genome-wide after bromodomain inhibition. We identified extensive regulation of transcription by BRD9 bromodomain activity, including repression of myeloid maturation factors and tumor suppressor genes, while standard AML chemotherapy targets were repressed by inhibition of the BRD9 bromodomain. BRD9 bromodomain activity maintained accessible chromatin at both gene promoters and gene-distal putative enhancer regions, in a manner that qualitatively correlated with enrichment of BRD9 binding. Furthermore, we identified reduced chromatin accessibility at GATA, ETS, and AP-1 motifs and increased chromatin accessibility at SNAIL-, HIC-, and TP53-recognized motifs after BRD9 inhibition. These data suggest a role for BRD9 in regulating AML cell differentiation through modulation of accessibility at hematopoietic transcription factor binding sites.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-23-0382
  11. Int J Hematol. 2023 Dec 19.
    FLT3 targeting in the modern era: from clonal selection to combination therapies.
    Vanessa E Kennedy, Catherine C Smith.
      Fms-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia (AML). Modern targeting of FLT3 with inhibitors has improved clinical outcomes and FLT3 inhibitors have been incorporated into the treatment of AML in all phases of the disease, including the upfront, relapsed/refractory and maintenance settings. This review will discuss the current understanding of FLT3 biology, the clinical use of FLT3 inhibitors, resistance mechanisms and emerging combination treatment strategies.
    Keywords:  AML; Acute Myeloid Leukemia; Clonal Evolution; FLT3; FLT3 inhibitor
    DOI:  https://doi.org/10.1007/s12185-023-03681-0
  12. Front Immunol. 2023 ;14 1320497
    AML alters bone marrow stromal cell osteogenic commitment via Notch signaling.
    Chiara Tomasoni, Corinne Arsuffi, Samantha Donsante, Alessandro Corsi, Mara Riminucci, Andrea Biondi, Alice Pievani, Marta Serafini.
      Introduction: Acute myeloid leukemia (AML) is a highly heterogeneous malignancy caused by various genetic alterations and characterized by the accumulation of immature myeloid blasts in the bone marrow (BM). This abnormal growth of AML cells disrupts normal hematopoiesis and alters the BM microenvironment components, establishing a niche supportive of leukemogenesis. Bone marrow stromal cells (BMSCs) play a pivotal role in giving rise to essential elements of the BM niche, including adipocytes and osteogenic cells. Animal models have shown that the BM microenvironment is significantly remodeled by AML cells, which skew BMSCs toward an ineffective osteogenic differentiation with an accumulation of osteoprogenitors. However, little is known about the mechanisms by which AML cells affect osteogenesis.Methods: We studied the effect of AML cells on the osteogenic commitment of normal BMSCs, using a 2D co-culture system.
    Results: We found that AML cell lines and primary blasts, but not normal hematopoietic CD34+ cells, induced in BMSCs an ineffective osteogenic commitment, with an increase of the early-osteogenic marker tissue non-specific alkaline phosphatase (TNAP) in the absence of the late-osteogenic gene up-regulation. Moreover, the direct interaction of AML cells and BMSCs was indispensable in influencing osteogenic differentiation. Mechanistic studies identified a role for AML-mediated Notch activation in BMSCs contributing to their ineffective osteogenic commitment. Inhibition of Notch using a γ-secretase inhibitor strongly influenced Notch signaling in BMSCs and abrogated the AML-induced TNAP up-regulation.
    Discussion: Together, our data support the hypothesis that AML infiltration produces a leukemia-supportive pre-osteoblast-rich niche in the BM, which can be partially ascribed to AML-induced activation of Notch signaling in BMSCs.
    Keywords:  AML niche; BMSCs (bone marrow stromal cells); Notch signaling; acute myeloid leukemia; osteogenesis
    DOI:  https://doi.org/10.3389/fimmu.2023.1320497
  13. Lancet Haematol. 2024 Jan;pii: S2352-3026(23)00338-1. [Epub ahead of print]11(1): e15-e26
    Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study.
    Guillermo Garcia-Manero, James McCloskey, Elizabeth A Griffiths, Karen W L Yee, Amer M Zeidan, Aref Al-Kali, H Joachim Deeg, Prapti A Patel, Mitchell Sabloff, Mary-Margaret Keating, Nancy Zhu, Nashat Y Gabrail, Salman Fazal, Joseph Maly, Olatoyosi Odenike, Hagop Kantarjian, Amy E DeZern, Casey L O'Connell, Gail J Roboz, Lambert Busque, Rena Buckstein, Harshad Amin, Jasleen Randhawa, Brian Leber, Aditi Shastri, Kim-Hien Dao, Aram Oganesian, Yong Hao, Harold N Keer, Mohammad Azab, Michael R Savona.
      BACKGROUND: The DNA methyltransferase inhibitors azacitidine and decitabine for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in parenteral form. Oral therapy with similar exposure for these diseases would offer potential treatment benefits. We aimed to compare the safety and pharmacokinetics of oral decitabine plus the cytidine deaminase inhibitor cedazuridine versus intravenous decitabine.METHODS: We did a registrational, multicentre, open-label, crossover, phase 3 trial of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia and individuals with acute myeloid leukaemia, enrolled as separate cohorts; results for only participants with myelodysplastic syndromes or chronic myelomonocytic leukaemia are reported here. In 37 academic and community-based clinics in Canada and the USA, we enrolled individuals aged 18 years or older who were candidates to receive intravenous decitabine, with Eastern Cooperative Oncology Group performance status 0 or 1 and a life expectancy of at least 3 months. Participants were randomly assigned (1:1) to receive 5 days of oral decitabine-cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) or intravenous decitabine (20 mg/m2 per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by 5 days of the other formulation in the next treatment cycle. Thereafter, all participants received oral decitabine-cedazuridine from the third cycle on until treatment discontinuation. The primary endpoint was total decitabine exposure over 5 days with oral decitabine-cedazuridine versus intravenous decitabine for cycles 1 and 2, measured as area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC0-24 for both oral decitabine-cedazuridine and intravenous decitabine (ie, paired cycles). On completion of the study, all patients were rolled over to a maintenance study. This study is registered with ClinicalTrials.gov, NCT03306264.
    FINDINGS: Between Feb 8, 2018, and June 7, 2021, 173 individuals were screened, 138 (80%) participants were randomly assigned to a treatment sequence, and 133 (96%) participants (87 [65%] men and 46 [35%] women; 121 [91%] White, four [3%] Black or African-American, three [2%] Asian, and five [4%] not reported) received treatment. Median follow-up was 966 days (IQR 917-1050). Primary endpoint of total exposure of oral decitabine-cedazuridine versus intravenous decitabine was 98·93% (90% CI 92·66-105·60), indicating equivalent pharmacokinetic exposure on the basis of area under the curve. The safety profiles of oral decitabine-cedazuridine and intravenous decitabine were similar. The most frequent adverse events of grade 3 or worse were thrombocytopenia (81 [61%] of 133 participants), neutropenia (76 [57%] participants), and anaemia (67 [50%] participants). The incidence of serious adverse events in cycles 1-2 was 31% (40 of 130 participants) with oral decitabine-cedazuridine and 18% (24 of 132 participants) with intravenous decitabine. There were five treatment-related deaths; two deemed related to oral therapy (sepsis and pneumonia) and three to intravenous treatment (septic shock [n=2] and pneumonia [n=1]).
    INTERPRETATION: Oral decitabine-cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine. The results support use of oral decitabine-cedazuridine as a safe and effective alternative to intravenous decitabine for treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia.
    FUNDING: Astex Pharmaceuticals.
    DOI:  https://doi.org/10.1016/S2352-3026(23)00338-1
  14. Curr Opin Hematol. 2023 Dec 18.
    Age-related micro-environmental changes as drivers of clonal hematopoiesis.
    Tal Bacharach, Nathali Kaushansky, Liran I Shlush.
