bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024‒03‒24
forty-four papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes.
  2. Loss of Dnmt3a increased self-renewal and resistance to pegIFNα in JAK2-V617F-positive myeloproliferative neoplasms.
  3. The TLK-ASF1 histone chaperone pathway plays a critical role in IL-1b-mediated AML progression.
  4. Cancer patients with clonal hematopoiesis die from primary malignancy or comorbidities despite higher rates of transformation to myeloid neoplasms.
  5. Multiomic Profiling of Human Clonal Hematopoiesis Reveals Genotype and Cell-Specific Inflammatory Pathway Activation.
  6. A phase 1 study of the irreversible FLT3 inhibitor FF-10101 in relapsed or refractory acute myeloid leukemia.
  7. Improvements in Posttransplant Outcomes Over Two Decades in Older Patients with Acute Myeloid Leukemia in the EBMT ALWP Study.
  8. Therapy-related chronic myelomonocytic leukemia does not have the high-risk features of a therapy-related neoplasm.
  9. Malignant progression of pre-leukemic disorders.
  10. Using Proton Pump Inhibitors is not Associated With Adverse Outcomes in Patients With Chronic Myeloid Leukemia Treated With Dasatinib.
  11. Clonal hematopoiesis and its impact on the aging osteo-hematopoietic niche.
  12. Targeting hematologic malignancies by inhibiting E-selectin: A sweet spot for AML therapy?
  13. Pracinostat combined with azacitidine in newly diagnosed adult acute myeloid leukemia (AML) patients unfit for standard induction chemotherapy: PRIMULA phase III study.
  14. Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis.
  15. The CDK4/6 inhibitor Palbociclib synergizes with ATRA to induce differentiation in AML.
  16. Treosulfan compared to busulfan in allogeneic haematopoietic stem cell transplantation for myelofibrosis: a registry-based study from the Chronic Malignancies Working Party of the EBMT.
  17. SF3B1 mutations provide genetic vulnerability to copper ionophores in human acute myeloid leukemia.
  18. Differentiation syndrome associated with treatment with IDH2 inhibitor enasidenib - pooled analysis from clinical trials.
  19. Developmental hematopoietic stem cell variation explains clonal hematopoiesis later in life.
  20. Differential in vivo roles of Mpl cytoplasmic tyrosine residues in murine hematopoiesis and myeloproliferative disease.
  21. RAD21 mutations in acute myeloid leukemia.
  22. Impact of CRISPR/HDR editing versus lentiviral transduction on long-term engraftment and clonal dynamics of HSPCs in rhesus macaques.
  23. Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling.
  24. A lineage-specific STAT5BN642H mouse model to study NK-cell leukemia.
  25. Metabolic instruction of the graft-versus-leukemia immunity.
  26. An immunophenotype-coupled transcriptomic atlas of human hematopoietic progenitors.
  27. Loss of RNA-binding protein CELF2 promotes acute leukemia development via FAT10-mTORC1.
  28. Targeting glycolysis to rescue 2-hydroxyglutarate immunosuppressive effects in dendritic cells and acute myeloid leukemia.
  29. RUNX1 C-terminal Mutations Impair Blood Cell Differentiation by Perturbing Specific Enhancer-Promoter Networks.
  30. Calr type 1/like mutation in myelofibrosis is the most prominent predictor of momelotinib drug survival and longevity without transplant.
  31. Comparison of clinical outcomes of several risk stratification tools in newly diagnosed AML patients: A real-world evidence in our current therapeutic era.
  32. Momelotinib for myelofibrosis: our 14 years of experience with 100 clinical trial patients and recent FDA approval.
  33. CD38 and BCL2 expression guides treatment with daratumumab and venetoclax in tagraxofusp-refractory blastic plasmacytoid dendritic cell neoplasm (BPDCN) featuring dynamic loss of CD123.
  34. Management of adult patients with CMML undergoing allo-HCT: recommendations from the EBMT PH&G Committee.
  35. Quantifying NPM1 MRD in AML patients prior to allogeneic stem cell transplantation: Where to draw the line?
  36. Investigations of the prognostic value of RUNX1 mutation in acute myeloid leukemia patients: Data from a real-world study.
  37. Momelotinib vs. ruxolitinib in myelofibrosis patient subgroups by baseline hemoglobin levels in the SIMPLIFY-1 trial.
  38. Resilient anatomy and local plasticity of naive and stress haematopoiesis.
  39. Identification of Red blood cell distribution width as a prognostic factor in acute myeloid leukemia.
  40. Paroxysmal nocturnal hemoglobinuria-related thrombosis in the era of novel therapies: a 2043 patient/years analysis.
  41. Impaired binding affinity of YTHDC1 with METTL3/METTL14 results in R-loop accumulation in myelodysplastic neoplasms with DDX41 mutation.
  42. Unveiling myeloid transformation: T-LGLL with eosinophilia masking myeloid-associated STAT5B mutation culminating in AML.
  43. Leukemia aggressiveness is driven by chromatin remodeling and expression changes of core regulators.
  44. Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1.
  1. Nat Commun. 2024 Mar 18. 15(1): 2428
    Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes.
    Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Feiyang Ma, Kelly Chien, Monica Del Rey, Sanam Loghavi, Guillermo Montalban-Bravo, Vera Adema, Bethany Wildeman, Rashmi Kanagal-Shamanna, Alexandre Bazinet, Helen T Chifotides, Natthakan Thongon, Xavier Calvo, Jesús María Hernández-Rivas, Maria Díez-Campelo, Guillermo Garcia-Manero, Simona Colla.
      The molecular mechanisms of venetoclax-based therapy failure in patients with acute myeloid leukemia were recently clarified, but the mechanisms by which patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated. Here, we show an expansion of MDS hematopoietic stem cells (HSCs) with a granulo-monocytic-biased transcriptional differentiation state in MDS patients who initially responded to venetoclax but eventually relapsed. While MDS HSCs in an undifferentiated cellular state are sensitive to venetoclax treatment, differentiation towards a granulo-monocytic-biased transcriptional state, through the acquisition or expansion of clones with STAG2 or RUNX1 mutations, affects HSCs' survival dependence from BCL2-mediated anti-apoptotic pathways to TNFα-induced pro-survival NF-κB signaling and drives resistance to venetoclax-mediated cytotoxicity. Our findings reveal how hematopoietic stem and progenitor cell (HSPC) can eventually overcome therapy-induced depletion and underscore the importance of using close molecular monitoring to prevent HSPC hierarchical change in MDS patients enrolled in clinical trials of venetoclax.
    DOI:  https://doi.org/10.1038/s41467-024-46424-3
  2. Blood. 2024 Mar 17. pii: blood.2023020270. [Epub ahead of print]
    Loss of Dnmt3a increased self-renewal and resistance to pegIFNα in JAK2-V617F-positive myeloproliferative neoplasms.
    Marc Usart, Jan Stetka, Damien Luque Paz, Nils Hansen, Quentin Kimmerlin, Tiago Almeida Fonseca, Melissa Lock, Lucia Kubovcakova, Riikka Karjalainen, Hui Hao-Shen, Anastasiya Börsch, Athimed El Taher, Jessica Schulz, Jean-Christophe Leroux, Stefan Dirnhofer, Radek C Skoda.
      Pegylated interferon alpha (pegIFNα) can induce molecular remissions in JAK2-V617F-positive myeloproliferative neoplasms (MPN) patients by targeting long-term hematopoietic stem cells (LT-HSCs). Additional somatic mutations in genes regulating LT-HSC self-renewal, such as DNMT3A, have been reported to have poorer responses to pegIFNα. We investigated if DNMT3A loss leads to alterations in JAK2-V617F LT-HSCs functions conferring resistance to pegIFNα treatment in a mouse model of MPN and in hematopoietic progenitors from MPN patients. Long-term treatment with pegIFNα normalized blood parameters, reduced splenomegaly and JAK2-V617F-chimerism in single-mutant JAK2-V617F (VF) mice. However, pegIFNα in VF;Dnmt3aΔ/Δ (VF;DmΔ/Δ) mice worsened splenomegaly and failed to reduce JAK2-V617F-chimerism. Furthermore, LT-HSCs from VF;DmΔ/Δ mice compared to VF were less prone to accumulate DNA damage and exit dormancy upon pegIFNα treatment. RNA-sequencing showed that IFNα induced stronger upregulation of inflammatory pathways in LT-HSCs from VF;DmΔ/Δ compared to VF mice, indicating that the resistance of VF;DmΔ/Δ LT-HSC was not due to failure in IFNα signaling. Transplantations of bone marrow from pegIFNα treated VF;DmΔ/Δ mice gave rise to more aggressive disease in secondary and tertiary recipients. Liquid cultures of hematopoietic progenitors from MPN patients with JAK2-V617F and DNMT3A mutation showed increased percentages of JAK2-V617F-positive colonies upon IFNα exposure, whereas in patients with JAK2-V617F alone the percentages of JAK2-V617F-positive colonies decreased or remained unchanged. PegIFNα combined with 5-azacytidine only partially overcame resistance in VF;DmΔ/Δ mice. However, this combination strongly decreased the JAK2-mutant allele burden in mice carrying VF mutation only, showing potential to inflict substantial damage preferentially to the JAK2-mutant clone.
