bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023–07–16
25 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Venetoclax Abrogates the Prognostic Impact of Splicing Factor Gene Mutations in Newly Diagnosed Acute Myeloid Leukemia.
  2. A phase 1/2 study of azacitidine, venetoclax and pevonedistat in newly diagnosed secondary AML and in MDS or CMML after failure of hypomethylating agents.
  3. Somatic TP53 single nucleotide variants, indels and copy number alterations in chronic myelomonocytic leukemia (CMML).
  4. A retrospective validation of the IPSS-M molecular score in primary and therapy-related myelodysplastic syndromes (MDS).
  5. In vivo CRISPR/Cas9 Screening Identifies Pbrm1 as a Regulator of Mouse Myeloid Leukemia Development.
  6. Germline predisposition to clonal hematopoiesis.
  7. Biallelic disruption of DDX41 activity is associated with distinct genomic and immunophenotypic hallmarks in acute leukemia.
  8. The bone marrow stroma in human myelodysplastic syndrome reveals alterations that regulate disease progression.
  9. Leukemic progenitor compartment serves as a prognostic measure of cancer stemness in patients with acute myeloid leukemia.
  10. Targeting PP2A-dependent autophagy enhances sensitivity to ruxolitinib in JAK2V617F myeloproliferative neoplasms.
  11. Deciphering the mitophagy receptor network identifies a crucial role for OPTN (optineurin) in acute myeloid leukemia.
  12. MAPK-negative feedback regulation confers dependence to JAK2V617F signaling.
  13. Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome.
  14. Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo.
  15. Dose-dependent expression of GFI1 alters metabolism in the haematopoietic progenitors and MLL::AF9-induced leukaemic cells.
  16. Integrated genomic and single-cell transcriptomic analyses reveal clonal evolution and immune signature in donor cell leukemia after haploidentical allogeneic hematopoietic stem cell transplantation.
  17. Incidence and predictors of anthracycline-related left ventricular dysfunction in acute myeloid leukemia.
  18. Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia.
  19. Evaluation of hypereosinophilia in a case of FLT3-mutant acute myeloid leukemia treated with gilteritinib.
  20. Clinical features and genomic landscape of myeloproliferative neoplasm (MPN) patients with autoimmune and inflammatory diseases (AID).
  21. Dose optimisation of ponatinib in chronic phase chronic myeloid leukemia.
  22. Acute myeloid leukemias with JAK2/STAT mutations are associated with PD-L1 upregulation.
  23. Vitamin C Deficiency in Patients with Acute Myeloid Leukemia; A Case Series and Review of the Literature.
  24. Re-induction with venetoclax combinations or IDH inhibitors result in similar remission rates and lower treatment related morbidity among AML patients initially receiving intensive induction chemotherapy.
  25. Indole-based FLT3 inhibitors and related scaffolds as potential therapeutic agents for acute myeloid leukemia.
  1. Blood. 2023 Jul 13. pii: blood.2023020649. [Epub ahead of print]
    Venetoclax Abrogates the Prognostic Impact of Splicing Factor Gene Mutations in Newly Diagnosed Acute Myeloid Leukemia.
    Jayastu Senapati, Samuel Urrutia, Sanam Loghavi, Nicholas J Short, Ghayas C Issa, Abhishek Maiti, Hussein A Abbas, Naval G Daver, Naveen Pemmaraju, Sherry A Pierce, Kelly Sharon Chien, Koji Sasaki, Tapan M Kadia, Danielle Hammond, Gautam Borthakur, Keyur P Patel, Farhad Ravandi, Hagop M Kantarjian, Guillermo Garcia-Manero, Courtney D DiNardo.
      Mutations in splicing factor (SF) genes SRSF2, U2AF1, SF3B1 and ZRSR2 are now classified as adverse risk (AR) in the European LeukemiaNet 2022 risk stratification for acute myeloid leukemia (AML). The prognostic impact of SF mutations in AML has been predominantly derived from younger patients treated with intensive (INT) therapy. We evaluated 994 patients with newly diagnosed AML, including 266 (27%) with a SFmut. Median age was 67 years overall, with SFmut pts older at 72 years. SRSF2 (=140, 53%) was the most common amongst SFmut. Amongst patients treated with INT therapy, median relapse-free survival (RFS) (9.6 versus 21.4 months, p=0.04) and overall survival (OS)(15.9 versus 26.7 months, p=0.06) were shorter for the SFmut compared to SFwt patients, however this significance abrogated when evaluating patients who received venetoclax with INT therapy (RFS 15.4 versus 20.3 months, p=0.36 and OS 19.6 versus 30.7 months, p=0.98). In patients treated with low-intensity (LI) therapy, median RFS (9.3 versus 7.7 months, p=0.35) and OS (12.3 versus 8.5 months, p=0.14) were similar for SFmut and SFwt patients, and outcomes improved in all groups with the receipt of venetoclax. On multivariate analysis, SFmut did not affect the hazards of relapse and death for INT therapy arm, arms but reduced both these hazards in the LI therapy arm. In this large AML dataset with >60% of patients receiving venetoclax with LI/ INT therapy, SFmut did not demonstrate independent prognostic impact. Newer prognostic models that consider LI therapy and the use of venetoclax amongst other factors are warranted.
    DOI:  https://doi.org/10.1182/blood.2023020649
  2. J Hematol Oncol. 2023 Jul 08. 16(1): 73
    A phase 1/2 study of azacitidine, venetoclax and pevonedistat in newly diagnosed secondary AML and in MDS or CMML after failure of hypomethylating agents.