      PURPOSE OF REVIEW: Both aging and reduced diversity at the hematopoietic stem cells (HSCs) level are ubiquitous. What remains unclear is why some individuals develop clonal hematopoiesis (CH), and why does CH due to specific mutations occur in specific individuals. Much like aging, reduced diversity of HSCs is a complex phenotype shaped by numerous factors (germline & environment). The purpose of the current review is to discuss the role of two other age-related ubiquitous processes that might contribute to the dynamics and characteristics of losing HSC diversity and the evolution of CH. These processes have not been reviewed in depth so far and include the accumulation of fatty bone marrow (FBM), and the decline in sex hormones.RECENT FINDINGS: Interestingly, sex hormone decline can directly shape HSC function, but also reshape the delicate balance of BM supporting cells, with a shift towards FBM. FBM accumulation can shape the clonal expansion of preleukemic mutations, particularly DNMT3A mutations, through IL-6 mediation. DNMT3A mutations are one of the only preleukemic mutations which is more prevalent in women, and especially in women with early menopause, demonstrating an association between age-related hormone decline and CH evolution, the mechanisms of which are yet to be discovered.
    SUMMARY: Aging is a multifactorial phenotype and the same is true for the aging of the blood system. While many factors which can shape CH have been discussed, we shed more light on FBM and sex hormone decline. Much more is missing: how and should we even try to prevent these phenomena? Why do they occur? and how they are connected to other age-related blood factors?
    DOI:  https://doi.org/10.1097/MOH.0000000000000798
  15. Leukemia. 2023 Dec 21.
    The SNP rs460089 in the gene promoter of the drug transporter OCTN1 has prognostic value for treatment-free remission in chronic myeloid leukemia patients treated with imatinib.
    Katerina Machova Polakova, Ali Albeer, Vaclava Polivkova, Monika Krutska, Katerina Vlcanova, Nikola Curik, Alice Fabarius, Hana Klamova, Birgit Spiess, Cornelius F Waller, Tim H Brümmendorf, Jolanta Dengler, Volker Kunzmann, Andreas Burchert, Petra Belohlavkova, Satu Mustjoki, Edgar Faber, Jiri Mayer, Daniela Zackova, Panayiotis Panayiotidis, Johan Richter, Henrik Hjorth-Hansen, Magdalena Kamińska, Magdalena Płonka, Elżbieta Szczepanek, Monika Szarejko, Grażyna Bober, Iwona Hus, Olga Grzybowska-Izydorczyk, Ewa Wasilewska, Edyta Paczkowska, Joanna Niesiobędzka-Krężel, Krzysztof Giannopoulos, Francois X Mahon, Tomasz Sacha, Susanne Saußele, Markus Pfirrmann.
      Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60-82%) compared to patients with GG (51%, 95% CI: 41-61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR.
    DOI:  https://doi.org/10.1038/s41375-023-02109-2
  16. Commun Biol. 2023 Dec 21. 6(1): 1294
    Hyperactive Natural Killer cells in Rag2 knockout mice inhibit the development of acute myeloid leukemia.
    Emi Sugimoto, Jingmei Li, Yasutaka Hayashi, Kohei Iida, Shuhei Asada, Tsuyoshi Fukushima, Moe Tamura, Shiori Shikata, Wenyu Zhang, Keita Yamamoto, Kimihito Cojin Kawabata, Tatsuya Kawase, Takeshi Saito, Taku Yoshida, Satoshi Yamazaki, Yuta Kaito, Yoichi Imai, Tamami Denda, Yasunori Ota, Tomofusa Fukuyama, Yosuke Tanaka, Yutaka Enomoto, Toshio Kitamura, Susumu Goyama.
      Immunotherapy has attracted considerable attention as a therapeutic strategy for cancers including acute myeloid leukemia (AML). In this study, we found that the development of several aggressive subtypes of AML is slower in Rag2-/- mice despite the lack of B and T lymphocytes, even compared to the immunologically normal C57BL/6 mice. Furthermore, an orally active p53-activating drug shows stronger antileukemia effect on AML in Rag2-/- mice than C57BL/6 mice. Intriguingly, Natural Killer (NK) cells in Rag2-/- mice are increased in number, highly express activation markers, and show increased cytotoxicity to leukemia cells in a coculture assay. B2m depletion that triggers missing-self recognition of NK cells impairs the growth of AML cells in vivo. In contrast, NK cell depletion accelerates AML progression in Rag2-/- mice. Interestingly, immunogenicity of AML keeps changing during tumor evolution, showing a trend that the aggressive AMLs generate through serial transplantations are susceptible to NK cell-mediated tumor suppression in Rag2-/- mice. Thus, we show the critical role of NK cells in suppressing the development of certain subtypes of AML using Rag2-/- mice, which lack functional lymphocytes but have hyperactive NK cells.
    DOI:  https://doi.org/10.1038/s42003-023-05606-3
  17. Leukemia. 2023 Dec 22.
    Interleukin-15 and -21-activated, donor-derived NK cell infusion after haploidentical HCT in high-risk AML and MDS-a cohort analysis.
    Kyoo-Hyung Lee, Sewon Lee, Young Hoon Park, Yeung-Chul Mun, Eun-Ji Choi, Yunsuk Choi, Han-Seung Park, Jung-Hee Lee, Je-Hwan Lee, Soo-Yeon Park, Suk Ran Yoon, Inpyo Choi.
      
    DOI:  https://doi.org/10.1038/s41375-023-02121-6
  18. Clin Lymphoma Myeloma Leuk. 2023 Oct 20. pii: S2152-2650(23)02149-3. [Epub ahead of print]
    Real-World Effectiveness of Dasatinib Versus Imatinib in Newly Diagnosed Patients With Chronic Myeloid Leukemia.
    Andrew J Klink, Scott J Keating, John Brokars, Bruce Feinberg, Elias Jabbour.
      INTRODUCTION: Limited data exist comparing dasatinib with imatinib in clinical practice. This study assessed real-world outcomes associated with first-line (1L) dasatinib or imatinib treatment of chronic myeloid leukemia (CML).PATIENTS AND METHODS: This retrospective, observational, United States multisite cohort study analyzed electronic medical record data from adults with Philadelphia chromosome-positive (Ph+) CML in the chronic phase (CML-CP) after 1L dasatinib or imatinib between January 2014 and September 2018. Rates of and times to major molecular response (MMR) and deep molecular response (DMR) were assessed overall and in subgroups (low vs. intermediate/high risk, aged <65 vs. ≥65 years, low/normal vs. high body mass index [BMI]).
    RESULTS: The dasatinib cohort (n = 309) experienced higher rates of MMR (n = 304, 79% vs. 65%, P < .001) and DMR (44% vs. 25%, P < .001) vs. the imatinib cohort with shorter median times to MMR (11.9 vs. 14.7 months, P < .001) and DMR (30.3 vs. 66.1 months, P < .001). Patients with intermediate-/high-risk disease and those aged <65 years had higher MMR and DMR rates and achieved response earlier with dasatinib (P < .01). Patients with low-risk disease treated with dasatinib had higher rates of DMR (60% vs. 32%, P = .01). Across BMI strata, rates of MMR and DMR were higher with dasatinib (P < .05).
    CONCLUSIONS: Patients with CML-CP treated with 1L dasatinib achieved higher rates of, with shorter times to, MMR and DMR versus 1L imatinib. These clinically meaningful improvements were observed across subgroups.
    Keywords:  Clinical outcomes; First-line; Molecular response; Patient subgroups; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1016/j.clml.2023.10.005
  19. Blood Cancer J. 2023 Dec 21. 13(1): 193
    Lymphopenia confers poorer prognosis in Myelodysplastic Syndromes with very low and low IPSS-M.
    David Fandrei, Tony Huynh, Marie Sébert, Lorea Aguinaga, Valeria Bisio, Rathana Kim, Emmanuelle Clappier, Marion Espéli, Karl Balabanian, Hélène Moins-Teisserenc, Antoine Toubert, Nicolas Dulphy, Pierre Fenaux, Lionel Adès, Lin-Pierre Zhao.