    DOI:  https://doi.org/10.1182/blood.2023020270
  3. Blood. 2024 Mar 18. pii: blood.2023022079. [Epub ahead of print]
    The TLK-ASF1 histone chaperone pathway plays a critical role in IL-1b-mediated AML progression.
    Hsin-Yun Lin, Mona M Hosseini, John McClatchy, Marina Villamor-Payà, Sophia Jeng, Daniel Bottomly, Chia-Feng Tsai, Camilo Posso, Jeremy Jacobson, Andrew C Adey, Sara J C Gosline, Tao Liu, Shannon K McWeeney, Travis H Stracker, Anupriya Agarwal.
      Identifying and targeting microenvironment-driven pathways that are active across acute myeloid leukemia (AML) genetic subtypes should allow the development of more broadly effective therapies. The pro-inflammatory cytokine IL-1 is abundant in the AML microenvironment and promotes leukemic growth. Through RNA-sequencing analysis, we identify that IL-1 upregulated ASF1B (anti-silencing function-1B), a histone chaperone, in AML progenitors compared to healthy progenitors. ASF1B, along with its paralogous protein ASF1A recruits H3-H4 histones onto the replication fork during S-phase, a process regulated by tousled-like kinase 1 and 2 (TLKs). While ASF1s and TLKs are known to be overexpressed in multiple solid tumors and associated with poor prognosis, their functional roles in hematopoiesis and inflammation-driven leukemia remain unexplored. In this study, we identify that ASF1s and TLKs are over-expressed in multiple genetic subtypes of AML. We demonstrate that depletion of ASF1s significantly reduces leukemic cell growth in both in vitro and in vivo models using human cells. Using a murine model we show that overexpression of ASF1B accelerates leukemia progression. Moreover, Asf1b or Tlk2 deletion delayed leukemia progression while these proteins are dispensable for normal hematopoiesis. Through proteomics and phosphoproteomics analyses, we uncover that the TLK-ASF1 pathway promotes leukemogenesis by impacting the cell cycle and DNA damage pathways. Collectively, our findings identify the TLK1-ASF1 pathway as a novel mediator of inflammatory signaling and a promising therapeutic target for AML treatment across diverse genetic subtypes. Selective inhibition of this pathway offers potential opportunities to intervene effectively, address intratumoral heterogeneity, and ultimately improve clinical outcomes in AML.
    DOI:  https://doi.org/10.1182/blood.2023022079
  4. Cancer Med. 2024 Mar;13(5): e7093
    Cancer patients with clonal hematopoiesis die from primary malignancy or comorbidities despite higher rates of transformation to myeloid neoplasms.
    Kelly S Chien, Faustine Ong, Kunhwa Kim, Ziyi Li, Rashmi Kanagal-Shamanna, Courtney D DiNardo, Koichi Takahashi, Guillermo Montalban-Bravo, Danielle Hammond, Koji Sasaki, Sherry A Pierce, Hagop M Kantarjian, Guillermo Garcia-Manero.
      BACKGROUND: The occurrence of somatic mutations in patients with no evidence of hematological disorders is called clonal hematopoiesis (CH). CH, whose subtypes include CH of indeterminate potential and clonal cytopenia of undetermined significance, has been associated with both hematologic cancers and systemic comorbidities. However, CH's effect on patients, especially those with concomitant malignancies, is not fully understood.METHODS: We performed a retrospective evaluation of all patients with CH at a tertiary cancer center. Patient characteristics, mutational data, and outcomes were collected and analyzed.
    RESULTS: Of 78 individuals included, 59 (76%) had a history of cancer and 60 (77%) had moderate to severe comorbidity burdens. DNMT3A, TET2, TP53, and ASXL1 were the most common mutations. For the entire cohort, the 2-year overall survival rate was 79% (95% CI: 70, 90), while the median survival was not reached. Of 20 observed deaths, most were related to primary malignancies (n = 7, 35%), comorbidities (n = 4, 20%), or myeloid neoplasms (n = 4, 20%). Twelve patients (15%) experienced transformation to a myeloid neoplasm. According to the clonal hematopoiesis risk score, the 3-year transformation rate was 0% in low-risk, 15% in intermediate-risk (p = 0.098), and 28% in high-risk (p = 0.05) patients. By multivariate analysis, transformation was associated with variant allele frequency ≥0.2 and hemoglobin <10 g/dL.
    CONCLUSIONS: In a population including mostly cancer patients, CH was associated with comorbidities and myeloid transformation in patients with higher mutational burdens and anemia. Nevertheless, such patients were less likely to die of their myeloid neoplasm than of primary malignancy or comorbidities.
    Keywords:  CCUS; CHIP; clonal cytopenia of undetermined significance; clonal hematopoiesis; clonal hematopoiesis of indeterminate potential
    DOI:  https://doi.org/10.1002/cam4.7093
  5. Blood Adv. 2024 Mar 20. pii: bloodadvances.2023011445. [Epub ahead of print]
    Multiomic Profiling of Human Clonal Hematopoiesis Reveals Genotype and Cell-Specific Inflammatory Pathway Activation.
    Jonathan Brett Heimlich, Pawan Bhat, Alyssa Parker, Matthew T Jenkins, Caitlyn Vlasschaert, Jessica Ulloa, Joseph Van Amburg, Chad R Potts, Sydney Olson, Alexander J Silver, Ayesha Ahmad, Brian Sharber, Donovan Brown, Ningning Hu, Peter van Galen, Michael R Savona, Alexander G Bick, Paul Brent Ferrell.
      Clonal hematopoiesis (CH) is an age-associated phenomenon that increases risk for hematologic malignancy and cardiovascular disease. CH is thought to enhance disease risk through inflammation in the peripheral blood1. Here, we profile peripheral blood gene expression in 66,968 single cells from a cohort of 17 CH patients and 7 controls. Using a novel mitochondrial DNA barcoding approach, we were able to identify and separately compare mutant TET2 and DNMT3A cells to non-mutant counterparts. We discovered the vast majority of mutated cells were in the myeloid compartment. Additionally, patients harboring DNMT3A and TET2 CH mutations possessed a pro-inflammatory profile in CD14+ monocytes through previously unrecognized pathways such as galectin and macrophage Inhibitory Factor (MIF). We also found that T cells from CH patients, though mostly un-mutated, had decreased expression of GTPase of the immunity associated protein (GIMAP) genes, which are critical to T cell development, suggesting that CH impairs T cell function.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011445
  6. Blood Adv. 2024 Mar 19. pii: bloodadvances.2023010619. [Epub ahead of print]
    A phase 1 study of the irreversible FLT3 inhibitor FF-10101 in relapsed or refractory acute myeloid leukemia.
    Mark J Levis, Alexander E Perl, Gary J Schiller, Amir T Fathi, Gail J Roboz, Eunice S Wang, Jessica K Altman, Trivikram Rajkhowa, Makoto Ando, Takeaki Suzuki, Ruth Ann Subach, Gary Maier, Timothy Madden, Mary Johansen, Kin Cheung, Michael Kurman, Catherine C Smith.
      FLT3 tyrosine kinase inhibitors (TKIs) have clinical efficacy for patients with FLT3-mutated AML (acute myeloid leukemia), but their impact is limited by resistance in the setting of monotherapy and by tolerability problems when used in combination therapies. FF-10101 is a novel compound that covalently binds to a cysteine residue near the active site of FLT3, irreversibly inhibiting receptor signaling. It is effective against most FLT3 activating mutations, and unlike other inhibitors is minimally vulnerable to resistance induced by FLT3 ligand (FL). We conducted a phase 1 dose escalation study of oral FF-10101 (NCT03194685) in patients with relapsed and/or refractory AML, the majority of whom harbored FLT3-activating mutations and/or had prior exposure to FLT3 inhibitors. Fifty-four participants enrolled in cohorts ranging from 10 to 225 mg per day and 50 to 100 mg twice daily (BID). The dose limiting toxicities (DLT) were diarrhea and QT prolongation. Among 40 response-evaluable participants, the composite complete response rate was 10%, and the overall response rate (including partial responses) was 12.5%, including patients who had progressed on gilteritinib. 56% of participants had prior exposure to FLT3 inhibitors. The recommended phase 2 dose (RP2D) was 75 mg BID. FF-10101 potentially represents a next-generation advance in the management of FLT3-mutated AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010619
  7. Clin Cancer Res. 2024 Mar 22. OF1-OF10
    Improvements in Posttransplant Outcomes Over Two Decades in Older Patients with Acute Myeloid Leukemia in the EBMT ALWP Study.
    Ali Bazarbachi, Myriam Labopin, Nour Moukalled, Nicolaus Kröger, Christina Rautenberg, Johannes Schetelig, Jürgen Finke, Igor Wolfgang Blau, Didier Blaise, Matthias Stelljes, Matthias Eder, Uwe Platzbecker, Peter Dreger, Wolfgang Bethge, Johanna Tischer, David Burns, Henrik Sengeloev, Eolia Brissot, Sebastian Giebel, Arnon Nagler, Fabio Ciceri, Mohamad Mohty.
      PURPOSE: Acute myeloid leukemia (AML) is a disease of older patients. Progress in allogeneic hematopoietic cell transplantation (allo-HCT) allowed the delivery of allo-HCT to older patients. We assessed changes over time in transplant characteristics and outcomes in patients with AML ages 65 years and above.PATIENTS AND METHODS: We identified 7,215 patients with AML (median age 68 years, range 65-80) allografted between 2000 and 2021 in first complete remission (CR1; 64%), second or subsequent remission (CR2+; 14%), or active disease (22%).