    Nicholas J Short, Muharrem Muftuoglu, Faustine Ong, Lewis Nasr, Walid Macaron, Guillermo Montalban-Bravo, Yesid Alvarado, Mahesh Basyal, Naval Daver, Courtney D Dinardo, Gautam Borthakur, Nitin Jain, Maro Ohanian, Elias Jabbour, Ghayas C Issa, Wei Qiao, Xuelin Huang, Rashmi Kanagal-Shamanna, Keyur P Patel, Prithviraj Bose, Farhad Ravandi, Ricardo Delumpa, Regina Abramova, Guillermo Garcia-Manero, Michael Andreeff, Jorge Cortes, Hagop Kantarjian.
       BACKGROUND: Pevonedistat is a first-in-class, small molecular inhibitor of NEDD8-activating enzyme that has clinical activity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical data suggest synergy of pevonedistat with azacitidine and venetoclax.
    METHODS: This single-center, phase 1/2 study evaluated the combination of azacitidine, venetoclax and pevonedistat in older adults with newly diagnosed secondary AML or with MDS or chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents. Patients received azacitidine 75 mg/m2 IV on days 1-7, venetoclax at maximum dose of 200-400 mg orally on days 1-21 (AML cohort) or days 1-14 (MDS/CMML cohort) and pevonedistat 20 mg/m2 IV on days 1, 3 and 5 for up to 24 cycles. The primary endpoints for the phase 2 portion of the study were the CR/CRi rate in the AML cohort and the overall response rate (CR + mCR + PR + HI) in the MDS/CMML cohort.
    FINDINGS: Forty patients were enrolled (32 with AML and 8 with MDS/CMML). In the AML cohort, the median age was 74 years (range 61-86 years), and 27 patients (84%) had at least one adverse risk cyto-molecular feature, including 15 (47%) with a TP53 mutation or MECOM rearrangement; seventeen patients (53%) had received prior therapy for a preceding myeloid disorder. The CR/CRi rate was 66% (CR 50%; CRi 16%), and the median overall survival (OS) was 8.1 months. In the MDS/CMML cohort, 7 patients (87%) were high or very high risk by the IPSS-R. The overall response rate was 75% (CR 13%; mCR with or without HI 50%; HI 13%). The most common grade 3-4 adverse events were infection in 16 patients (35%), febrile neutropenia in 10 patients (25%) and hypophosphatemia in 9 patients (23%). In an exploratory analysis, early upregulation of NOXA expression was observed, with subsequent decrease in MCL-1 and FLIP, findings consistent with preclinical mechanistic studies of pevonedistat. Upregulation of CD36 was observed, which may have contributed to therapeutic resistance.
    CONCLUSIONS: The triplet combination of azacitidine, venetoclax and pevonedistat shows encouraging activity in this very poor-risk population of patients with AML, MDS or CMML. Trial registration ClinicalTrials.gov (NCT03862157).
    Keywords:  Clinical trial; Elderly; Myeloid diseases; Protein neddylation; Therapy
    DOI:  https://doi.org/10.1186/s13045-023-01476-8
  3. Leukemia. 2023 Jul 08.
    Somatic TP53 single nucleotide variants, indels and copy number alterations in chronic myelomonocytic leukemia (CMML).
    Mark Gurney, Abhishek A Mangaonkar, Terra Lasho, Christy Finke, Aref Al-Kali, Naseema Gangat, Mithun V Shah, Hassan B Alkhateeb, Ayalew Tefferi, David Sallman, Zhuoer Xie, David Viswanatha, Kaaren Reichard, Najla Al Ali, Rami Komrokji, Eric Padron, Mrinal M Patnaik.
      
    DOI:  https://doi.org/10.1038/s41375-023-01964-3
  4. Leuk Lymphoma. 2023 Jul 13. 1-6
    A retrospective validation of the IPSS-M molecular score in primary and therapy-related myelodysplastic syndromes (MDS).
    Jean M G Sabile, Andy Kaempf, Kaitlyn Tomic, Gurusidda P Manu, Ronan Swords, Yazan Migdady.
      A molecular scoring system (IPSS-M) was recently proposed for myelodysplastic syndrome (MDS). We conducted a retrospective study of adults with MDS referred 2019-2021. The primary outcomes were leukemia-free survival (LFS) and overall survival (OS). One hundred and forty-four patients diagnosed between 2011 and 2021 were analyzed. After IPSS-M re-stratification, 33% of patients were up-staged and 11% down-staged. Median follow-up was 2.8 years and 53 patients died (37%). Cumulative incidence of acute myeloid leukemia (AML) transformation was 20% at 3 years post-diagnosis. International Prognostic Scoring System (IPSS), revised version (IPSS-R) was significantly associated with LFS (log-rank p = 9.2e-05; 'very high' vs. 'low' risk HR = 3.85, p = 5.8e-04) and OS (log-rank p = 7.2e-06; 'very high' vs. 'low' HR = 5.09, p = 1.7e-04). IPSS-M was also a significant predictor of LFS (log-rank p = 1.1e-06; 'very high' vs. 'low' HR = 4.97, p = 2.2e-05) and OS (log-rank p = 4.8e-07; 'very high' vs. 'low' HR = 6.42, p = 2.5e-05) while providing better discrimination than IPSS-R for both outcomes. This mutation-incorporating prognostic index has greater discriminative potential than IPSS-R to predict AML transformation and any-cause mortality.
    Keywords:  IPSS-M; Myelodysplastic syndrome; risk stratification; secondary acute leukemia
    DOI:  https://doi.org/10.1080/10428194.2023.2232491
  5. Blood Adv. 2023 Jul 10. pii: bloodadvances.2022009455. [Epub ahead of print]
    In vivo CRISPR/Cas9 Screening Identifies Pbrm1 as a Regulator of Mouse Myeloid Leukemia Development.
    Bin E Li, Grace Y Li, Wenqing Cai, Qian Zhu, Davide Seruggia, Yuko Fujiwara, Christopher R Vakoc, Stuart Orkin.