      
    DOI:  https://doi.org/10.1038/s41408-023-00965-w
  20. Am J Hematol. 2023 Dec 15.
    Toward an improved understanding of hypomethylating agent and venetoclax therapies.
    Courtney D DiNardo.
      
    DOI:  https://doi.org/10.1002/ajh.27178
  21. Blood. 2023 Dec 21. 142(25): 2129-2130
    A traffic light for TFR by lineage-specific MRD.
    Massimo Breccia.
      
    DOI:  https://doi.org/10.1182/blood.2023022059
  22. Lancet Haematol. 2024 Jan;pii: S2352-3026(23)00340-X. [Epub ahead of print]11(1): e51-e61
    Predicting cytopenias, progression, and survival in patients with clonal cytopenia of undetermined significance: a prospective cohort study.
    Catherine Cargo, Elsa Bernard, Tumas Beinortas, Kelly L Bolton, Paul Glover, Helen Warren, Daniel Payne, Rukhsaar Ali, Alesia Khan, Mike Short, Suzan Van Hoppe, Alex Smith, Jan Taylor, Paul Evans, Elli Papaemmanuil, Simon Crouch.
      BACKGROUND: Somatic mutations are frequently reported in individuals with cytopenia but without a confirmed haematological diagnosis (clonal cytopenia of undetermined significance; CCUS). These patients have an increased risk of progression to a myeloid malignancy and worse overall survival than those with no such mutations. To date, studies have been limited by retrospective analysis or small patient numbers. We aimed to establish the natural history of CCUS by prospectively investigating outcome in a large, well defined patient cohort.METHODS: This prospective cohort study was conducted at the Haematological Malignancy Diagnostic Service, a diagnostic laboratory in Leeds, UK. Patients aged at least 18 years who were referred for investigation of cytopenia were eligible for inclusion; those with a history of myeloid malignancy were not eligible. Targeted sequencing was conducted alongside routine clinical testing. Baseline mutation analysis was then correlated with the main study outcomes: longitudinal blood counts, disease progression to a myeloid malignancy, and overall survival with a median follow-up of 4·54 years (IQR 4·03-5·04). Data were collected manually from hospital records or extracted from laboratory or clinical outcome databases.
    FINDINGS: Bone marrow samples from 2348 patients were received at the Haematological Malignancy Diagnostic Service between July 1, 2014, and July 31, 2016. Of these, 2083 patients (median age 72 years [IQR 63-80, range 18-99]; 854 [41·0%] female and 1229 [59·0%] male) met the inclusion criteria and had samples of sufficient quality for further analysis. 598 (28·7%) patients received a diagnosis on the basis of their biopsy sample, whereas 1485 (71·3%) samples were classified as non-diagnostic; of these, CCUS was confirmed in 400 (26·9%) patients (256 [64·0%] male and 144 [36·0%] female). TET2, SRSF2, and DNMT3A were the most frequently mutated genes in patients with CCUS, with 320 (80%) of 400 patients harbouring a mutation in at least one of these genes. Age (p<0·0001), sex (p=0·0027), and mutations in ASXL1 (p=0·0009), BCOR (p=0·0056), and TP53 (p=0·0055) correlated with a worse overall survival; however, the number of mutations was the strongest predictor for progression to a myeloid malignancy (two mutations, p=0·0024; three or more mutations, p=0·0004). Extended sequencing of samples from a subgroup of patients with sequential samples and no mutations in the initial myeloid gene panel showed recurrent mutations in both DDX41 and UBA1, suggesting that these genes should be included in clinical test panels.
    INTERPRETATION: Mutation analysis is advised in patients who have undergone bone marrow examination and have an otherwise-unexplained cytopenia. High-risk genetic mutations and increased numbers of mutations are predictive of both survival and progression within 5 years of presentation, warranting clinical surveillance and, when necessary, intervention.
    FUNDING: MDS Foundation.
    DOI:  https://doi.org/10.1016/S2352-3026(23)00340-X
  23. Nat Commun. 2023 Dec 15. 14(1): 8372
    BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state.
    Muran Xiao, Shinji Kondo, Masaki Nomura, Shinichiro Kato, Koutarou Nishimura, Weijia Zang, Yifan Zhang, Tomohiro Akashi, Aaron Viny, Tsukasa Shigehiro, Tomokatsu Ikawa, Hiromi Yamazaki, Miki Fukumoto, Atsushi Tanaka, Yasutaka Hayashi, Yui Koike, Yumi Aoyama, Hiromi Ito, Hiroyoshi Nishikawa, Toshio Kitamura, Akinori Kanai, Akihiko Yokoyama, Tohru Fujiwara, Susumu Goyama, Hideki Noguchi, Stanley C Lee, Atsushi Toyoda, Kunihiko Hinohara, Omar Abdel-Wahab, Daichi Inoue.
      ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.
    DOI:  https://doi.org/10.1038/s41467-023-44081-6
  24. Oncogene. 2023 Dec 16.
    USP47 stabilizes YBX1 to promote the progression of acute myeloid leukemia.
    Hu Lei, Hanzhang Xu, Li Yang, Yingying Wang, Youping Zhang, Yingli Wu.
      
    DOI:  https://doi.org/10.1038/s41388-023-02921-1
  25. Am J Hematol. 2023 Dec 18.
    Diagnostic capabilities, clinical features, and longitudinal UBA1 clonal dynamics of a nationwide VEXAS cohort.
    Carmelo Gurnari, Maria Rosaria Pascale, Antonio Vitale, Elisa Diral, Alessandro Tomelleri, Elisa Galossi, Giulia Falconi, Alessandro Bruno, Francesca Crisafulli, Micol Frassi, Chiara Cattaneo, Diego Bertoli, Massimo Bernardi, Annalisa Condorelli, Erika Morsia, Antonella Poloni, Elena Crisà, Daniela Caravelli, Paola Triggianese, Luisa Brussino, Giorgia Battipaglia, Sara Bindoli, Paolo Sfriso, Federico Caroni, Matteo Dragani, Flavia Mallegni, Federica Pilo, Davide Firinu, Antonio Curti, Cristina Papayannidis, Attilio Olivieri, Sharham Kordasti, Francesco Albano, Fabrizio Pane, Pellegrino Musto, Monica Bocchia, Elisabetta Lugli, Massimo Breccia, Marco Frigeni, Lorenzo Dagna, Raffaella Greco, Franco Franceschini, Corrado Campochiaro, Luca Cantarini, Maria Teresa Voso.
      VEXAS is a prototypic hemato-inflammatory disease combining rheumatologic and hematologic disorders in a molecularly defined nosological entity. In this nationwide study, we aimed at screenshotting the current diagnostic capabilities and clinical-genomic features of VEXAS, and tracked UBA1 longitudinal clonal dynamics upon different therapeutics, including allogeneic hematopoietic cell transplant. We leveraged a collaboration between the Italian Society of Experimental Hematology and of Rheumatology and disseminated a national survey to collect clinical and molecular patient information. Overall, 13/29 centers performed UBA1 genomic testing locally, including Sanger sequencing (46%), next-generation sequencing (23%), droplet digital polymerase chain reaction (8%), or combination (23%). A total of 41 male patients were identified, majority (51%) with threonine substitutions at Met41 hotspot, followed by valine and leucine (27% and 8%). Median age at VEXAS diagnosis was 67 years. All patients displayed anemia (median hemoglobin 9.1 g/dL), with macrocytosis. Bone marrow vacuoles were observed in most cases (89%). The most common rheumatologic association was polychondritis (49%). A concomitant myelodysplastic neoplasm/syndrome (MDS) was diagnosed in 71% of patients (n = 28), chiefly exhibiting lower Revised International Prognostic Scoring System risk profiles. Karyotype was normal in all patients, except three MDS cases showing -Y, t(12;16)(q13;q24), and +8. The most frequently mutated gene was DNMT3A (n = 10), followed by TET2 (n = 3). At last follow-up, five patients died and two patients progressed to acute leukemia. Longitudinal UBA1 clonal dynamics demonstrated mutational clearance following transplant. We collected a nationwide interdisciplinary VEXAS patient cohort, characterized by heterogeneous rheumatologic manifestations and treatments used. MDS was diagnosed in 71% of cases. Patients exhibited various longitudinal UBA1 clonal dynamics.