    RESULTS: Median follow-up was 40 months. The 3-year cumulative relapse incidence (RI) gradually and significantly decreased from 37% to 31%, then to 30% (P = 0.001) over the three time periods (2000-2009; 2010-2014; 2015-2021), whereas nonrelapse mortality (NRM) decreased from 31% and 31% to 27% (P = 0.003). The 3-year leukemia-free survival (LFS) and overall survival (OS) gradually and significantly improved from 32% to 38%, and then to 44% (P = 0.001) and from 37% to 42%, and then to 49% (P = 0.001), respectively. In multivariate analysis, significant improvement in the RI, LFS, and OS were noted after 2015, whereas NRM was not significantly affected. This improvement was observed regardless of disease status at transplant.
    CONCLUSIONS: In older patients with AML, we observed an impressive improvement over time in posttransplant outcomes, mostly attributed to decreased RI rather than decreased NRM, and regardless of disease status at transplant. These large-scale, real-world data can serve as a benchmark for future studies in this setting and indicate that the opportunity for transplant for the elderly should be mandatory and no longer an option.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-3673
  8. Blood Adv. 2024 Mar 21. pii: bloodadvances.2024012565. [Epub ahead of print]
    Therapy-related chronic myelomonocytic leukemia does not have the high-risk features of a therapy-related neoplasm.
    Alex Bataller, Georgina Gener-Ricos, Emmanuel Almanza, Kelly Sharon Chien, Samuel Urrutia, Alexandre Bazinet, Juan Jose Rodriguez-Sevilla, Danielle Hammond, Koji Sasaki, Koichi Takahashi, Courtney D DiNardo, Farhad Ravandi, Gautam Borthakur, Tapan M Kadia, Rashmi Kanagal-Shamanna, Hagop M Kantarjian, Guillermo Garcia-Manero, Guillermo Montalban-Bravo.
      Therapy-related myeloid neoplasms (t-MNs) arise after exposure to cytotoxic therapies and are associated with high-risk genetic features and poor outcomes. We analyzed a cohort of patients with therapy-related chronic myelomonocytic leukemia (tCMML; n = 71) and compared its features to that of de novo CMML (dnCMML; n = 461). Median time from cytotoxic therapy to tCMML diagnosis was 6.5 years. Compared with dnCMML, chromosome 7 abnormalities (4% vs. 13%; P = .005), but not complex karyotype (3% vs. 7%; P = .15), were more frequent in tCMML. tCMML was characterized by higher TP53 mutation frequency (4% vs. 12%; P = .04) and lower NRAS (6% vs 22%, P =0.007) and CBL (4% vs 12%, P =0.04) mutation frequency. Prior therapy with antimetabolites (OR, 1.22 [95% CI, 1.05-1.42]; P = .01) and mitotic inhibitors (OR, 1.24 [95% CI, 1.06-1.44]; P = .009) was associated with NF1 and SETBP1 mutations while prior mitotic inhibitor therapy was associated with lower TET2 mutation frequency (OR, 0.71 [95% CI, 0.55-0.92]; P = .01). Although no differences in median overall survival (OS) were observed among tCMML and dnCMML (34.7 months vs 35.9 months, P = .26), multivariate analysis for OS revealed that prior chemotherapy was associated with increased risk of death (HR 1.76 [95% CI, 1.07-2.89]; P = .026). Compared to a cohort of therapy-related myelodysplastic syndrome, tCMML had lower TP53 mutation frequency (12% vs 44.4%, P <.001) and less unfavorable outcomes. In summary, tCMML does not exhibit the high-risk features and poor outcomes of t-MNs.
    DOI:  https://doi.org/10.1182/bloodadvances.2024012565
  9. Blood. 2024 Mar 18. pii: blood.2023020817. [Epub ahead of print]
    Malignant progression of pre-leukemic disorders.
    Trent Hall, Sandeep Gurbuxani, John D Crispino.
      The spectrum of myeloid disorders ranges from aplastic bone marrow failure characterized by an empty bone marrow completely lacking in hematopoiesis to acute myeloid leukemia where the marrow space is replaced by undifferentiated leukemic blasts. Recent advances in the capacity to sequence bulk tumor population as well as at a single cell level has provided significant insight into the stepwise process of transformation to acute myeloid leukemia. Using models of progression in the context of germline predisposition (trisomy 21, GATA2 deficiency, SAMD9/9L syndrome), premalignant states (clonal hematopoiesis and clonal cytopenia of unknown significance) and myelodysplastic syndrome, we review the mechanisms of progression focusing on the hierarchy of clonal mutation and potential roles of transcription factor alterations, splicing factor mutations and the bone marrow environment in progression to acute myeloid leukemia. Despite major advances in our understanding, preventing progression of these disorders or treating them at the acute leukemia phase remains a major area of unmet medical need.
    DOI:  https://doi.org/10.1182/blood.2023020817
  10. Clin Lymphoma Myeloma Leuk. 2024 Feb 29. pii: S2152-2650(24)00092-2. [Epub ahead of print]
    Using Proton Pump Inhibitors is not Associated With Adverse Outcomes in Patients With Chronic Myeloid Leukemia Treated With Dasatinib.
    Fadi G Haddad, Cedric Nasnas, Koji Sasaki, Shilpa Paul, Ghayas C Issa, Caitlin Rausch, Elias Jabbour, Hagop Kantarjian.
      
    Keywords:  Antacid; H2 blocker; Response; Tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1016/j.clml.2024.02.014
  11. Leukemia. 2024 Mar 21.
    Clonal hematopoiesis and its impact on the aging osteo-hematopoietic niche.
    Susann Winter, Katharina S Götze, Judith S Hecker, Klaus H Metzeler, Borhane Guezguez, Kevin Woods, Hind Medyouf, Alexander Schäffer, Marc Schmitz, Rebekka Wehner, Ingmar Glauche, Ingo Roeder, Martina Rauner, Lorenz C Hofbauer, Uwe Platzbecker.
      Clonal hematopoiesis (CH) defines a premalignant state predominantly found in older persons that increases the risk of developing hematologic malignancies and age-related inflammatory diseases. However, the risk for malignant transformation or non-malignant disorders is variable and difficult to predict, and defining the clinical relevance of specific candidate driver mutations in individual carriers has proved to be challenging. In addition to the cell-intrinsic mechanisms, mutant cells rely on and alter cell-extrinsic factors from the bone marrow (BM) niche, which complicates the prediction of a mutant cell's fate in a shifting pre-malignant microenvironment. Therefore, identifying the insidious and potentially broad impact of driver mutations on supportive niches and immune function in CH aims to understand the subtle differences that enable driver mutations to yield different clinical outcomes. Here, we review the changes in the aging BM niche and the emerging evidence supporting the concept that CH can progressively alter components of the local BM microenvironment. These alterations may have profound implications for the functionality of the osteo-hematopoietic niche and overall bone health, consequently fostering a conducive environment for the continued development and progression of CH. We also provide an overview of the latest technology developments to study the spatiotemporal dependencies in the CH BM niche, ideally in the context of longitudinal studies following CH over time. Finally, we discuss aspects of CH carrier management in clinical practice, based on work from our group and others.
    DOI:  https://doi.org/10.1038/s41375-024-02226-6
  12. Blood Rev. 2024 Feb 28. pii: S0268-960X(24)00017-1. [Epub ahead of print] 101184
    Targeting hematologic malignancies by inhibiting E-selectin: A sweet spot for AML therapy?
    Geoffrey L Uy, Daniel J DeAngelo, Jay N Lozier, Dennis M Fisher, Brian A Jonas, John L Magnani, Pamela S Becker, Hillard M Lazarus, Ingrid G Winkler.
      E-selectin, a cytoadhesive glycoprotein, is expressed on venular endothelial cells and mediates leukocyte localization to inflamed endothelium, the first step in inflammatory cell extravasation into tissue. Constitutive marrow endothelial E-selectin expression also supports bone marrow hematopoiesis via NF-κB-mediated signaling. Correspondingly, E-selectin interaction with E-selectin ligand (sialyl Lewisx) on acute myeloid leukemia (AML) cells leads to chemotherapy resistance in vivo. Uproleselan (GMI-1271) is a carbohydrate analog of sialyl Lewisx that blocks E-selectin binding. A Phase 2 trial of MEC chemotherapy combined with uproleselan for relapsed/refractory AML showed a median overall survival of 8.8 months and low (2%) rates of severe oral mucositis. Clinical trials seek to confirm activity in AML and mitigation of neutrophil-mediated adverse events (mucositis and diarrhea) after intensive chemotherapy. In this review we summarize E-selectin biology and the rationale for uproleselan in combination with other therapies for hematologic malignancies. We also describe uproleselan pharmacology and ongoing clinical trials.
    Keywords:  Acute myeloid leukemia (AML); E-selectin; Hematologic malignancies; Selectin; Uproleselan
    DOI:  https://doi.org/10.1016/j.blre.2024.101184
  13. Leuk Res. 2024 Mar 12. pii: S0145-2126(24)00046-8. [Epub ahead of print]140 107480
    Pracinostat combined with azacitidine in newly diagnosed adult acute myeloid leukemia (AML) patients unfit for standard induction chemotherapy: PRIMULA phase III study.