      CRISPR/Cas9 screening approaches are powerful tools to identify in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which sequential acquisition of somatic mutations generates clonal diversity. With time, additional cooperating mutations may drive disease progression. Using an in vivo pooled gene editing screen of epigenetic factors in primary murine hematopoietic stem and progenitor cells (HSPCs), we sought to uncover unrecognized genes that contribute to leukemia progression. We first modeled myeloid leukemia in mice by functionally abrogating both Tet2 and Tet3 in HSPCs followed by transplantation. We then performed pooled CRISPR/Cas9 editing of genes encoding epigenetic factors and identified Pbrm1/Baf180, a subunit of polybromo BRG1/BRM-associated factor (PBAF) SWI/SNF chromatin remodeling complex, as a negative driver of disease progression. We found that Pbrm1 loss promoted leukemogenesis with significantly shortened latency. Pbrm1-deficient leukemia cells were less immunogenic, and characterized by attenuated interferon signaling and reduced MHC II expression. We explored potential relevance to human leukemia by assessing the involvement of PBRM1 in control of interferon pathway components and found that PBRM1 binds at promoters of a subset of these genes, and most notably at IRF1, which in turn regulates MHC II expression. Our findings revealed a novel role of Pbrm1 in leukemia progression. More generally, CRISPR/Cas9 screening, coupled with phenotypic readouts in vivo, has identified a pathway by which transcriptional control of interferon signaling influences leukemia cell interactions with the immune system.
    DOI:  https://doi.org/10.1182/bloodadvances.2022009455
  6. Leuk Res. 2023 Jun 19. pii: S0145-2126(23)00609-4. [Epub ahead of print]132 107344
    Germline predisposition to clonal hematopoiesis.
    Jie Liu, Afaf E G Osman, Kelly Bolton, Lucy A Godley.
      We now recognize that with aging, hematopoietic stem and progenitor cells (HSPCs) acquire mutations that confer a fitness advantage and clonally expand in a process now termed clonal hematopoiesis (CH). Because CH predisposes to a variety of health problems, including cancers, cardiovascular diseases, and inflammatory conditions, there is intense interest in the inherited alleles associated with the development of CH. DNA variants near TERT, SMC4, KPNA4, IL12A, CD164, and ATM confer the strongest associations. In this review, we discuss our current state of knowledge regarding germline predisposition to CH.
    DOI:  https://doi.org/10.1016/j.leukres.2023.107344
  7. Front Oncol. 2023 ;13 1153082
    Biallelic disruption of DDX41 activity is associated with distinct genomic and immunophenotypic hallmarks in acute leukemia.
    Anne Tierens, Elizabeth Kagotho, Satoru Shinriki, Andrew Seto, Adam C Smith, Melanie Care, Dawn Maze, Hassan Sibai, Karen W Yee, Andre C Schuh, Dennis Dong Hwan Kim, Vikas Gupta, Mark D Minden, Hirotaka Matsui, José-Mario Capo-Chichi.
       Introduction: Inherited DDX41 mutations cause familial predisposition to hematologic malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), with the majority of DDX41 mutated MDS/AMLs described to date harboring germline DDX41 and co-occurring somatic DDX41 variants. DDX41-AMLs were shown to share distinguishing clinical features such as a late AML onset and an indolent disease associated with a favorable outcome. However, genotype-phenotype correlation in DDX41-MDS/AMLs remain poorly understood.
    Methods: Here, we studied the genetic profile, bone marrow morphology and immunophenotype of 51 patients with DDX41 mutations. We further assessed the functional impact of ten previously uncharacterized DDX41 variants of uncertain significance.
    Results: Our results demonstrate that MDS/AML cases harboring two DDX41 variants share specific clinicopathologic hallmarks that are not seen in other patients with monoallelic DDX41 related hematologic malignancies. We further showed that the features seen in these individuals with two DDX41 variants were concordant with biallelic DDX41 disruption.
    Discussion: Here, we expand on previous clinicopathologic findings on DDX41 mutated hematologic malignancies. Functional analyses conducted in this study unraveled previously uncharacterized DDX41 alleles and further illustrate the implication of biallelic disruption in the pathophysiology of this distinct AML entity.
    Keywords:  DDX41 mutations; acute leukemia; biallelic; clinical pathology; myelodysplastic syndrome
    DOI:  https://doi.org/10.3389/fonc.2023.1153082
  8. Blood Adv. 2023 Jul 14. pii: bloodadvances.2022008268. [Epub ahead of print]
    The bone marrow stroma in human myelodysplastic syndrome reveals alterations that regulate disease progression.
    Youmna S Kfoury, Fei Ji, Esha Jain, Michael C Mazzola, Giulia Schiroli, Ani Papazian, Francois Emile Mercier, David Brian Sykes, Anna Kiem, Mark A Randolph, Omar I Abdel-Wahab, Laura Maria Calvi, Ruslan Sadreyev, David T Scadden.