    DOI:  https://doi.org/10.1002/ajh.27169
  26. Life Sci Alliance. 2024 Mar;pii: e202302309. [Epub ahead of print]7(3):
    Single-cell time series analysis reveals the dynamics of HSPC response to inflammation.
    Brigitte J Bouman, Yasmin Demerdash, Shubhankar Sood, Florian Grünschläger, Franziska Pilz, Abdul R Itani, Andrea Kuck, Valérie Marot-Lassauzaie, Simon Haas, Laleh Haghverdi, Marieke Ag Essers.
      Hematopoietic stem and progenitor cells (HSPCs) are known to respond to acute inflammation; however, little is understood about the dynamics and heterogeneity of these stress responses in HSPCs. Here, we performed single-cell sequencing during the sensing, response, and recovery phases of the inflammatory response of HSPCs to treatment (a total of 10,046 cells from four time points spanning the first 72 h of response) with the pro-inflammatory cytokine IFNα to investigate the HSPCs' dynamic changes during acute inflammation. We developed the essential novel computational approaches to process and analyze the resulting single-cell time series dataset. This includes an unbiased cell type annotation and abundance analysis post inflammation, tools for identification of global and cell type-specific responding genes, and a semi-supervised linear regression approach for response pseudotime reconstruction. We discovered a variety of different gene responses of the HSPCs to the treatment. Interestingly, we were able to associate a global reduced myeloid differentiation program and a locally enhanced pyroptosis activity with reduced myeloid progenitor and differentiated cells after IFNα treatment. Altogether, the single-cell time series analyses have allowed us to unbiasedly study the heterogeneous and dynamic impact of IFNα on the HSPCs.
    DOI:  https://doi.org/10.26508/lsa.202302309
  27. Blood Cancer J. 2023 Dec 18. 13(1): 188
    Targeting S100A9 protein affects mTOR-ER stress signaling and increases venetoclax sensitivity in Acute Myeloid Leukemia.
    Rong Fan, Hatice Satilmis, Niels Vandewalle, Emma Verheye, Elke De Bruyne, Eline Menu, Nathan De Beule, Ann De Becker, Gamze Ates, Ann Massie, Tessa Kerre, Marie Törngren, Helena Eriksson, Karin Vanderkerken, Karine Breckpot, Ken Maes, Kim De Veirman.
      Acute Myeloid Leukemia (AML) is a heterogeneous disease with limited treatment options and a high demand for novel targeted therapies. Since myeloid-related protein S100A9 is abundantly expressed in AML, we aimed to unravel the therapeutic impact and underlying mechanisms of targeting both intracellular and extracellular S100A9 protein in AML cell lines and primary patient samples. S100A9 silencing in AML cell lines resulted in increased apoptosis and reduced AML cell viability and proliferation. These therapeutic effects were associated with a decrease in mTOR and endoplasmic reticulum stress signaling. Comparable results on AML cell proliferation and mTOR signaling could be observed using the clinically available S100A9 inhibitor tasquinimod. Interestingly, while siRNA-mediated targeting of S100A9 affected both extracellular acidification and mitochondrial metabolism, tasquinimod only affected the mitochondrial function of AML cells. Finally, we found that S100A9-targeting approaches could significantly increase venetoclax sensitivity in AML cells, which was associated with a downregulation of BCL-2 and c-MYC in the combination group compared to single agent therapy. This study identifies S100A9 as a novel molecular target to treat AML and supports the therapeutic evaluation of tasquinimod in venetoclax-based regimens for AML patients.
    DOI:  https://doi.org/10.1038/s41408-023-00962-z
  28. Blood. 2023 Dec 21. 142(25): 2222
    NIH natural history study of FPDMM patients.
      
    DOI:  https://doi.org/10.1182/blood.2023023126
  29. Curr Oncol. 2023 Dec 12. 30(12): 10410-10436
    The Clinical Utility of FLT3 Mutation Testing in Acute Leukemia: A Canadian Consensus.
    Julie Bergeron, Jose-Mario Capo-Chichi, Hubert Tsui, Etienne Mahe, Philip Berardi, Mark D Minden, Joseph M Brandwein, Andre C Schuh.
      FMS-like tyrosine kinase 3 (FLT3) mutations are detected in approximately 20-30% of patients with acute myeloid leukemia (AML), with the presence of a FLT3 internal tandem duplication (FLT3-ITD) mutation being associated with an inferior outcome. Assessment of FLT3 mutational status is now essential to define optimal upfront treatment in both newly diagnosed and relapsed AML, to support post-induction allogeneic hematopoietic stem cell transplantation (alloSCT) decision-making, and to evaluate treatment response via measurable (minimal) residual disease (MRD) evaluation. In view of its importance in AML diagnosis and management, the Canadian Leukemia Study Group/Groupe canadien d'étude sur la leucémie (CLSG/GCEL) undertook the development of a consensus statement on the clinical utility of FLT3 mutation testing, as members reported considerable inter-center variability across Canada with respect to testing availability and timing of use, methodology, and interpretation. The CLSG/GCEL panel identified key clinical and hematopathological questions, including: (1) which patients should be tested for FLT3 mutations, and when?; (2) which is the preferred method for FLT3 mutation testing?; (3) what is the clinical relevance of FLT3-ITD size, insertion site, and number of distinct FLT3-ITDs?; (4) is there a role for FLT3 analysis in MRD assessment?; (5) what is the clinical relevance of the FLT3-ITD allelic burden?; and (6) how should results of FLT3 mutation testing be reported? The panel followed an evidence-based approach, taken together with Canadian clinical and laboratory experience and expertise, to create a consensus document to facilitate a more uniform approach to AML diagnosis and treatment across Canada.
    Keywords:  FLT3 testing; FLT3-ITD; FLT3-TKD; acute myeloid leukemia; allelic ratio; fragment analysis; next-generation sequencing
    DOI:  https://doi.org/10.3390/curroncol30120759
  30. Cell Rep. 2023 Dec 19. pii: S2211-1247(23)01620-0. [Epub ahead of print]43(1): 113608
    Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms.
    Jessica E Pritchard, Juliette E Pearce, Inge A M Snoeren, Stijn N R Fuchs, Katrin Götz, Fabian Peisker, Silke Wagner, Adam Benabid, Niklas Lutterbach, Vanessa Klöker, James S Nagai, Monica T Hannani, Anna K Galyga, Ellen Sistemich, Bella Banjanin, Niclas Flosdorf, Eric Bindels, Kathrin Olschok, Katharina Biaesch, Nicolas Chatain, Neha Bhagwat, Andrew Dunbar, Rita Sarkis, Olaia Naveiras, Marie-Luise Berres, Steffen Koschmieder, Ross L Levine, Ivan G Costa, Hélène F E Gleitz, Rafael Kramann, Rebekka K Schneider.
      The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis.
    Keywords:  CP: Stem cell research; Gli1; Hedgehog signaling; MIF; bone marrow fibrosis; cellular crosstalk; hematopoietic stem cells; mesenchymal stromal cells; myeloproliferative neoplasms; single-cell RNA sequencing; therapeutic target
    DOI:  https://doi.org/10.1016/j.celrep.2023.113608
  31. Kidney Int Rep. 2023 Dec;8(12): 2733-2741
    Chronic Myelomonocytic Leukemia Patients With Lysozyme Nephropathy and Renal Infiltration Display Markers of Severe Disease.