    Guillermo Garcia-Manero, Maciej Kazmierczak, Agnieszka Wierzbowska, Chun Yew Fong, Michael K Keng, Gianluca Ballinari, Francesco Scarci, Lionel Adès.
      Non-intensive therapies such as the hypomethylating agent (HMA) azacitidine (AZA) have been used in patients with AML ineligible for intensive induction chemotherapy (IC) or stem cell transplant due to advanced age, comorbidities, and/or risk factors. However, response rates and survival remain dismal. Pre-clinical studies indicate the epigenetic combination of HMAs and HDAC inhibitors induce re-expression of silenced genes synergistically. The activity of pracinostat, an oral pan-HDAC inhibitor, has been shown in xenograft tumor models of AML and promising efficacy was seen in a Phase 2 study. This Phase 3 study (NCT03151408) evaluated the efficacy/safety of pracinostat administered with AZA in adult patients with newly diagnosed AML ineligible to receive IC. Patients were randomized to either pracinostat plus AZA or placebo/AZA and stratified by cytogenetic risk and ECOG status. As planned, an interim analysis was performed when 232/390 events (deaths) occurred. A total of 406 patients were randomized (203/group) at the time of the analysis. Median overall survival was 9.95 months for both treatment groups (p=0.8275). There was no significant difference between treatments in secondary efficacy endpoints, reflecting a lack of clinical response. This study did not show a benefit of adding pracinostat to AZA in elderly patients unfit for IC.
    Keywords:  AML; Azacitidine; HDAC inhibitor; Hypomethylating agent; Pracinostat
    DOI:  https://doi.org/10.1016/j.leukres.2024.107480
  14. Nat Commun. 2024 Mar 15. 15(1): 2340
    Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis.
    Maryam Ghashghaei, Yilin Liu, James Ettles, Giuseppe Bombaci, Niveditha Ramkumar, Zongmin Liu, Leo Escano, Sandra Spencer Miko, Yerin Kim, Joseph A Waldron, Kim Do, Kyle MacPherson, Katie A Yuen, Thilelli Taibi, Marty Yue, Aaremish Arsalan, Zhen Jin, Glenn Edin, Aly Karsan, Gregg B Morin, Florian Kuchenbauer, Fabiana Perna, Martin Bushell, Ly P Vu.
      Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML.
    DOI:  https://doi.org/10.1038/s41467-024-46665-2
  15. Mol Cancer Ther. 2024 Mar 20.
    The CDK4/6 inhibitor Palbociclib synergizes with ATRA to induce differentiation in AML.
    Linhui Hu, Qian Li, Jiyu Wang, Huiping Wang, Xiyang Ren, Keke Huang, Yangyang Wang, Xue Liang, Lianfang Pu, Shudao Xiong, Zhimin Zhai.
      Differentiation therapy based on ATRA almost cured acute promyelocytic leukemia (APL). However, it is disappointing that ATRA is not effective against other acute myeloid leukemia (AML) subtypes. Developing new and effective anti-AML therapies that promote leukemia differentiation is necessary. The CDK4/6-cyclin D pathway is a key initiator of the G1/S phase transition, which determines cell fate. Herein, we investigated whether the CDK4/6 inhibitor palbociclib would synergize with ATRA to promote leukemia differentiation in vitro and in vivo. Our findings revealed that CDK4/6-cyclin D pathway genes were aberrantly expressed in AML, and we observed that palbociclib sensitized AML cells to ATRA-induced morphologic, biochemical, and functional changes indicative of myeloid differentiation. The combination of palbociclib and ATRA attenuated AML cell expansion in vivo. These enhanced differentiation effects may be associated with the regulation of transcription factors, including RARα, E2F1, and STAT1. Overall, our findings demonstrate that CDK4/6 inhibition sensitizes AML cells to ATRA and could guide the development of novel therapeutic strategies for AML patients.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-23-0528
  16. Bone Marrow Transplant. 2024 Mar 15.
    Treosulfan compared to busulfan in allogeneic haematopoietic stem cell transplantation for myelofibrosis: a registry-based study from the Chronic Malignancies Working Party of the EBMT.
    Marie Robin, Simona Iacobelli, Linda Koster, Jakob Passweg, Daniele Avenoso, Keith M O Wilson, Urpu Salmenniemi, Peter Dreger, Peter von dem Borne, John A Snowden, Stephen Robinson, Maria Chiara Finazzi, Thomas Schroeder, Matthew Collin, Matthias Eder, Edouard Forcade, Michael Loschi, Stefania Bramanti, Jose Antonio Pérez-Simón, Tomasz Czerw, Nicola Polverelli, Joanna Drozd-Sokolowska, Kavita Raj, Juan Carlos Hernández-Boluda, Donal P McLornan.
      We aimed to compare outcomes following treosulfan (TREO) or busulfan (BU) conditioning in a large cohort of myelofibrosis (MF) patients from the EBMT registry. A total of 530 patients were included; 73 received TREO and 457 BU (BU ≤ 6.4 mg/kg in 134, considered RIC, BU > 6.4 mg/kg in 323 considered higher dose (HD)). Groups were compared using adjusted Cox models. Cumulative incidences of engraftment and acute GVHD were similar across the 3 groups. The TREO group had significantly better OS than BU-HD (HR:0.61, 95% CI: 0.39-0.93) and a trend towards better OS over BU-RIC (HR: 0.66, 95% CI: 0.41-1.05). Moreover, the TREO cohort had a significantly better Progression-Free-Survival (PFS) than both the BU-HD (HR: 0.57, 95% CI: 0.38-0.84) and BU-RIC (HR: 0.60, 95% CI: 0.39-0.91) cohorts, which had similar PFS estimates. Non-relapse mortality (NRM) was reduced in the TREO and BU-RIC cohorts (HR: 0.44, 95% CI: 0.24-0.80 TREO vs BU-HD; HR: 0.54, 95% CI: 0.28-1.04 TREO vs BU-RIC). Of note, relapse risk did not significantly differ across the three groups. In summary, within the limits of a registry-based study, TREO conditioning may improve PFS in MF HSCT and have lower NRM than BU-HD with a similar relapse risk to BU-RIC. Prospective studies are needed to confirm these findings.
    DOI:  https://doi.org/10.1038/s41409-024-02269-4
  17. Sci Adv. 2024 Mar 22. 10(12): eadl4018
    SF3B1 mutations provide genetic vulnerability to copper ionophores in human acute myeloid leukemia.
    Céline Moison, Deanne Gracias, Julie Schmitt, Simon Girard, Jean-François Spinella, Simon Fortier, Isabel Boivin, Rodrigo Mendoza-Sanchez, Bounkham Thavonekham, Tara MacRae, Nadine Mayotte, Eric Bonneil, Mark Wittman, James Carmichael, Réjean Ruel, Pierre Thibault, Josée Hébert, Anne Marinier, Guy Sauvageau.
      In a phenotypical screen of 56 acute myeloid leukemia (AML) patient samples and using a library of 10,000 compounds, we identified a hit with increased sensitivity toward SF3B1-mutated and adverse risk AMLs. Through structure-activity relationship studies, this hit was optimized into a potent, specific, and nongenotoxic molecule called UM4118. We demonstrated that UM4118 acts as a copper ionophore that initiates a mitochondrial-based noncanonical form of cell death known as cuproptosis. CRISPR-Cas9 loss-of-function screen further revealed that iron-sulfur cluster (ISC) deficiency enhances copper-mediated cell death. Specifically, we found that loss of the mitochondrial ISC transporter ABCB7 is synthetic lethal to UM4118. ABCB7 is misspliced and down-regulated in SF3B1-mutated leukemia, creating a vulnerability to copper ionophores. Accordingly, ABCB7 overexpression partially rescued SF3B1-mutated cells to copper overload. Together, our work provides mechanistic insights that link ISC deficiency to cuproptosis, as exemplified by the high sensitivity of SF3B1-mutated AMLs. We thus propose SF3B1 mutations as a biomarker for future copper ionophore-based therapies.
    DOI:  https://doi.org/10.1126/sciadv.adl4018
  18. Blood Adv. 2024 Mar 20. pii: bloodadvances.2023011914. [Epub ahead of print]
    Differentiation syndrome associated with treatment with IDH2 inhibitor enasidenib - pooled analysis from clinical trials.
    Pau Montesinos, Amir T Fathi, Stéphane de Botton, Eytan M Stein, Amer M Zeidan, Yue Zhu, Thomas Prebet, Carlos Enrique Vigil, Iryna Bluemmert, Xin Yu, Courtney D DiNardo.
      Treatment with enasidenib, a selective mutant-IDH2 inhibitor, has been associated with the development of differentiation syndrome (DS) in patients with acute myeloid leukemia (AML). Studies on the incidence and clinical features of DS are limited in this setting, and diagnosis is challenging due to non-specific symptoms. This study assessed the incidence, diagnostic criteria, risk factors, and correlation with clinical response of DS based on the pooled analysis of 4 clinical trials in patients with IDH2-mutated AML treated with enasidenib as monotherapy, or in combination with azacitidine or with chemotherapy. Across the total AML population, 10.4% (67/643) had ≥1 any-grade DS event, with highest incidence in patients who received enasidenib plus azacitidine and lowest incidence in patients who received enasidenib plus chemotherapy (17.6% [13/74] and 2.2% [2/93]). The most common symptoms of DS were dyspnea/hypoxia (80.6%) and pulmonary infiltrate (73.1%). Median time to onset of first DS event across all studies was 32 days (range: 4-129 days). Most patients (88.1%) received systemic steroids for treatment of DS. Evaluation of baseline risk factors for DS identified higher levels of bone marrow blasts and lactate dehydrogenase as independent factors associated with increased grade 3-5 DS risk. Overall, these results suggest that DS associated with IDH inhibition is manageable, given the benefits of enasidenib treatment in IDH2-mutated AML. We further characterized enasidenib-related DS in these patients and identified risk factors, which could be used for DS management in clinical practice. Clinical Trials #: NCT01915498, NCT02577406, NCT02677922, NCT02632708.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011914
  19. bioRxiv. 2024 Mar 05. pii: 2024.03.02.583106. [Epub ahead of print]
    Developmental hematopoietic stem cell variation explains clonal hematopoiesis later in life.