      Myelodysplastic syndromes (MDS) are a heterogenous group of diseases affecting the hematopoietic stem cell that are curable only by stem cell transplantation. Both hematopoietic cell intrinsic changes and extrinsic signals from the bone marrow (BM) niche seem to ultimately lead to MDS. Animal models of MDS indicate that alterations in specific mesenchymal progenitor subsets in the BM microenvironment can induce or select for abnormal hematopoietic cells. Here we identify a subset of human BM mesenchymal cells marked by the expression of CD271, CD146 and CD106. This subset of human mesenchymal cells is comparable to mouse mesenchymal cells that, when perturbed, result in an MDS-like syndrome. Transcriptional analysis of them identified Osteopontin (SPP1) as the most overexpressed gene. Selective depletion of Spp1 in the microenvironment of the mouse MDS model, Vav-driven Nup98-HoxD13, resulted in an accelerated progression as demonstrated by increased chimerism, higher mutant myeloid cell burden and a more pronounced anemia when compared with wild type microenvironment controls. These data indicate that molecular perturbations can occur in specific BM mesenchymal subsets of MDS patients. However, the niche adaptations to dysplastic clones include Spp1 overexpression that can constrain disease fitness and potentially progression. Therefore, niche changes with malignant disease can also serve to protect the host.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008268
  9. Cell Rep Med. 2023 Jul 04. pii: S2666-3791(23)00236-7. [Epub ahead of print] 101108
    Leukemic progenitor compartment serves as a prognostic measure of cancer stemness in patients with acute myeloid leukemia.
    Allison L Boyd, Justin Lu, Cameron G Hollands, Lili Alsostovar, Shiva Murali, Jennifer C Reid, Wendy Ye, Sean Vandersluis, Paige Johnson, Amro ElRafie, Deanna P Porras, Dimetri Xenocostas, Andrew Leber, Brian Leber, Ronan Foley, Michael Trus, Tobias Berg, Eri Kawata, Anargyros Xenocostas, Mickie Bhatia.
      We systematically investigate functional and molecular measures of stemness in patients with acute myeloid leukemia (AML) using a cohort of 121 individuals. We confirm that the presence of leukemic stem cells (LSCs) detected through in vivo xenograft transplantation is associated with poor survival. However, the measurement of leukemic progenitor cells (LPCs) through in vitro colony-forming assays provides an even stronger predictor of overall and event-free survival. LPCs not only capture patient-specific mutations but also retain serial re-plating ability, demonstrating their biological relevance. Notably, LPC content represents an independent prognostic factor in multivariate analyses including clinical guidelines of risk stratification. Our findings suggest that LPCs provide a robust functional measure of AML, enabling quantitative and rapid assessment of a wide range of patients. This highlights the potential of LPCs as a valuable prognostic factor in AML management.
    Keywords:  acute myeloid leukemia; cancer stem cell; colony forming unit; leukemic progenitor cell; leukemic stem cell; prognostic; survival; xenotransplantation
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101108
  10. Blood Cancer J. 2023 Jul 10. 13(1): 106
    Targeting PP2A-dependent autophagy enhances sensitivity to ruxolitinib in JAK2V617F myeloproliferative neoplasms.
    Charly Courdy, Loïc Platteeuw, Charlotte Ducau, Isabelle De Araujo, Emeline Boet, Ambrine Sahal, Estelle Saland, Valérie Edmond, Suzanne Tavitian, Sarah Bertoli, Pierre Cougoul, Fanny Granat, Laura Poillet, Caroline Marty, Isabelle Plo, Jean-Emmanuel Sarry, Stéphane Manenti, Véronique Mansat-De Mas, Carine Joffre.
      The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are chronic malignancies associated with high-risk complications and suboptimal responses to JAK inhibitors such as ruxolitinib. A better understanding of cellular changes induced by ruxolitinib is required to develop new combinatory therapies to improve treatment efficacy. Here, we demonstrate that ruxolitinib induced autophagy in JAK2V617F cell lines and primary MPN patient cells through the activation of protein phosphatase 2A (PP2A). Inhibition of autophagy or PP2A activity along with ruxolitinib treatment reduced proliferation and increased the death of JAK2V617F cells. Accordingly, proliferation and clonogenic potential of JAK2V617F-driven primary MPN patient cells, but not of normal hematopoietic cells, were markedly impaired by ruxolitinib treatment with autophagy or PP2A inhibitor. Finally, preventing ruxolitinib-induced autophagy with a novel potent autophagy inhibitor Lys05 improved leukemia burden reduction and significantly prolonged the mice's overall survival compared with ruxolitinib alone. This study demonstrates that PP2A-dependent autophagy mediated by JAK2 activity inhibition contributes to resistance to ruxolitinib. Altogether, our data support that targeting autophagy or its identified regulator PP2A could enhance sensitivity to ruxolitinib of JAK2V617F MPN cells and improve MPN patient care.
    DOI:  https://doi.org/10.1038/s41408-023-00875-x
  11. Autophagy. 2023 Jul 13. 1-15
    Deciphering the mitophagy receptor network identifies a crucial role for OPTN (optineurin) in acute myeloid leukemia.
    Laura M Meyer, Sebastian E Koschade, Jonas B Vischedyk, Marlyn Thoelken, Andrea Gubas, Martin Wegner, Marion Basoglu, Stefan Knapp, Manuel Kaulich, Stefan Eimer, Shabnam Shaid, Christian H Brandts.
      The selective autophagic degradation of mitochondria via mitophagy is essential for preserving mitochondrial homeostasis and, thereby, disease maintenance and progression in acute myeloid leukemia (AML). Mitophagy is orchestrated by a variety of mitophagy receptors whose interplay is not well understood. Here, we established a pairwise multiplexed CRISPR screen targeting mitophagy receptors to elucidate redundancies and gain a deeper understanding of the functional interactome governing mitophagy in AML. We identified OPTN (optineurin) as sole non-redundant mitophagy receptor and characterized its unique role in AML. Knockdown and overexpression experiments demonstrated that OPTN expression is rate-limiting for AML cell proliferation. In a MN1-driven murine transplantation model, loss of OPTN prolonged overall median survival by 7 days (+21%). Mechanistically, we found broadly impaired mitochondrial respiration and function with increased mitochondrial ROS, that most likely caused the proliferation defect. Our results decipher the intertwined network of mitophagy receptors in AML for both ubiquitin-dependent and receptor-mediated mitophagy, identify OPTN as a non-redundant tool to study mitophagy in the context of leukemia and suggest OPTN inhibition as an attractive therapeutic strategy.Abbreviations: AML: acute myeloid leukemia; CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats; CTRL: control; DFP: deferiprone; GI: genetic interaction; KD: knockdown; KO: knockout; ldMBM, lineage-depleted murine bone marrow; LFC: log2 fold change; LIR: LC3-interacting region; LSC: leukemic stem cell; MAGeCK: Model-based Analysis of Genome-wide CRISPR-Cas9 Knockout; MDIVI-1: mitochondrial division inhibitor 1; MOI: multiplicity of infection; MOM: mitochondrial outer membrane; NAC: N-acetyl-L-cysteine; OA: oligomycin-antimycin A; OCR: oxygen consumption rate; OE: overexpression; OPTN: optineurin; PINK1: PTEN induced putative kinase 1; ROS: reactive oxygen species; SEM: standard error of the mean; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; UBD: ubiquitin-binding domain; WT: wild type.