    MINHEMON, GFM and French VEXAS group
      Introduction: Chronic myelomonocytic leukemia (CMML) is a hematologic disorder that is an overlap syndrome between myelodysplastic syndromes and myeloproliferative neoplasms, and can be associated with autoimmune and inflammatory diseases. This study aimed to describe kidney involvement in patients with CMML, their treatments, and outcomes.Methods: We conducted a French and American multicenter retrospective study in 15 centers, identifying patients with CMML with acute kidney injury (AKI), chronic kidney disease (CKD), and urine abnormalities.
    Results: Sixteen patients (males, n = 14; median age 76.5 years [71.9-83]) developed a kidney disease 6 months [1.6-25.6] after the diagnosis of CMML. At the time of kidney disease diagnosis, median urinary protein-to-creatinine ratio was 2 g/g [1.25-3.4], and median serum creatinine was 2.26 mg/dl [1.46-2.68]. Fourteen patients (87.5%) underwent a kidney biopsy, and the 2 main pathological findings were lysozyme nephropathy (56%) and renal infiltration by the CMML (37.5%). Ten patients received a new treatment following the CMML-associated kidney injury. Among patients with monitored kidney function, and after a median follow-up of 15 months [9.9-34.9], 4 patients had CKD stage 3, 4 had CKD stage 4, 1 had an end-stage kidney disease. In our patient series, 2 patients evolved to an acute myeloid leukemia (AML), and 5 died. Compared with 116 CMML controls, patients who had a kidney involvement had a higher monocyte count (P < 0.001), had more CMML-1 (P = 0.005), were more susceptible to develop an AML (P = 0.02), and were more eligible to receive a specific hematologic treatment, with hydroxyurea, or hypomethylating agents (P < 0.001), but no survival difference was seen between the 2 groups (P = 0.6978).
    Conclusion: In this cohort of patients with CMML with a kidney injury, the 2 most frequent renal complications were lysozyme-induced nephropathy and renal infiltration by the CMML. Kidney involvement should be closely monitored in patients with CMML.
    Keywords:  acute kidney injury; chronic myelomonocytic leukemia
    DOI:  https://doi.org/10.1016/j.ekir.2023.09.005
  32. Leukemia. 2023 Dec 21.
    Allogeneic hematopoietic cell transplantation for patients with acute myeloid leukemia not in remission.
    Masamitsu Yanada, Satoshi Yamasaki, Tadakazu Kondo, Takahito Kawata, Kaito Harada, Naoyuki Uchida, Noriko Doki, Satoshi Yoshihara, Yuta Katayama, Tetsuya Eto, Masatsugu Tanaka, Satoru Takada, Toshiro Kawakita, Tetsuya Nishida, Shuichi Ota, Kentaro Serizawa, Makoto Onizuka, Yoshinobu Kanda, Takahiro Fukuda, Yoshiko Atsuta, Takaaki Konuma.
      Allogeneic hematopoietic cell transplantation (HCT) is the last option for long-term survival for patients with chemotherapy-refractory acute myeloid leukemia (AML). By using the Japanese nationwide registry data, we analyzed 6927 adults with AML having undergone first allogeneic HCT while not in complete remission (CR) between 2001 and 2020. The 5-year overall survival (OS), relapse, and non-relapse mortality (NRM) rates were 23%, 53%, and 27%, respectively. Multivariate analysis identified several factors predictive of OS mainly through their effects on relapse (cytogenetics, percentage of blasts in the peripheral blood, and transplantation year) and NRM (age, sex, and performance status). As regards disease status, relapsed disease was associated with a higher risk of overall mortality than primary induction failure (PIF). The shorter duration of the first CR increased the risks of relapse and overall mortality for the relapsed group, and the longer time from diagnosis to transplantation did so for the PIF group. Our experience compiled over the past two decades demonstrated that >20% of patients still enjoy long-term survival with allogeneic HCT performed during non-CR and identified those less likely to benefit from allogeneic HCT. Future efforts are needed to reduce the risk of posttransplant relapse in these patients.
    DOI:  https://doi.org/10.1038/s41375-023-02119-0
  33. Bone Marrow Transplant. 2023 Dec 18.
    Galectin-3 predicts acute GvHD and overall mortality post reduced intensity allo-HCT: a BMT-CTN biorepository study.
    Philip L McCarthy, Kristopher M Attwood, Xiaojun Liu, George L Chen, Hans Minderman, Amin Alousi, Asad Bashey, Robert Lowsky, David B Miklos, John Hansen, Peter Westervelt, Gregory Yanik, Edmund K Waller, Alan Howard, Bruce R Blazar, Paul K Wallace, Ran Reshef, Mary M Horowitz, Richard T Maziarz, John E Levine, Hemn Mohammadpour.
      Identifying plasma biomarkers early after allo-HCT may become crucial to prevent and treat severe aGvHD. We utilized samples from 203 allo-HCT patients selected from the Blood & Marrow Transplant Clinical Trials Network (BMT CTN) to identify new biomarker models to predict aGvHD and overall mortality. Two new biomarkers (Gal-3 and LAG-3), and previously identified biomarkers (ST2/IL33R, IL6, Reg3A, PD-1, TIM-3, TNFR1) were screened. Increased Gal-3 levels measured at Day +7 post-transplant predicted the development of aGvHD (grade 2-4) in the total population [AUC: 0.602; P = 0.045] while higher Day +14 levels predicted overall mortality due to toxicity among patients receiving reduced intensity conditioning [P = 0.028] but not myeloablative conditioning. Elevated LAG-3 levels (Day +21) were associated with less severe aGvHD [159.1 ng/mL vs 222.0 ng/mL; P = 0.046]. We developed a model utilizing Gal-3, LAG-3, and PD-1 levels at Days +14 and +21 with an improved performance to predict aGvHD and overall non-relapse mortality. We confirmed four informative biomarkers (Reg3A, ST2, TIM-3, and TNFR1) predict severe aGvHD at day +14 and day +21 (grade 3-4). In conclusion, the combination of Gal-3 alone or in combination with LAG-3, and PD-1 is a new informative model to predict aGvHD development and overall non-relapse mortality after allo-HCT.
    DOI:  https://doi.org/10.1038/s41409-023-02168-0
  34. Leukemia. 2023 Dec 20.
    Backtracking to the future: unraveling the origins of childhood leukemia.
    Adam J de Smith, Joseph L Wiemels, Adam J Mead, Irene Roberts, Anindita Roy, Logan G Spector.
      
    DOI:  https://doi.org/10.1038/s41375-023-02111-8
  35. Blood Cancer J. 2023 Dec 21. 13(1): 194
    Myeloid neoplasm occurrence during stable molecular remission of NPM1-mutated AML: are we facing secondary disease or AML relapse?
    Carlotta Giupponi, Diego Bertoli, Erika Borlenghi, Chiara Cattaneo, Tatiana Zollner, Lorenzo Masina, Samuele Bagnasco, Elisa Cerqui, Francesca Federico, Chiara Pagani, Silvana Archetti, Duilio Brugnoni, Giuseppe Rossi, Alessandra Tucci.
      
    DOI:  https://doi.org/10.1038/s41408-023-00959-8
  36. Blood. 2023 Dec 21. 142(25): 2127-2128
    Seeding the future: the natural history of RUNX1 deficiency.
    Tim Ripperger.
      
    DOI:  https://doi.org/10.1182/blood.2023022427
  37. Blood Cancer J. 2023 Dec 21. 13(1): 192
    Sociodemographic associations with uptake of novel therapies for acute myeloid leukemia.
    Andrew Hantel, Colin Cernik, Hajime Uno, Thomas P Walsh, Gregory S Calip, Daniel J DeAngelo, Christopher S Lathan, Gregory A Abel.