    Jesse Kreger, Jazlyn A Mooney, Darryl Shibata, Adam L MacLean.
      Clonal hematopoiesis becomes increasingly common with age, but its cause is enigmatic because driver mutations are often absent. Serial observations infer weak selection indicating variants are acquired much earlier in life with unexplained initial growth spurts. Here we use fluctuating CpG methylation as a lineage marker to track stem cell clonal dynamics of hematopoiesis. We show, via the shared prenatal circulation of monozygotic twins, that weak selection conferred by stem cell variation created before birth can reliably yield clonal hematopoiesis later in life. Theory indicates weak selection will lead to dominance given enough time and large enough population sizes. Human hematopoiesis satisfies both these conditions. Stochastic loss of weakly selected variants is naturally prevented by the expansion of stem cell lineages during development. The dominance of stem cell clones created before birth is supported by blood fluctuating CpG methylation patterns that exhibit low correlation between unrelated individuals but are highly correlated between many elderly monozygotic twins. Therefore, clonal hematopoiesis driven by weak selection in later life appears to reflect variation created before birth.
    DOI:  https://doi.org/10.1101/2024.03.02.583106
  20. Leukemia. 2024 Mar 15.
    Differential in vivo roles of Mpl cytoplasmic tyrosine residues in murine hematopoiesis and myeloproliferative disease.
    Kira Behrens, Maria Kauppi, Elizabeth M Viney, Andrew J Kueh, Craig D Hyland, Tracy A Willson, Liam Salleh, Carolyn A de Graaf, Jeffrey J Babon, Marco J Herold, Nicos A Nicola, Warren S Alexander.
      Thrombopoietin (Tpo), which binds to its specific receptor, the Mpl protein, is the major cytokine regulator of megakaryopoiesis and circulating platelet number. Tpo binding to Mpl triggers activation of Janus kinase 2 (Jak2) and phosphorylation of the receptor, as well as activation of several intracellular signalling cascades that mediate cellular responses. Three tyrosine (Y) residues in the C-terminal region of the Mpl intracellular domain have been implicated as sites of phosphorylation required for regulation of major Tpo-stimulated signalling pathways: Mpl-Y565, Mpl-Y599 and Mpl-Y604. Here, we have introduced mutations in the mouse germline and report a consistent physiological requirement for Mpl-Y599, mutation of which resulted in thrombocytopenia, deficient megakaryopoiesis, low hematopoietic stem cell (HSC) number and function, and attenuated responses to myelosuppression. We further show that in models of myeloproliferative neoplasms (MPN), where Mpl is required for pathogenesis, thrombocytosis was dependent on intact Mpl-Y599. In contrast, Mpl-Y565 was required for negative regulation of Tpo responses; mutation of this residue resulted in excess megakaryopoiesis at steady-state and in response to myelosuppression, and exacerbated thrombocytosis associated with MPN.
    DOI:  https://doi.org/10.1038/s41375-024-02219-5
  21. Leuk Lymphoma. 2024 Mar 20. 1-7
    RAD21 mutations in acute myeloid leukemia.
    Dorottya Laczko, Corey Poveda-Rogers, Andrew H Matthews, Oraine Snaith, Selina Luger, Adam Bagg, Gabriel C Caponetti, Jennifer J D Morrissette, Guang Yang.
      The cohesin complex is a ring-shaped protein structure involved in DNA repair and chromosomal segregation. Studies have showed that genomic alterations in the cohesin complex members are among the initial occurrences in the development of acute myeloid leukemia (AML). STAG2 is the most commonly mutated and best-studied member of the cohesin complex in AML and mutations in this gene have been associated with adverse outcomes and are diagnostically relevant. However, the exact role of mutations in other members of the cohesin complex in the development of myeloid neoplasia is controversial. In this single institution study, we retrospectively reviewed data from the molecular profiles of 1,381 AML patients and identified 14 patients with mutations in RAD21, another member of the cohesin complex. We evaluated the frequency, mutational profile, clinico-pathologic features, and prognostic impact of RAD21 in this cohort. This study showed that RAD21-mutated AML often associates with monocytic differentiation, CD7 expression, co-existing mutations in epigenetic regulators, a normal karyotype, and poor prognosis. Our findings provide additional insights into the morphologic, immunophenotypic, and genomic profile of RAD21 mutation-positive AML and suggest that RAD21 mutations should be evaluated for independent prognostic significance in AML.
    Keywords:  AML; RAD21; cohesin; mutation
    DOI:  https://doi.org/10.1080/10428194.2024.2328233
  22. Cell Stem Cell. 2024 Mar 12. pii: S1934-5909(24)00053-5. [Epub ahead of print]
    Impact of CRISPR/HDR editing versus lentiviral transduction on long-term engraftment and clonal dynamics of HSPCs in rhesus macaques.
    Byung-Chul Lee, Ashley Gin, Chuanfeng Wu, Komudi Singh, Max Grice, Ryland Mortlock, Diana Abraham, Xing Fan, Yifan Zhou, Aisha AlJanahi, Uimook Choi, Suk See DeRavin, Taehoon Shin, Sogun Hong, Cynthia E Dunbar.
      For precise genome editing via CRISPR/homology-directed repair (HDR), effective and safe editing of long-term engrafting hematopoietic stem cells (LT-HSCs) is required. The impact of HDR on true LT-HSC clonal dynamics in a relevant large animal model has not been studied. To track the output and clonality of HDR-edited cells and to provide a comparison to lentivirally transduced HSCs in vivo, we developed a competitive rhesus macaque (RM) autologous transplantation model, co-infusing HSCs transduced with a barcoded GFP-expressing lentiviral vector (LV) and HDR edited at the CD33 locus. CRISPR/HDR-edited cells showed a two-log decrease by 2 months following transplantation, with little improvement via p53 inhibition, in comparison to minimal loss of LV-transduced cells long term. HDR long-term clonality was oligoclonal in contrast to highly polyclonal LV-transduced HSCs. These results suggest marked clinically relevant differences in the impact of current genetic modification approaches on HSCs.
    Keywords:  CRISPR-Cas editing; HSC gene therapy; ex vivo; genetic barcoding; hematopoietic stem cells; homology-directed repair; lentiviral gene addition; precise genome editing; rhesus macaque
    DOI:  https://doi.org/10.1016/j.stem.2024.02.010
  23. Cell Death Discov. 2024 Mar 19. 10(1): 147
    Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling.
    Ana Carolina B da C Rodrigues, Suellen L R Silva, Ingrid R S B Dias, Rafaela G A Costa, Maiara de S Oliveira, Milena B P Soares, Rosane B Dias, Ludmila F Valverde, Clarissa A G Rocha, Emily M Johnson, Cristina Pina, Daniel P Bezerra.
      Acute myeloid leukaemia (AML) is a haematological malignancy characterised by the accumulation of transformed myeloid progenitors in the bone marrow. Piplartine (PL), also known as piperlongumine, is a pro-oxidant small molecule extracted from peppers that has demonstrated antineoplastic potential in solid tumours and other haematological malignancies. In this work, we explored the potential of PL to treat AML through the use of a combination of cellular and molecular analyses of primary and cultured leukaemia cells in vitro and in vivo. We showed that PL exhibits in vitro cytotoxicity against AML cells, including CD34+ leukaemia-propagating cells, but not healthy haematopoietic progenitors, suggesting anti-leukaemia selectivity. Mechanistically, PL treatment increased reactive oxygen species (ROS) levels and induced ROS-mediated apoptosis in AML cells, which could be prevented by treatment with the antioxidant scavenger N-acetyl-cysteine and the pancaspase inhibitor Z-VAD(OMe)-FMK. PL treatment reduced NFKB1 gene transcription and the level of NF-κB p65 (pS536), which was depleted from the nucleus of AML cells, indicating suppression of NF-κB p65 signalling. Significantly, PL suppressed AML development in a mouse xenograft model, and its combination with current AML treatments (cytarabine, daunorubicin and azacytidine) had synergistic effects, indicating translational therapeutic potential. Taken together, these data position PL as a novel anti-AML candidate drug that can target leukaemia stem/progenitors and is amenable to combinatorial therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41420-024-01909-4
  24. Blood. 2024 Mar 18. pii: blood.2023022655. [Epub ahead of print]
    A lineage-specific STAT5BN642H mouse model to study NK-cell leukemia.
    Klara Klein, Sebastian Kollmann, Angela Hiesinger, Julia List, Jonatan Kendler, Thorsten Klampfl, Mehak Randhawa, Jana Trifinopoulos, Barbara Maurer, Reinhard Grausenburger, Christof A Bertram, Richard H Moriggl, Thomas Rülicke, Charles G Mullighan, Agnieszka Witalisz-Siepracka, Wencke Walter, Gregor Hoermann, Veronika Sexl, Dagmar Gotthardt.