    Keywords:  AML; MN1-driven mouse model; Mitochondrial ROS; Multiplex CRISPR screen; genetic interactions; leukemia
    DOI:  https://doi.org/10.1080/15548627.2023.2230839
  12. Leukemia. 2023 Jul 10.
    MAPK-negative feedback regulation confers dependence to JAK2V617F signaling.
    Meenu Kesarwani, Zachary Kincaid, Mohammad Azhar, Jacob Menke, Joshua Schwieterman, Sekhu Ansari, Angela Reaves, Michael E Deininger, Ross Levine, H Leighton Grimes, Mohammad Azam.
      Despite significant advances in developing selective JAK2 inhibitors, JAK2 kinase inhibitor (TKI) therapy is ineffective in suppressing the disease. Reactivation of compensatory MEK-ERK and PI3K survival pathways sustained by inflammatory cytokine signaling causes treatment failure. Concomitant inhibition of MAPK pathway and JAK2 signaling showed improved in vivo efficacy compared to JAK2 inhibition alone but lacked clonal selectivity. We hypothesized that cytokine signaling in JAK2V617F induced MPNs increases the apoptotic threshold that causes TKI persistence or refractoriness. Here, we show that JAK2V617F and cytokine signaling converge to induce MAPK negative regulator, DUSP1. Enhanced DUSP1 expression blocks p38 mediated p53 stabilization. Deletion of Dusp1 increases p53 levels in the context of JAK2V617F signaling that causes synthetic lethality to Jak2V617F expressing cells. However, inhibition of Dusp1 by a small molecule inhibitor (BCI) failed to impart Jak2V617F clonal selectivity due to pErk1/2 rebound caused by off-target inhibition of Dusp6. Ectopic expression of Dusp6 and BCI treatment restored clonal selectively and eradicated the Jak2V617F cells. Our study shows that inflammatory cytokines and JAK2V617F signaling converge to induce DUSP1, which downregulates p53 and establishes a higher apoptotic threshold. These data suggest that selectively targeting DUSP1 may provide a curative response in JAK2V617F-driven MPN.
    DOI:  https://doi.org/10.1038/s41375-023-01959-0
  13. Blood Adv. 2023 Jul 14. pii: bloodadvances.2023009742. [Epub ahead of print]
    Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome.
    Francesca Guijarro, Mònica López-Guerra, Jordi Morata, Alex Bataller, Sara Paz, Josep Maria Cornet-Masana, Antònia Banús-Mulet, Laia Cuesta-Casanovas, Josep Maria Carbó, Sandra Castaño-Díez, Carlos Jiménez-Vicente, Albert Cortés-Bullich, Ana Triguero, Alexandra Martínez-Roca, Daniel Esteban, Marta Gómez-Hernando, José Ramón Álamo Moreno, Irene López-Oreja, Marta Garrote, Ruth Muñoz Risueño, Raul Tonda, Ivo G Gut, Dolors Colomer, Marina Díaz-Beya, Jordi Esteve.
      Germline predisposition in acute myeloid leukemia (AML) has gained importance in recent years due to a non-negligible frequency and impact on management of patients and their relatives. Risk alleles for AML development may be present in patients without a clinical suspicion of hereditary hematologic malignancy syndrome. In this study we investigated the presence of germline variants (GV) in 288 genes related to cancer predisposition in 47 patients with available paired tumor-normal material, namely bone marrow stroma cells (BMSC, n=29), post-remission bone marrow (PRBM, n=17) and saliva (n=1). These patients correspond to two broad AML categories with heterogeneous genetic background (AML myelodysplasia-related and AML defined by differentiation) and none of them had phenotypic abnormalities, previous history of cytopenia nor strong cancer aggregation. We found 11 pathogenic or likely pathogenic variants, six affecting genes related to autosomal dominant cancer predisposition syndromes (ATM, DDX41 and CHEK2) and 5 related to autosomal recessive bone marrow failure syndromes (FANCA, FANCM, SBDS, DNAJC21 and CSF3R). We did not find differences in clinical characteristics nor outcome between GV carriers vs non-carriers. Further studies in unselected AML cohorts are needed to determine GV incidence and penetrance and, in particular, to clarify the role of ATM nonsense mutations in AML predisposition.
    DOI:  https://doi.org/10.1182/bloodadvances.2023009742
  14. Mol Cancer. 2023 Jul 08. 22(1): 107
    Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo.
    Ehsan Bahrami, Jan Philipp Schmid, Vindi Jurinovic, Martin Becker, Anna-Katharina Wirth, Romina Ludwig, Sophie Kreissig, Tania Vanessa Duque Angel, Diana Amend, Katharina Hunt, Rupert Öllinger, Roland Rad, Joris Maximilian Frenz, Maria Solovey, Frank Ziemann, Matthias Mann, Binje Vick, Christian Wichmann, Tobias Herold, Ashok Kumar Jayavelu, Irmela Jeremias.