      Inequitable uptake of novel therapies (NT) in non-cancer settings are known for patients with lower socioeconomic status (SES), People of Color (POC), and older adults. NT uptake equity in acute myeloid leukemia (AML) is not well known. We performed a retrospective cohort study (1/2014-8/2022) of the United States nationwide Flatiron HealthTM electronic health record-derived, de-identified database. We estimated sociodemographic associations with AML NT receipt using incidence rate ratios (IRR). Odds ratios (OR) assessed differences in venetoclax (the most common NT) receipt at community sites and between site characteristics and NT adoption. Of 8081 patients (139 sites), 3102 (38%) received a NT. NT use increased annually (IRR 1.14, 95% confidence interval [1.07, 1.22]). NT receipt was similar between Non-Hispanic-Whites and POC (IRR 1.03, [0.91, 1.17]) and as age increased (IRR 1.02 [0.97, 1.07]). At community sites, Non-Hispanic-Whites were less likely to receive venetoclax (OR 0.77 [0.66, 0.91]); older age (OR 1.05 [1.04, 1.05]) and higher area-level SES were associated with venetoclax receipt (OR 1.23 [1.05, 1.43]). Early NT adopting sites had more prescribing physicians (OR 1.25 [1.13, 1.43]) and higher SES strata patients (OR 2.81 [1.08, 7.66]). Inequities in AML NT uptake were seen by SES; for venetoclax, differential uptake reflects its label indication for older adults and those with comorbidities.
    DOI:  https://doi.org/10.1038/s41408-023-00964-x
  38. Sci Transl Med. 2023 Dec 20. 15(727): eadf8366
    Inhibition of RIP1 improves immune reconstitution and reduces GVHD mortality while preserving graft-versus-leukemia effects.
    Mariano Prado-Acosta, Seihwan Jeong, Alberto Utrero-Rico, Tatiana Goncharov, Joshua D Webster, Ernst Holler, George Morales, Sergio Dellepiane, John E Levine, Michael E Rothenberg, Domagoj Vucic, James L M Ferrara.
      Graft-versus-host disease (GVHD) remains the major cause of morbidity and nonrelapse mortality (NRM) after hematopoietic cell transplantation (HCT). Inflammatory cytokines mediate damage to key GVHD targets such as intestinal stem cells (ISCs) and also activate receptor interacting protein kinase 1 (RIP1; RIPK1), a critical regulator of apoptosis and necroptosis. We therefore investigated the role of RIP1 in acute GVHD using samples from HCT patients, modeling GVHD damage in vitro with both human and mouse gastrointestinal (GI) organoids, and blocking RIP1 activation in vivo using several well-characterized mouse HCT models. Increased phospho-RIP1 expression in GI biopsies from patients with acute GVHD correlated with tissue damage and predicted NRM. Both the genetic inactivation of RIP1 and the RIP1 inhibitor GNE684 prevented GVHD-induced apoptosis of ISCs in vivo and in vitro. Daily administration of GNE684 for 14 days reduced inflammatory infiltrates in three GVHD target organs (intestine, liver, and spleen) in mice. Unexpectedly, GNE684 administration also reversed the marked loss of regulatory T cells in the intestines and liver during GVHD and reduced splenic T cell exhaustion, thus improving immune reconstitution. Pharmacological and genetic inhibition of RIP1 improved long-term survival without compromising the graft-versus-leukemia (GVL) effect in lymphocytic and myeloid leukemia mouse models. Thus, RIP1inhibition may represent a nonimmunosuppressive treatment for GVHD.
    DOI:  https://doi.org/10.1126/scitranslmed.adf8366
  39. Mol Oncol. 2023 Dec 17.
    A newly identified 45-kDa JAK2 variant with an altered kinase domain structure represents a novel mode of JAK2 kinase inhibitor resistance.
    Sivahari Prasad Gorantla, Tony Andreas Mueller, Corinna Albers-Leischner, Martina Rudelius, Nikolas von Bubnoff, Justus Duyster.
      Tyrosine-protein kinase (janus kinase; JAK)-signal transducer and activator of transcription (STAT) signaling plays a pivotal role in the development of myeloproliferative neoplasms (MPNs). Treatment with the potent JAK1/JAK2-specific inhibitor, ruxolitinib, significantly reduces tumor burden; however, ruxolitinib treatment does not fully eradicate the malignant clone. As the molecular basis for the disease persistence is not well understood, we set out to gain new insights by generating ruxolitinib-resistant cell lines. Surprisingly, these cells harbor a 45 kDa JAK2 variant (FERM-JAK2) consisting of the N-terminal FERM domain directly fused to the C-terminal kinase domain in 80% of sublines resistant to ruxolitinib. At the molecular level, FERM-JAK2 is able to directly bind and activate STAT5 in the absence of cytokine receptors. Furthermore, phosphorylation of activation-loop tyrosines is dispensable for FERM-JAK2-mediated STAT5 activation and cellular transformation, in contrast to JAK2-V617F. As a result, FERM-JAK2 is highly resistant to several ATP-competitive JAK2 inhibitors, whereas it is particularly sensitive to HSP90 inhibition. A murine model of FERM-JAK2 leukemogenesis showed an accelerated MPN phenotype with pronounced splenomegaly. Notably, most current protocols for the monitoring of emerging JAK variants are unable to detect FERM-JAK2, highlighting the urgent need for implementing next-generation sequencing approaches in MPN patients receiving ruxolitinib.
    Keywords:  JAK2-V617F; myeloproliferative neoplasm; ruxolitinib resistance
    DOI:  https://doi.org/10.1002/1878-0261.13566
  40. bioRxiv. 2023 Dec 10. pii: 2023.12.08.570880. [Epub ahead of print]
    Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A.
    C K Brierley, B H Yip, G Orlando, H Goyal, S Wen, J Wen, M F Levine, G M Jakobsdottir, A Rodriguez-Meira, A Adamo, M Bashton, A Hamblin, S A Clark, J O'Sullivan, L Murphy, A A Olijnik, A Cotton, S Narina, S M Pruett-Miller, A Enshaei, C Harrison, M Drummond, S Knapper, A Tefferi, I Antony-Debré, S Thongjuea, D C Wedge, S Constantinescu, E Papaemmanuil, B Psaila, J D Crispino, A J Mead.
      Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ∼25% of patients ('chr21amp'). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A , a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo , and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.
    DOI:  https://doi.org/10.1101/2023.12.08.570880
  41. Cell Rep Med. 2023 Dec 19. pii: S2666-3791(23)00546-3. [Epub ahead of print]4(12): 101329
    NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy.
    Laura Hurtado-Navarro, Ernesto José Cuenca-Zamora, Lurdes Zamora, Beatriz Bellosillo, Esperanza Such, Eva Soler-Espejo, Helios Martínez-Banaclocha, Jesús M Hernández-Rivas, Javier Marco-Ayala, Laura Martínez-Alarcón, Lola Linares-Latorre, Sara García-Ávila, Paula Amat-Martínez, Teresa González, Montserrat Arnan, Helena Pomares-Marín, Gonzalo Carreño-Tarragona, Tzu Hua Chen-Liang, María T Herranz, Carlos García-Palenciano, María Luz Morales, Andrés Jerez, María L Lozano, Raúl Teruel-Montoya, Pablo Pelegrín, Francisca Ferrer-Marín.
      Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cell proliferation and survival and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1β release. Here, we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1β release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRASG12D mutation using the IL-1 receptor blocker anakinra inhibits NLRP3 inflammasome activation, reduces monocyte count, and improves the patient's clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers.
    Keywords:  CMML; IL-1 blockers; KRAS; NLRP3 blockers; NLRP3 inflammasome; RAS mutations; anakinra; inflammation; myelodysplastic syndromes; myeloproliferative neoplasms
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101329
  42. Leukemia. 2023 Dec 20.
    Chemical genetic control of cytokine signaling in CAR-T cells using lenalidomide-controlled membrane-bound degradable IL-7.
    Michael C Kann, Emily M Schneider, Antonio J Almazan, Isabel C Lane, Amanda A Bouffard, Valentina M Supper, Hana N Takei, Alexander Tepper, Mark B Leick, Rebecca C Larson, Benjamin L Ebert, Marcela V Maus, Max Jan.