      Patients with T- and NK-cell neoplasms frequently have somatic STAT5B gain-of-function mutations. The most frequent STAT5B mutation is STAT5BN642H, which is known to drive murine T-cell leukemia although its role in NK-cell malignancies is unclear. Introduction of the STAT5BN642H mutation into human NK-cell lines enhances their potential to induce leukemia in mice. We have generated a mouse model that enables tissue-specific expression of STAT5BN642H and have selectively expressed the mutated STAT5B in hematopoietic cells (N642Hvav/+) or exclusively in NK cells (N642HNK/NK). All N642Hvav/+ mice rapidly develop an aggressive T-/NK T-cell leukemia, whereas N642HNK/NK mice display an indolent NK-large granular lymphocytic leukemia (NK-LGLL) that progresses to an aggressive leukemia with age. Samples from NK-cell leukemia patients have a distinctive transcriptional signature driven by mutant STAT5B, which overlaps with that of murine leukemic N642HNK/NK NK cells. We have generated the first reliable STAT5BN642H-driven pre-clinical mouse model that displays an indolent NK-LGLL progressing to aggressive NK-cell leukemia. This novel in vivo tool will enable us to explore the transition from an indolent to an aggressive disease and will thus permit the study of prevention and treatment options for NK-cell malignancies.
    DOI:  https://doi.org/10.1182/blood.2023022655
  25. Front Immunol. 2024 ;15 1347492
    Metabolic instruction of the graft-versus-leukemia immunity.
    Ann-Cathrin Burk, Petya Apostolova.
      Allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed to cure hematological malignancies, such as acute myeloid leukemia (AML), through the graft-versus-leukemia (GVL) effect. In this immunological process, donor immune cells eliminate residual cancer cells in the patient and exert tumor control through immunosurveillance. However, GVL failure and subsequent leukemia relapse are frequent and associated with a dismal prognosis. A better understanding of the mechanisms underlying AML immune evasion is essential for developing novel therapeutic strategies to boost the GVL effect. Cellular metabolism has emerged as an essential regulator of survival and cell fate for both cancer and immune cells. Leukemia and T cells utilize specific metabolic programs, including the orchestrated use of glucose, amino acids, and fatty acids, to support their growth and function. Besides regulating cell-intrinsic processes, metabolism shapes the extracellular environment and plays an important role in cell-cell communication. This review focuses on recent advances in the understanding of how metabolism might affect the anti-leukemia immune response. First, we provide a general overview of the mechanisms of immune escape after allo-HCT and an introduction to leukemia and T cell metabolism. Further, we discuss how leukemia and myeloid cell metabolism contribute to an altered microenvironment that impairs T cell function. Next, we review the literature linking metabolic processes in AML cells with their inhibitory checkpoint ligand expression. Finally, we focus on recent findings concerning the role of systemic metabolism in sustained GVL efficacy. While the majority of evidence in the field still stems from basic and preclinical studies, we discuss translational findings and propose further avenues for bridging the gap between bench and bedside.
    Keywords:  T cells; acute myeloid leukemia; allogeneic hematopoietic cell transplantation; anti-tumor immunity; graft-versus-leukemia effect; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2024.1347492
  26. Nat Immunol. 2024 Mar 21.
    An immunophenotype-coupled transcriptomic atlas of human hematopoietic progenitors.
    Xuan Zhang, Baobao Song, Maximillian J Carlino, Guangyuan Li, Kyle Ferchen, Mi Chen, Evrett N Thompson, Bailee N Kain, Dan Schnell, Kairavee Thakkar, Michal Kouril, Kang Jin, Stuart B Hay, Sidharth Sen, David Bernardicius, Siyuan Ma, Sierra N Bennett, Josh Croteau, Ornella Salvatori, Melvin H Lye, Austin E Gillen, Craig T Jordan, Harinder Singh, Diane S Krause, Nathan Salomonis, H Leighton Grimes.
      Analysis of the human hematopoietic progenitor compartment is being transformed by single-cell multimodal approaches. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) enables coupled surface protein and transcriptome profiling, thereby revealing genomic programs underlying progenitor states. To perform CITE-seq systematically on primary human bone marrow cells, we used titrations with 266 CITE-seq antibodies (antibody-derived tags) and machine learning to optimize a panel of 132 antibodies. Multimodal analysis resolved >80 stem, progenitor, immune, stromal and transitional cells defined by distinctive surface markers and transcriptomes. This dataset enables flow cytometry solutions for in silico-predicted cell states and identifies dozens of cell surface markers consistently detected across donors spanning race and sex. Finally, aligning annotations from this atlas, we nominate normal marrow equivalents for acute myeloid leukemia stem cell populations that differ in clinical response. This atlas serves as an advanced digital resource for hematopoietic progenitor analyses in human health and disease.
    DOI:  https://doi.org/10.1038/s41590-024-01782-4
  27. Oncogene. 2024 Mar 21.
    Loss of RNA-binding protein CELF2 promotes acute leukemia development via FAT10-mTORC1.
    Tengxiao Guo, Yuxia Wang, Xiaolu Sun, Shuaibing Hou, Yanjie Lan, Shengnan Yuan, Shuang Yang, Fei Zhao, Yajing Chu, Yuanwu Ma, Tao Cheng, Jia Yu, Bing Liu, Weiping Yuan, Xiaomin Wang.
      RNA-binding proteins (RBPs) are critical regulators for RNA transcription and translation. As a key member of RBPs, ELAV-like family protein 2 (CELF2) has been shown to regulate RNA splicing and embryonic hematopoietic development and was frequently seen dysregulated in acute myeloid leukemia (AML). However, the functional role(s) of CELF2 in hematopoiesis and leukemogenesis has not been fully elucidated. In the current study, we showed that Celf2 deficiency in hematopoietic system led to enhanced HSCs self-renewal and differentiation toward myeloid cells in mice. Loss of Celf2 accelerated myeloid cell transformation and AML development in MLL-AF9-induced AML murine models. Gene expression profiling integrated with RNA immunoprecipitation sequencing (RIP-Seq), together with biochemical experiments revealed that CELF2 deficiency stabilizes FAT10 mRNA, promotes FAT10 translation, thereby increases AKT phosphorylation and mTORC1 signaling pathway activation. Notably, combination therapy with a mTORC1 inhibitor (Rapamycin) and a MA9/DOTL1 inhibitor (EPZ-5676) reduced the leukemia burden in MLL-AF9 mice lacking Celf2 in vivo. Our study elucidated a novel mechanism by which the CELF2/FAT10-AKT/mTORC1 axis regulates the proliferation of normal blood cells and the development of AML, thus providing potential therapeutic targets for myeloid leukemia suppression.
    DOI:  https://doi.org/10.1038/s41388-024-03006-3
  28. Haematologica. 2024 Mar 14.
    Targeting glycolysis to rescue 2-hydroxyglutarate immunosuppressive effects in dendritic cells and acute myeloid leukemia.
    Angela Maria Savino, Lucille Stuani.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2023.284893
  29. Blood Adv. 2024 Mar 21. pii: bloodadvances.2023011484. [Epub ahead of print]
    RUNX1 C-terminal Mutations Impair Blood Cell Differentiation by Perturbing Specific Enhancer-Promoter Networks.
    Nathan Daniel Jayne, Zhengyu Liang, Do-Hwan Lim, Poshen Benson Chen, Cristina Diaz, Kei-Ichiro Arimoto, Lingbo Xia, Mengdan Liu, Bing Ren, Xiang-Dong Fu, Dong-Er Zhang.
      The transcription factor RUNX1 is a master regulator of hematopoiesis and is frequently mutated in myeloid malignancies. Mutations in its runt homology domain (RHD) frequently disrupt DNA binding and result in loss of RUNX1 function. However, it is not clearly understood how other RUNX1 mutations contribute to disease development. Here, we characterize RUNX1 mutations outside of the RHD. Our analysis of patient datasets revealed that mutations within the C-terminus frequently occur in hematopoietic disorders. Remarkably, most of these mutations were nonsense or frameshift and predicted to be exempt from nonsense mediated mRNA decay. Therefore, this class of mutation is projected to produce DNA-binding proteins that contribute to pathogenesis in a distinct manner. To model this, we introduced the RUNX1R320* mutation into the endogenous gene locus and demonstrated the production of RUNX1R320* protein. Expression of RUNX1R320* resulted in the disruption of RUNX1 regulated processes such as megakaryocytic differentiation through a transcriptional signature different from RUNX1 depletion. To understand the underlying mechanisms, we utilized Global RNA Interactions with DNA by deep sequencing (GRID-seq) to examine enhancer-promoter connections. We identified wide-spread alteration of enhancer-promoter networks within RUNX1 mutant cells. Additionally, we uncovered enrichment of RUNX1R320* and FOXK2 binding at the MYC super enhancer locus, significantly upregulating MYC transcription and signaling pathways. Together, our study demonstrates that most RUNX1 mutations outside the DNA binding domain are not subject to nonsense mediated decay, producing protein products that act in concert with additional cofactors to dysregulate hematopoiesis through mechanisms distinct from that induced by RUNX1 depletion.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011484
  30. Blood Cancer J. 2024 Mar 19. 14(1): 51
    Calr type 1/like mutation in myelofibrosis is the most prominent predictor of momelotinib drug survival and longevity without transplant.