       BACKGROUND: Acute leukemias represent deadly malignancies that require better treatment. As a challenge, treatment is counteracted by a microenvironment protecting dormant leukemia stem cells.
    METHODS: To identify responsible surface proteins, we performed deep proteome profiling on minute numbers of dormant patient-derived xenograft (PDX) leukemia stem cells isolated from mice. Candidates were functionally screened by establishing a comprehensive CRISPR‒Cas9 pipeline in PDX models in vivo.
    RESULTS: A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as an essential vulnerability required for the survival and growth of different types of acute leukemias in vivo, and reconstitution assays in PDX models confirmed the relevance of its sheddase activity. Of translational importance, molecular or pharmacological targeting of ADAM10 reduced PDX leukemia burden, cell homing to the murine bone marrow and stem cell frequency, and increased leukemia response to conventional chemotherapy in vivo.
    CONCLUSIONS: These findings identify ADAM10 as an attractive therapeutic target for the future treatment of acute leukemias.
    Keywords:  ADAM10; Acute leukemia; CRISPR-Cas9 in vivo screen; Leukemia stem cells; PDX; Proteomics
    DOI:  https://doi.org/10.1186/s12943-023-01803-0
  15. Br J Haematol. 2023 Jul 09.
    Dose-dependent expression of GFI1 alters metabolism in the haematopoietic progenitors and MLL::AF9-induced leukaemic cells.
    Pradeep Kumar Patnana, Longlong Liu, Daria Frank, Subbaiah Chary Nimmagadda, Matthias Behrens, Helal Ahmed, Xiaoqing Xie, Marie Liebmann, Lanying Wei, Andrea Gerdemann, Aniththa Thivakaran, Hans-Ulrich Humpf, Luisa Klotz, Martin Dugas, Julian Varghese, Marija Trajkovic-Arsic, Jens T Siveke, Helmut Hanenberg, Bertram Opalka, Ulrich Dührsen, Hans Christian Reinhardt, Ulrich Guenther, Nikolas von Bubnoff, Cyrus Khandanpour.
      Growth factor independence 1 (GFI1) is a transcriptional repressor protein that plays an essential role in the differentiation of myeloid and lymphoid progenitors. We and other groups have shown that GFI1 has a dose-dependent role in the initiation, progression, and prognosis of acute myeloid leukaemia (AML) patients by inducing epigenetic changes. We now demonstrate a novel role for dose-dependent GFI1 expression in regulating metabolism in haematopoietic progenitor and leukaemic cells. Using in-vitro and ex-vivo murine models of MLL::AF9-induced human AML and extra-cellular flux assays, we now demonstrate that a lower GFI1 expression enhances oxidative phosphorylation rate via upregulation of the FOXO1- MYC axis. Our findings underscore the significance of therapeutic exploitation in GFI1-low-expressing leukaemia cells by targeting oxidative phosphorylation and glutamine metabolism.
    Keywords:  AML; GFI1; metabolism
    DOI:  https://doi.org/10.1111/bjh.18939
  16. Leuk Lymphoma. 2023 Jul 10. 1-8
    Integrated genomic and single-cell transcriptomic analyses reveal clonal evolution and immune signature in donor cell leukemia after haploidentical allogeneic hematopoietic stem cell transplantation.
    Huiqiao Chen, Xiujie Zhao, Wenjue Pan, Haowen Xiao.
      The pathogenesis of donor cell leukemia (DCL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear and likely multifactorial. Leukemic transformation of healthy donor HSCs in recipient's bone marrow microenvironment provides a useful in vivo model for investigating the mechanisms involved in leukemogenesis. Here, we report a rare case of late-onset DCL developing in a recipient. Whole-genome sequencing indicates that donor-derived cells harboring clonal hematopoiesis of indeterminate potential (CHIP)-associated genetic alterations expand and eventually transform to full-blown AML via acquisition of additional somatic mutations within the recipient's bone marrow microenvironment. The 10× single-cell RNA sequencing reveals the abundance of GMP-like cells with a specific transcriptional signature in DCL. Moreover, impaired immune surveillance, including dysfunction of cytotoxic T lymphocytes (CTLs) and decreased number of canonical NK cells, is discovered in DCL. Our data add valuable information to the current understanding of the mechanisms of DCL.
    Keywords:  Clonal evolution; clonal hematopoiesis of indeterminate potential; donor cell leukemia; immune surveillance
    DOI:  https://doi.org/10.1080/10428194.2023.2232493
  17. Leuk Res. 2023 Jul 12. pii: S0145-2126(23)00616-1. [Epub ahead of print]132 107351
    Incidence and predictors of anthracycline-related left ventricular dysfunction in acute myeloid leukemia.
    Maximilian Stahl, Gerard Giblin, Yiwen Liu, Eric S Winer, Jacqueline S Garcia, Evan Chen, Martha Wadleigh, Kelly Ling, R Coleman Lindsley, Shai Shimony, Kevin Copson, Anne Charles, Daniel J DeAngelo, Richard M Stone, Anju Nohria, Marlise R Luskin.
       INTRODUCTION: Anthracycline-related left ventricular dysfunction (ARLVD) is a concern in patients with acute myeloid leukemia (AML) undergoing anthracyclinecontaining induction chemotherapy. However, the incidence of ARLVD in the modern era of routine pretreatment left ventricular ejection fraction (LVEF) echocardiographic assessment, as well as the clinical and genetic predictors of ARLVD are not well understood.