      CAR-T cell therapy has emerged as a breakthrough therapy for the treatment of relapsed and refractory hematologic malignancies. However, insufficient CAR-T cell expansion and persistence is a leading cause of treatment failure. Exogenous or transgenic cytokines have great potential to enhance CAR-T cell potency but pose the risk of exacerbating toxicities. Here we present a chemical-genetic system for spatiotemporal control of cytokine function gated by the off-patent anti-cancer molecular glue degrader drug lenalidomide and its analogs. When co-delivered with a CAR, a membrane-bound, lenalidomide-degradable IL-7 fusion protein enforced a clinically favorable T cell phenotype, enhanced antigen-dependent proliferative capacity, and enhanced in vivo tumor control. Furthermore, cyclical pharmacologic combined control of CAR and cytokine abundance enabled the deployment of highly active, IL-7-augmented CAR-T cells in a dual model of antitumor potency and T cell hyperproliferation.
    DOI:  https://doi.org/10.1038/s41375-023-02113-6
  43. Cancer Gene Ther. 2023 Dec 22.
    STAT5a and SH2B3 novel mutations display malignancy roles in a triple-negative primary myelofibrosis patient.
    Shubing Zhang, Jinhua Yan, Lan He, Zhiping Jiang, Hao Jiang.
      Primary myelofibrosis (PMF) patients frequently have JAK2 (V617F), CALR (exon 9), or MPL (W515 or exon 10) strong driver gene mutation, which triggers abnormal activation of the JAK2-STATs signaling pathway that plays a complex role in the occurrence of PMF. However, about 10-15% of PMF patients have no above typical mutations in these strong driver genes, known as being "triple-negative", which are associated with poor prognosis. In this paper, we reported a unique secondary acute myeloid leukemia (sAML) case transformed from triple-negative PMF combined with lung cancer and erythroderma occurrence at the same time, which has not been reported so far. Through whole blood exome sequencing, four novel noncanonical mutations were detected in key regulatory genes SH2B3 (Q748 and S710) and STAT5a (C350 and K354). Meanwhile, STAT5a-S710 and SH2B3-K354 noncanonical mutations gained strong malignant biofunction on promoting cell growth and tumorigenesis by accelerating the G1/S transition. In the mechanistic study, these pernicious phenotypes driven by noncanonical mutations might be initial PMF by activating p-STAT5a/c-Myc/CyclinD1 and p-STAT3/p-AKT/p-ERK1/2 signaling axes. Therefore, our study explored the deleterious roles of novel noncanonical mutations in STAT5a and SH2B3, which may serve as susceptibility genes and display the oncogenic biofunction in the progression of PMF to acute myeloid leukemia-M2a (AML-M2a).
    DOI:  https://doi.org/10.1038/s41417-023-00719-7
  44. Biomedicines. 2023 Nov 30. pii: 3186. [Epub ahead of print]11(12):
    An Overview on Lipid Droplets Accumulation as Novel Target for Acute Myeloid Leukemia Therapy.
    Clelia Nisticò, Emanuela Chiarella.
      Metabolic reprogramming is a key alteration in tumorigenesis. In cancer cells, changes in metabolic fluxes are required to cope with large demands on ATP, NADPH, and NADH, as well as carbon skeletons. In particular, dysregulation in lipid metabolism ensures a great energy source for the cells and sustains cell membrane biogenesis and signaling molecules, which are necessary for tumor progression. Increased lipid uptake and synthesis results in intracellular lipid accumulation as lipid droplets (LDs), which in recent years have been considered hallmarks of malignancies. Here, we review current evidence implicating the biogenesis, composition, and functions of lipid droplets in acute myeloid leukemia (AML). This is an aggressive hematological neoplasm originating from the abnormal expansion of myeloid progenitor cells in bone marrow and blood and can be fatal within a few months without treatment. LD accumulation positively correlates with a poor prognosis in AML since it involves the activation of oncogenic signaling pathways and cross-talk between the tumor microenvironment and leukemic cells. Targeting altered LD production could represent a potential therapeutic strategy in AML. From this perspective, we discuss the main inhibitors tested in in vitro AML cell models to block LD formation, which is often associated with leukemia aggressiveness and which may find clinical application in the future.
    Keywords:  PPARγ; acute myeloid leukemia (AML); chemotherapy resistance; lipid droplets (LDs); lipid metabolism
    DOI:  https://doi.org/10.3390/biomedicines11123186
  45. Haematologica. 2023 Dec 21.
    Home time among older adults with acute myeloid leukemia by therapy intensity.
    Christopher E Jensen, Allison M Deal, Alexis C Wardell, Hillary M Heiling, Konan E Beke, Daniel R Richardson.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2023.284133
  46. Nat Commun. 2023 Dec 20. 14(1): 8491
    Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells.
    Yixi Zhang, Hongyu Fang, Guocan Wang, Guangxun Yuan, Ruoyu Dong, Jijun Luo, Yu Lyu, Yajie Wang, Peng Li, Chun Zhou, Weiwei Yin, Haowen Xiao, Jie Sun, Xun Zeng.
      Chimeric antigen receptor (CAR)-T therapy requires autologous T lymphocytes from cancer patients, a process that is both costly and complex. Universal CAR-T cell treatment from allogeneic sources can overcome this limitation but is impeded by graft-versus-host disease (GvHD) and host versus-graft rejection (HvGR). Here, we introduce a mutated calcineurin subunit A (CNA) and a CD19-specific CAR into the T cell receptor α constant (TRAC) locus to generate cells that are resistant to the widely used immunosuppressant, cyclosporine A (CsA). These immunosuppressant-resistant universal (IRU) CAR-T cells display improved effector function in vitro and anti-tumour efficacy in a leukemia xenograft mouse model in the presence of CsA, compared with CAR-T cells carrying wild-type CNA. Moreover, IRU CAR-T cells retain effector function in vitro and in vivo in the presence of both allogeneic T cells and CsA. Lastly, CsA withdrawal restores HvGR, acting as a safety switch that can eliminate IRU CAR-T cells. These findings demonstrate the efficacy of CsA-resistant CAR-T cells as a universal, 'off-the-shelf' treatment option.
    DOI:  https://doi.org/10.1038/s41467-023-44176-0
  47. Blood Adv. 2023 Dec 22. pii: bloodadvances.2023012190. [Epub ahead of print]
    CHIP-JAK2V617F, Chronic Inflammation, Abnormal Megakaryocyte Morphology, Organ Failure, and Multimorbidties.
    Marie Hvelplund Kristiansen, Lasse Kjær, Vibe Skov, Morten Kranker Larsen, Christina Ellervik, Hans Carl Carl Hasselbalch, Troels Wienecke.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023012190
  48. Am J Hematol. 2023 Dec 22.
    Vacuoles in circulating immature myeloid cells in VEXAS syndrome and comparison with UBA1-wild type patients.
    Valentin Lacombe, Franck Genevieve, Floris Chabrun.
      We did not identify any vacuole-related differences in circulating immature myeloid cells between VEXAS patients and UBA1-WT 'VEXAS-like' patients. The similar vacuolization of circulating immature myeloid cells between VEXAS and UBA1-WT patients is explained by the main bloodstream passage of late precursors, in which the vacuolization is already similar in bone marrow in both cases.
    DOI:  https://doi.org/10.1002/ajh.27192
  49. Blood Adv. 2023 Dec 21. pii: bloodadvances.2023011002. [Epub ahead of print]
    Intensive Care Risk and Long-Term Outcomes in Pediatric Allogeneic Hematopoietic Cell Transplant Recipients.