    Ayalew Tefferi, Animesh Pardanani, Kebede H Begna, Aref Al-Kali, William J Hogan, Mark R Litzow, Rhett P Ketterling, Kaaren K Reichard, Naseema Gangat.
      
    DOI:  https://doi.org/10.1038/s41408-024-01028-4
  31. Cancer Med. 2024 Mar;13(6): e7103
    Comparison of clinical outcomes of several risk stratification tools in newly diagnosed AML patients: A real-world evidence in our current therapeutic era.
    Alexandre Iat, Michael Loschi, Sami Benachour, Anne Calleja, Edmond Chiche, Isabelle Sudaka, Danièle Aquaronne, Corinne Ferrero, Laurène Fenwarth, Alice Marceau, Elise Fournier, Berengere Dadone-Montaudie, Thomas Cluzeau.
      BACKGROUND OF THE STUDY: AML classification tools have been developed to stratify the risk at AML diagnosis. There is a need to evaluate these tools in the current therapeutic era.COHORT CHARACTERISTICS: In this retrospective study, we compared five classifiers: ELN 2017, ELN 2022, ALFA classifier, Papaemmanuil et al. classifier, and Lindsley et al. classifier, in a real-life cohort of 281 patients newly diagnosed for AML in Nice University Hospital. In our cohort median age was 68 years old, sex ratio was M/F 56%/44%, performance status was lower than 2 in 73.1% of patients, AML subtype was "De novo" in 71.5%, "secondary" in 22.4%, and "therapy-related" in 6.0% of patients. Intensive chemotherapy was used in 53.0% of patients, and non-intensive chemotherapy in 40.6% of patients. Molecular analysis was available in a large majority of patients and the main mutations found were NPM1 (22.7%), DNMT3A (17.4%), TP53 (13.1%), TET2 (12.4%), and FLT3-ITD (12.4%).
    RESULTS: In our findings, the comparison of overall survival between the three prognostic groups in the global cohort was statistically significant in all classifiers: ELN 2017 p < 0.0001, ELN 2022 p < 0.0001, ALFA classifier p < 0.0001, Papaemmanuil classifier p < 0.0001, Lindsley classifier p = 0.001. ELN 2017, ELN 2022, ALFA classifier, Papaemmanuil classifier, and Lindsley classifier were calculated respectively in 99%, 99%, 89%, 90%, and 89% of patients.
    CONCLUSIONS: Using Akaike's information criteria (AIC) to compare all five classifiers, ELN 2022 is the best classifier into younger and older patients and for prognosis.
    Keywords:  AML; ELN; WHO; classifier; prognosis
    DOI:  https://doi.org/10.1002/cam4.7103
  32. Blood Cancer J. 2024 Mar 18. 14(1): 47
    Momelotinib for myelofibrosis: our 14 years of experience with 100 clinical trial patients and recent FDA approval.
    Ayalew Tefferi, Animesh Pardanani.
      
    DOI:  https://doi.org/10.1038/s41408-024-01029-3
  33. Leuk Res. 2024 Mar 11. pii: S0145-2126(24)00045-6. [Epub ahead of print]139 107479
    CD38 and BCL2 expression guides treatment with daratumumab and venetoclax in tagraxofusp-refractory blastic plasmacytoid dendritic cell neoplasm (BPDCN) featuring dynamic loss of CD123.
    Xiaoyi Hu, Asiri Ediriwickrema, Atif Saleem, Brent Tan, Naveen Pemmaraju, Gabriel N Mannis.
      
    Keywords:  BPDCN; CD123; Daratumumab; Tagraxofusp; Venetoclax
    DOI:  https://doi.org/10.1016/j.leukres.2024.107479
  34. Blood. 2024 Mar 17. pii: blood.2023023476. [Epub ahead of print]
    Management of adult patients with CMML undergoing allo-HCT: recommendations from the EBMT PH&G Committee.
    Francesco Onida, Nico Gagelmann, Yves Chalandon, Guido Kobbe, Marie Robin, Argiris Symeonidis, Theo M de Witte, Raphaël A Itzykson, Madlen Jentzsch, Uwe Platzbecker, Valeria Santini, Guillermo F Sanz, Christoph Scheid, Eric Solary, Peter Valent, Raffaela Greco, Isabel Sánchez-Ortega, Ibrahim Yakoub-Agha, Lisa Pleyer.
      Chronic myelomonocytic leukemia (CMML) is a heterogeneous disease presenting with either myeloproliferative or myelodysplastic features. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative option, but the inherent toxicity of this procedure makes the decision to proceed to allo-HCT challenging, particularly as patients with CMML are mostly older and comorbid. Therefore, the decision between a non-intensive treatment approach and allo-HCT represents a delicate balance, especially since prospective randomized studies are lacking and retrospective data in the literature is conflicting. International consensus on the selection of patients and the ideal timing of allo-HCT specifically in CMML could not be reached in international recommendations published six years ago. Since then, new, CMML-specific data have been published. The European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines Committee assembled a panel of experts in the field to provide the first best practice recommendations on the role of allo-HCT specifically in CMML. Recommendations were based on the results of an international survey, a comprehensive review of the literature, and expert opinions on the subject, after structured discussion and circulation of recommendations. Algorithms for patient selection, timing of allo-HCT during the course of the disease, pre-transplant strategies, allo-HCT modality, as well as post-transplant management for patients with CMML were outlined.
    DOI:  https://doi.org/10.1182/blood.2023023476
  35. Hemasphere. 2024 Mar;8(3): e55
    Quantifying NPM1 MRD in AML patients prior to allogeneic stem cell transplantation: Where to draw the line?
    Sebastian Schwind, Lara Bischof, Marius Bill, Juliane Grimm, Jule Ussmann, Donata Backhaus, Dominic Brauer, Tung Pham Thanh, Maximilian Merz, Georg-Nikolaus Franke, Klaus H Metzeler, Vladan Vucinic, Marco Herling, Uwe Platzbecker, Madlen Jentzsch.
      
    DOI:  https://doi.org/10.1002/hem3.55
  36. Leuk Res. 2024 Mar 12. pii: S0145-2126(24)00049-3. [Epub ahead of print]139 107483
    Investigations of the prognostic value of RUNX1 mutation in acute myeloid leukemia patients: Data from a real-world study.
    Chao-Ling Wan, Yuan-Hong Huang, Si-Man Huang, Yan-Li Xu, Kai-Wen Tan, Yan-Qiu, Xiang-Dong Shen, Shuai-Shuai Ge, Han-Yu Cao, Yan-Yan Li, Song-Bai Liu, Jia-Jun Qi, Hai-Ping Dai, Sheng-Li Xue.
      RUNX1 is one of the recurrent mutated genes in newly diagnosed acute myeloid leukemia (AML). Although historically recognized as a provisional distinct entity, the AML subtype with RUNX1 mutations (AML-RUNX1mut) was eliminated from the 2022 WHO classification system. To gain more insight into the characteristics of AML-RUNX1mut, we retrospectively analyzed 1065 newly diagnosed adult AML patients from the First Affiliated Hospital of Soochow University between January 2017 and December 2021. RUNX1 mutations were identified in 112 patients (10.5%). The presence of RUNX1 mutation (RUNX1mut) conferred a lower composite complete remission (CRc) rate (40.2% vs. 58.4%, P＜0.001), but no significant difference was observed in the 5-year overall survival (OS) rate (50.2% vs. 53.9%; HR=1.293; P=0.115) and event-free survival (EFS) rate (51.5% vs. 49.4%; HR=1.487, P=0.089), even within the same risk stratification. Multivariate analysis showed that RUNX1mut was not an independent prognostic factor for OS (HR=1.352, P=0.068) or EFS (HR=1.129, P=0.513). When patients were stratified according to induction regimen, RUNX1mut was an unfavorable factor for CRc both on univariate and multivariate analysis in patients receiving conventional chemotherapy, and higher risk stratification predicted worse OS. In those who received venetoclax plus hypomethylating agents, RUNX1mut was not predictive of CRc and comparable OS and EFS were seen between intermediate-risk and adverse-risk groups. The results of this study revealed that the impact of RUNX1mut is limited. Its prognostic value depended more on treatment and co-occurrent abnormalities. VEN-HMA may abrogate the prognostic impact of RUNX1, which merits a larger prospective cohort to illustrate.
    Keywords:  Acute myeloid leukemia; Prognosis; RUNX1 mutation; Risk stratification
    DOI:  https://doi.org/10.1016/j.leukres.2024.107483
  37. Leuk Lymphoma. 2024 Mar 19. 1-13
    Momelotinib vs. ruxolitinib in myelofibrosis patient subgroups by baseline hemoglobin levels in the SIMPLIFY-1 trial.
    Vikas Gupta, Stephen Oh, Timothy Devos, Viviane Dubruille, John Catalano, Tim C P Somervaille, Uwe Platzbecker, Pilar Giraldo, Hiroshi Kosugi, Tomasz Sacha, Jiri Mayer, Arpad Illes, Catherine Ellis, Zhaohui Wang, Francisco J Gonzalez Carreras, Bryan Strouse, Ruben Mesa.