    METHODS: Consecutive adult patients with AML receiving anthracycline-containing induction chemotherapy at the Dana-Farber Cancer Institute from 2014 to 2022 were studied. Inclusion criteria included availability of a pre and post chemotherapy echocardiogram to assess the LVEF, pre-treatment LVEF > 50 %, as well as comprehensive diagnostic next generation sequencing assessing for the presence of myeloid mutations. The primary endpoint was the incidence of ARLVD defined as LVEF < 50 % post-induction.
    RESULTS: Out of 419 patients meeting inclusion criteria, 34 (8%) patients developed ARLVD. Among the 122/419 patients who did not undergo planned allogeneic stem cell transplantation (allo-SCT), ARLVD was the deciding factor for ineligibility in 4 patients (1%). Baseline cardiovascular comorbidities (hypertension, diabetes mellitus, hyperlipidemia, smoking and coronary artery disease) and cumulative anthracycline dose were not predictive of post-induction ARLVD. However, the presence of a JAK2 mutation (but not other myeloid mutations) was associated with an increased risk of ARLVD in multivariable analysis (OR 8.34, 95 % CI 1.55-39.3, p = 0.007).
    DISCUSSION: In a group of AML patients with normal LVEF prior to anthracycline-containing induction chemotherapy, ARLVD was infrequent and did not commonly preclude post-remission allo-SCT consolidation. Genetic predictors of ARLVD require further investigation in a larger patient cohort.
    Keywords:  AML; Acute myeloid leukemia; Anthracycline-related left ventricular dysfunction; Anthracyclines; Cardiomyopathy; Genetic predictors
    DOI:  https://doi.org/10.1016/j.leukres.2023.107351
  18. Leukemia. 2023 Jul 08.
    Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia.
    María Luz Morales, Roberto García-Vicente, Alba Rodríguez-García, Armando Reyes-Palomares, África Vincelle-Nieto, Noemí Álvarez, Alejandra Ortiz-Ruiz, Vanesa Garrido-García, Alicia Giménez, Gonzalo Carreño-Tarragona, Ricardo Sánchez, Rosa Ayala, Joaquín Martínez-López, María Linares.
      Despite the approval of several drugs for AML, cytarabine is still widely used as a therapeutic approach. However, 85% of patients show resistance and only 10% overcome the disease. Using RNA-seq and phosphoproteomics, we show that RNA splicing and serine-arginine-rich (SR) proteins phosphorylation were altered during cytarabine resistance. Moreover, phosphorylation of SR proteins at diagnosis were significantly lower in responder than non-responder patients, pointing to their utility to predict response. These changes correlated with altered transcriptomic profiles of SR protein target genes. Notably, splicing inhibitors were therapeutically effective in treating sensitive and resistant AML cells as monotherapy or combination with other approved drugs. H3B-8800 and venetoclax combination showed the best efficacy in vitro, demonstrating synergistic effects in patient samples and no toxicity in healthy hematopoietic progenitors. Our results establish that RNA splicing inhibition, alone or combined with venetoclax, could be useful for the treatment of newly diagnosed or relapsed/refractory AML.
    DOI:  https://doi.org/10.1038/s41375-023-01963-4
  19. Cold Spring Harb Mol Case Stud. 2023 06;pii: a006279. [Epub ahead of print]9(3):
    Evaluation of hypereosinophilia in a case of FLT3-mutant acute myeloid leukemia treated with gilteritinib.
    Leslie N Martinez-Gutierrez, Blake C Burgher, Manuel J Glynias, Daniel Alvarado, Elizabeth A Griffiths, Sean T Glenn, Pamela J Sung.
      Acute myeloid leukemias (AMLs) frequently harbor activating mutations in Fms-like tyrosine kinase 3 (FLT3). The use of FLT3 inhibitors (FLT3i) is the standard of care for treatment of newly diagnosed and relapsed patients with AML. Differentiation responses including clinical differentiation syndrome have been previously reported with FLT3i when used as single agents in relapsed disease. We present a case of hypereosinophilia in a patient on FLT3i therapy with persistent FLT3 polymerase chain reaction (PCR) positivity in peripheral blood. We sorted mature leukocytes by lineage to determine if the eosinophils were leukemia-derived. FLT3 PCR and next-generation sequencing analysis demonstrated monocytic differentiation of the FLT3-ITD leukemic clone with reactive hypereosinophilia that was derived from a preleukemic SF3B1, FLT3 wild-type clone. Our case is the first to definitively demonstrate the emergence of clonal FLT3-ITD monocytes with FLT3i and the first to demonstrate a differentiation response following decitabine, venetoclax, and gilteritinib triplet therapy.
    Keywords:  acute myeloid leukemia; eosinophilia
    DOI:  https://doi.org/10.1101/mcs.a006279
  20. Leukemia. 2023 Jul 11.
    Clinical features and genomic landscape of myeloproliferative neoplasm (MPN) patients with autoimmune and inflammatory diseases (AID).
    Dikelele Elessa, Lin-Pierre Zhao, Rafael Daltro de Oliveira, Nabih Maslah, Juliette Soret-Dulphy, Emmanuelle Verger, Clémence Marcault, Nathalie Parquet, Pierre Fenaux, Lionel Adès, Emmanuel Raffoux, Stéphane Giraudier, Olivier Fain, Bruno Cassinat, Jean-Jacques Kiladjian, Arsene Mekinian, Lina Benajiba.
      
    DOI:  https://doi.org/10.1038/s41375-023-01967-0
  21. Expert Rev Hematol. 2023 Jul 10.
    Dose optimisation of ponatinib in chronic phase chronic myeloid leukemia.
    Françoise Huguet, Delphine Réa, Emilie Cayssials, Gabriel Etienne, Franck-Emmanuel Nicolini.
       INTRODUCTION: Ponatinib exhibits a high inhibition potency on wild-type and most mutated forms of the BCR:ABL1 kinase, but also a significant cardiovascular toxicity. Improving the efficacy/safety ratio should allow patients to safely draw benefit from the drug.