    Matt S Zinter, Ruta Brazauskas, Joelle Strom, Stella Chen, Stephanie Bo-Subait, Akshay Sharma, Amer Beitinjaneh, Dimana Dimitrova, Gregory Guilcher, Jaime M Preussler, Kasiani C Myers, Neel S Bhatt, Olle Ringden, Peiman Hematti, Robert J Hayashi, Sagar S Patel, Satiro De Oliveira, Seth J Rotz, Sherif M Badawy, Taiga Nishihori, David K Buchbinder, Betty K Hamilton, Bipin N Savani, Hélène M Schoemans, Mohamed Lotfy Sorror, Lena E Winestone, Christine Duncan, Rachel Phelan, Christopher C Dvorak.
      Allogeneic hematopoietic cell transplantation (HCT) can be complicated by life-threatening organ toxicity and infection necessitating intensive care. Epidemiologic data have been limited by single-center studies, poor database granularity, and a lack of long-term survivors. To identify contemporary trends in ICU utilization and long-term outcomes, we merged data from the Center for International Blood and Marrow Transplant Research and the Virtual Pediatric Systems databases. We identified 6,995 pediatric HCT patients age ≤21 years who underwent 1st allogeneic HCT between 2008-2014 across 69 centers in the United States or Canada and followed patients until the year 2020. ICU admission was required for 1067 patients (8.3% by day +100, 12.8% by 1 year, and 15.3% by 5 years post-HCT), and was linked to demographic background, pre-transplant organ toxicity, allograft type and HLA-match, and the development of graft-versus-host disease or malignancy relapse. Survival to ICU discharge was 85.7% but more than half of ICU survivors required ICU readmission, leading to 52.5% and 42.6% survival at 1- and 5-years post-ICU transfer, respectively. ICU survival was worse among patients with malignant disease, poor pre-transplant organ function, and alloreactivity risk-factors. Among 1-year HCT survivors, those who required ICU in the first year had 10% lower survival at 5 years and developed new dialysis-dependent renal failure at a greater rate (p<0.001). Thus, while ICU management is common and survival to ICU discharge is high, ongoing complications necessitate recurrent ICU admission and lead to a poor 1-year outcome in select high-risk patients.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011002
  50. Blood Adv. 2023 Dec 15. pii: bloodadvances.2023010598. [Epub ahead of print]
    Cord blood transplantation for adult lymphoid neoplasms in Europe and Japan.
    Mizuki Watanabe, Junya Kanda, Fernanda Volt, Annalisa Ruggeri, Ritsuro Suzuki, Hanadi Rafii-Elayoubi, Fumihiko Kimura, Barbara Cappelli, Eisei Kondo, Graziana Maria Scigliuolo, Satoshi Takahashi, Chantal Kenzey, Monica Magdalena Rivera Franco, Shinichiro Okamoto, Vanderson Rocha, Patrice Chevallier, Jaime Sanz, Sabine Furst, Jan J Cornelissen, Noël J Milpied, Naoyuki Uchida, Yasuhiro Sugio, Takafumi Kimura, Tatsuo Ichinohe, Takahiro Fukuda, Mohamad Mohty, Régis Peffault de Latour, Yoshiko Atsuta, Eliane Gluckman.
      With the aim of identifying the different characteristics and prognostic factors of cord blood transplantation (CBT) in adult patients with lymphoid neoplasms in Europe and Japan, we conducted a collaborative study between European and Japanese registries. Patients aged 18-75 years receiving their first CBT (Europe: single CBT, n=192; double CBT, n=304; Japan: single CBT, n=1150) in 2000-2017 were analyzed. The number of patients with Hodgkin's lymphoma was higher in Europe (26% vs 5%) while that with mature T/NK-cell neoplasms was higher in Japan (20% vs 35%). The Japanese cohort comprised more elderly patients (>=50) (59% vs 39%) with higher refined disease risk index (rDRI) (high-very high: 49% vs 14%). High-very high rDRI (vs. low rDRI) was associated with inferior OS in common (Europe: HR 1.87 p=0.001; Japan: HR 2.34, p<0.001) with higher progression/relapse risks (Europe: HR 2.04, p=0.007; Japan: HR 2.96, p<0.001). Total body irradiation (TBI)-containing conditioning regimens contributed to superior OS both in Europe (vs TBI-RIC, non TBI-RIC: HR 1.93, p<0.001; non TBI-MAC: HR 1.90, p=0.003) and in Japan (non TBI-RIC: HR 1.71, p<0.001; non TBI-MAC: HR 1.50, p=0.007). The impact of HLA mismatches (>=2) on OS differed (Europe: HR 1.52, p=0.007; Japan: HR 1.18, p=0.107). Despite the different patient-disease-transplant characteristics, poor survival of patients receiving CBT for lymphoid neoplasms, especially in those with high rDRI was observed in both registries. The different impact of HLA mismatches on survival in the two registries calls attention to the fundamental differences among these populations. TBI should be considered in conditioning regimens.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010598
  51. Cancers (Basel). 2023 Dec 18. pii: 5888. [Epub ahead of print]15(24):
    Clinical, Histopathological and Molecular Spectrum of Cutaneous Lesions in Myelodysplastic Syndrome and Myeloproliferative Neoplasms (MDS/MPN): An Integrative Review.
    Lucía Prieto-Torres, Luis Requena, Socorro Maria Rodríguez-Pinilla.
      Myeloid neoplasms and acute leukemias include different entities that have been recently re-classified taking into account molecular and clinicopathological features. The myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) category comprises a heterogeneous group of hybrid neoplastic myeloid diseases characterized by the co-occurrence of clinical and pathological features of both myelodysplastic and myeloproliferative neoplasms. The most frequent entity in this category is chronic myelomonocytic leukemia (CMML) which is, after acute myeloid leukemia (AML), the main myeloid disorder prone to develop cutaneous manifestations. Skin lesions associated with myelodysplastic and myeloproliferative neoplasms include a broad clinical, histopathological and molecular spectrum of lesions, poorly understood and without a clear-cut classification in the current medical literature. The aim of this review is to describe and classify the main clinical, histopathological and molecular patterns of cutaneous lesions in the setting of MDS/MPN in order to improve the diagnostic skills of the dermatologists, hematologists and pathologists who deal with these patients.
    Keywords:  CMML; myelodysplastic and myeloproliferative neoplasms; skin
    DOI:  https://doi.org/10.3390/cancers15245888
  52. Blood Cancer J. 2023 Dec 15. 13(1): 187
    The impact of thrombosis on probabilities of death and disease progression in polycythemia vera: a multistate transition analysis of 1,545 patients.
    IWG-MRT group
      We applied a parametric Markov five-state model, on a well-characterized international cohort of 1,545 patients with polycythemia vera (PV; median age 61 years; females 51%), in order to examine the impact of incident thrombosis on the trajectory of death or disease progression. At a median follow-up of 6.9 years, 347 (23%) deaths, 50 (3%) blast phase (BP), and 138 (9%) fibrotic (post-PV MF) transformations were recorded. Incident thrombosis occurred at a rate of 2.62% pt/yr (arterial 1.59% and venous 1.05%). The probability of death, in the first 10 years, for 280 (18%) patients who developed thrombosis during follow-up was 40%, which was two-fold higher than that seen in the absence of thrombosis or any other transition state (20%; p < 0.01); the adverse impact from thrombosis was more apparent for arterial (HR 1.74; p < 0.01) vs venous thrombosis (p=NS) and was independent of other fixed (i.e., age, prior venous thrombosis, leukocytosis) or time-dependent (i.e., progression to BP or MF) risk variables. The transition probability to post-PV MF increased over time, in a linear fashion, with a rate of 5% capped at 5 and 10 years, in patients with or without incident thrombosis, respectively. The impact of thrombosis on transition probability to death or post-PV MF tapered off beyond 10 years and appeared to reverse direction of impact on MF evolution at the 12-year time point. These observations suggest thrombosis in PV to be a marker of aggressive disease biology or a disease-associated inflammatory state that is consequential to both thrombosis and disease progression.
    DOI:  https://doi.org/10.1038/s41408-023-00960-1
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