    AREAS COVERED: Based on pharmacological findings and international guidelines on chronic myeloid leukemia and cardiovascular risk management, as well as on the most recent data collected in real-life studies and in a randomized phase II trial, we propose a decision-tree of dose selection of the drug.
    EXPERT OPINION: We distinguish (1) highly resistant patients according to poor previous response to second generation tyrosine kinase inhibitors (complete hematologic response or less) or to mutationnal status (T315I, E255V, alone or within compound mutations), requiring a starting daily dose of 45 mg, reduced to 15 or 30 mg according to the patient's profile, preferentially upon major molecular achievement (3-log reduction or MR3, BCR:ABL1 ≤0.1%IS); (2) less resistant patients justifying an initial dose of 30 mg, reduced to 15 mg upon MR2 (BCR:ABL1 ≤1%IS) or preferentially MR3 in patients with a favorable safety profile; (3) intolerant patients to be treated by 15 mg.
    Keywords:  chronic myeloid leukemia; dose; ponatinib; response; safety
    DOI:  https://doi.org/10.1080/17474086.2023.2234084
  22. Leuk Lymphoma. 2023 Jul 10. 1-11
    Acute myeloid leukemias with JAK2/STAT mutations are associated with PD-L1 upregulation.
    Jiani Chai, Jui Choudhuri, Qing Wang, Yanan Fang, Yang Shi, Josette Kamel, Nishi Shah, R Alejandro Sica, Noah Kornblum, Marina Konopleva, Ioannis Mantzaris, Aditi Shastri, Kira Gritsman, Amit Verma, Mendel Goldfinger, Swati Goel, Yanhua Wang, Xuejun Tian.
      Even though overexpression of the immune checkpoint protein, programmed cell death ligand-1 (PD-L1), is observed in solid tumors, its expression patterns in acute myeloid leukemia remain understudied. As activation of the JAK/STAT pathway has been shown to enhance PD-L1 expression in preclinical models, we evaluated biopsies from AML patients with activating mutations in JAK2/STATs. PD-L1 expression was significantly upregulated in JAK2/STAT mutant cases when compared to JAK2 wildtype controls as demonstrated by PD-L1 immunohistochemistry staining and quantified using the combined positive score (CPS) system. There is significant overexpression of phosphorylated STAT3 expression in patients with oncogenic JAK2 activation and a positive correlation between p-STAT3 and PD-L1 expression. In conclusion, we demonstrate the CPS scoring system could be applied as a quantitative measure of PD-L1 expression in leukemias and that JAK2/STATs mutant AML can be potential candidates for checkpoint inhibitor trials.
    Keywords:  Acute myeloid leukemia (AML); JAK2 / STAT mutation; combined positive score (CPS); programmed cell death ligand-1 (PD-L1)
    DOI:  https://doi.org/10.1080/10428194.2023.2232494
  23. Blood Adv. 2023 Jul 11. pii: bloodadvances.2023009923. [Epub ahead of print]
    Vitamin C Deficiency in Patients with Acute Myeloid Leukemia; A Case Series and Review of the Literature.
    Heather C Milbar, Avrom S Caplan, Robert David Schwab, Alexandra J Coromilas, Emily Baumrin, Amy Forrestel, Katherine T Steele, Robert G Micheletti, Alexander E Perl, Misha Rosenbach.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023009923
  24. Leuk Res. 2023 Jun 28. pii: S0145-2126(23)00613-6. [Epub ahead of print]132 107348
    Re-induction with venetoclax combinations or IDH inhibitors result in similar remission rates and lower treatment related morbidity among AML patients initially receiving intensive induction chemotherapy.
    Skyler Taylor, Guru Subramanian Guru Murthy, Lyndsey Runaas, Laura C Michaelis, Karen Carlson, Ehab L Atallah, Sameem M Abedin.
      
    Keywords:  Acute myeloid leukemia; Reinduction; Venetoclax
    DOI:  https://doi.org/10.1016/j.leukres.2023.107348
  25. BMC Chem. 2023 Jul 12. 17(1): 73
    Indole-based FLT3 inhibitors and related scaffolds as potential therapeutic agents for acute myeloid leukemia.
    Hend A A Ezelarab, Taha F S Ali, Samar H Abbas, Heba A Hassan, Eman A M Beshr.
      Fms-like tyrosine kinase 3 (FLT3) mutation mechanisms are among the most common genetic abnormalities detected in about 30% of acute myeloid leukemia (AML) patients. These mutations are accompanied by poor clinical response, although all these progressions in identifying and interpreting biological AML bio-targets. Several small structured FLT3 inhibitors have been ameliorated to struggle against AML. Despite all these developments regarding these inhibitors, the Overall survival rate is about five years or more in less than one-third of diagnosed AML patients. Midostaurin was the first FDA-approved FLT3 inhibitor in 2017 in the United States and Europe for AML remedy. Next, Gilteritinib was an FDA-approved FLT3 inhibitor in 2018 and in the next year, Quizartinib was approved an as FLT3 inhibitor in Japan. Interestingly, indole-based motifs had risen as advantaged scaffolds with unusual multiple kinase inhibitory activity. This review summarises indole-based FLT3 inhibitors and related scaffolds, including FDA-approved drugs, clinical candidates, and other bioactive compounds. Furthermore, their chemotypes, mechanism of action, and interaction mode over both wild and mutated FLT3 target proteins had been judgmentally discussed. Therefore, this review could offer inspiring future perspectives into the finding of new FLT3-related AML therapies.
    Keywords:  Acute myeloid leukemia; FLT3 inhibitors; Indole analogues; Indoles
    DOI:  https://doi.org/10.1186/s13065-023-00981-8
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