      A key hallmark of myelofibrosis is anemia, which ranges from mild to severe based on hemoglobin levels. To more clearly define outcomes with the Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib by anemia severity, we performed a descriptive post hoc exploratory analysis of the double-blind, randomized, phase 3 SIMPLIFY-1 study (NCT01969838; N = 432, JAK inhibitor naive, momelotinib vs. ruxolitinib); subgroups were defined by baseline hemoglobin: <10 (moderate/severe), ≥10 to <12 (mild), or ≥12 g/dL (nonanemic). Spleen and symptom results were generally consistent with those previously reported for the intent-to-treat population. In anemic subgroups, momelotinib was associated with higher rates of transfusion independence and reduced/stable transfusion intensity vs. ruxolitinib. No new or unexpected safety signals were identified. Overall, momelotinib provides spleen, symptom, and anemia benefits to JAK inhibitor-naive patients with myelofibrosis regardless of baseline hemoglobin level, and greater anemia-related benefits vs. ruxolitinib in patients with hemoglobin <12 g/dL.
    Keywords:  Anemia; hemoglobin; momelotinib; myelofibrosis; ruxolitinib; transfusion independence
    DOI:  https://doi.org/10.1080/10428194.2024.2328800
  38. Nature. 2024 Mar 20.
    Resilient anatomy and local plasticity of naive and stress haematopoiesis.
    Qingqing Wu, Jizhou Zhang, Sumit Kumar, Siyu Shen, Morgan Kincaid, Courtney B Johnson, Yanan Sophia Zhang, Raphaël Turcotte, Clemens Alt, Kyoko Ito, Shelli Homan, Bryan E Sherman, Tzu-Yu Shao, Anastasiya Slaughter, Benjamin Weinhaus, Baobao Song, Marie Dominique Filippi, H Leighton Grimes, Charles P Lin, Keisuke Ito, Sing Sing Way, J Matthew Kofron, Daniel Lucas.
      The bone marrow adjusts blood cell production to meet physiological demands in response to insults. The spatial organization of normal and stress responses are unknown owing to the lack of methods to visualize most steps of blood production. Here we develop strategies to image multipotent haematopoiesis, erythropoiesis and lymphopoiesis in mice. We combine these with imaging of myelopoiesis1 to define the anatomy of normal and stress haematopoiesis. In the steady state, across the skeleton, single stem cells and multipotent progenitors distribute through the marrow enriched near megakaryocytes. Lineage-committed progenitors are recruited to blood vessels, where they contribute to lineage-specific microanatomical structures composed of progenitors and immature cells, which function as the production sites for each major blood lineage. This overall anatomy is resilient to insults, as it was maintained after haemorrhage, systemic bacterial infection and granulocyte colony-stimulating factor (G-CSF) treatment, and during ageing. Production sites enable haematopoietic plasticity as they differentially and selectively modulate their numbers and output in response to insults. We found that stress responses are variable across the skeleton: the tibia and the sternum respond in opposite ways to G-CSF, and the skull does not increase erythropoiesis after haemorrhage. Our studies enable in situ analyses of haematopoiesis, define the anatomy of normal and stress responses, identify discrete microanatomical production sites that confer plasticity to haematopoiesis, and uncover unprecedented heterogeneity of stress responses across the skeleton.
    DOI:  https://doi.org/10.1038/s41586-024-07186-6
  39. Exp Hematol. 2024 Mar 18. pii: S0301-472X(24)00065-1. [Epub ahead of print] 104206
    Identification of Red blood cell distribution width as a prognostic factor in acute myeloid leukemia.
    Qiaoxue Liu, Yujia Zhai, Yan Hui, Jiayuan Chen, Yingchang Mi, Jianxiang Wang, Hui Wei.
      Many prognostic factors have been identified in acute myeloid leukemia (AML). In this study, we investigated the novel prognostic biomarkers using machine learning and cox regression models in a prospective cohort of 591 AML patients and tried to identify potential therapeutic targets based on transcriptomic data. We found that elevated red blood cell distribution width (RDW) at diagnosis was an adverse prognostic factor for AML independent of 2022 European LeukemiaNet (ELN2022) genetic risk. As a continuous variable, higher RDW was associated with shorter OS (HR 1.087, 95% CI 1.036-1.139, P<0.001) and EFS (HR 1.078, 95% CI 1.033-1.124, P<0.001). Elevated RDW returned to normal after consolidation therapy, which indicated that leukemia cells resulted in abnormal RDW. We further investigated the relationship between RDW and transcriptome in another cohort of 191 AML patients and public datasets by GSEA and CIBERSORT. We found that patients in the high RDW group were significantly enriched in the positive regulation of erythroid differentiation and inflammation-related pathways. Finally, we identified the inflammation-associated gene IL12RB2, and verified its prognostic relevance with AML patients in public databases, suggesting it as a potential therapy target.
    Keywords:  acute myeloid leukemia; immune microenvironment; machine learning; red blood cell distribution width; therapeutic target
    DOI:  https://doi.org/10.1016/j.exphem.2024.104206
  40. Blood. 2024 Mar 21. pii: blood.2024023988. [Epub ahead of print]
    Paroxysmal nocturnal hemoglobinuria-related thrombosis in the era of novel therapies: a 2043 patient/years analysis.
    Carmelo Gurnari, Hussein Awada, Simona Pagliuca, Danai Dima, Fauzia Ullah, Naomi Kawashima, Yasuo Kubota, Ceylan Colak, Valeria Visconte, Bhumika J Patel, Vikram Dhillon, Naimisha Marneni, Suresh Kumar Balasubramanian, Ashwin Kishtagari, Taha Bat, Jaroslaw P Maciejewski.
      Thrombophilia is one of the principal features of paroxysmal nocturnal hemoglobinuria (PNH) and constitutes the main cause of disease morbidity/mortality. Anti-complement treatment has revolutionized the natural history of PNH with control of the hemolytic process and abolition of thrombotic events (TE). However, no guidelines exist for the management of thromboembolic complications in this setting, with type and duration of anti-coagulation depending on individual practices. Besides, a scarcity of data is present on the efficacy of direct oral anti-coagulants (DOACs). Herein, we accrued a large real-world cohort of PNH patients from four US centers to explore features, predictors of TE and anti-coagulation strategies. Among 267 patients followed-up for a total of 2043 patient/years, 56 (21%) developed TE. This occurred at disease onset in 43% of cases, involving more frequently the venous system, typically as Budd-Chiari syndrome. Rate of TE was halved in patients receiving complement inhibitors (21 vs 40 TE per 1000 patient/years in untreated cases, with a 2-year cumulative incidence of thrombosis of 3.9% vs 18.3% respectively), and varied according to PNH granulocytes and erythrocytes clone size, type, disease activity parameters, as well as number (>2 mutations or less) and variant allelic frequency of PIGA mutations. Anti-coagulation with warfarin (39%), DOACs (37%), and low-molecular-weight heparin (16%) was administered for a median of 29 months (9-61.8). No thrombotic recurrence was observed in 19 patients treated with DOACs at a median observation of 17.1 months (8.9-45) while 14 cases discontinued anti-coagulation without TE recurrence at a median time of 51.4 months (29.9-86.8).
    DOI:  https://doi.org/10.1182/blood.2024023988
  41. Leukemia. 2024 Mar 21.
    Impaired binding affinity of YTHDC1 with METTL3/METTL14 results in R-loop accumulation in myelodysplastic neoplasms with DDX41 mutation.
    Won Chan Hwang, Kibeom Park, Silvia Park, Na Young Cheon, Ja Yil Lee, Taejoo Hwang, Semin Lee, Jong-Mi Lee, Min Kyung Ju, Joo Rak Lee, Yong-Rim Kwon, Woo-Lam Jo, Myungshin Kim, Yoo-Jin Kim, Hongtae Kim.
      DEAD box helicase 41 (DDX41) mutations are the most prevalent predisposition to familial myelodysplastic syndrome (MDS). However, the precise roles of these variants in the pathogenesis of MDS have yet to be elucidated. Here, we discovered a novel mechanism by which DDX41 contributes to R-loop-induced DNA damage responses (DDR) in cooperation with the m6A-METTL complex (MAC) and YTHDC1 using DDX41 knockout (KO) and DDX41 knock-in (KI, R525H, Y259C) cell lines as well as primary samples from MDS patients. Compared to wild type (WT), DDX41 KO and KI led to increased levels of m6A RNA methylated R-loop. Interestingly, we found that DDX41 regulates m6A/R-loop levels by interacting with MAC components. Further, DDX41 promoted the recruitment of YTHDC1 to R-loops by promoting the binding between METTL3 and YTHDC1, which was dysregulated in DDX41-deficient cells, contributing to genomic instability. Collectively, we demonstrated that DDX41 plays a key role in the physiological control of R-loops in cooperation with MAC and YTHDC1. These findings provide novel insights into how defects in DDX41 influence MDS pathogenesis and suggest potential therapeutic targets for the treatment of MDS.
    DOI:  https://doi.org/10.1038/s41375-024-02228-4
  42. Br J Haematol. 2024 Mar 20.
    Unveiling myeloid transformation: T-LGLL with eosinophilia masking myeloid-associated STAT5B mutation culminating in AML.
    Qianze Dong, Yang Wang, Yan Xiu, Xiaogang Wu, Stacey O'Neill, Howard Meyerson, Suske Tobias, Richard Moriggl, Shimin Hu, Wei Wang, Chen Zhao.
      
    DOI:  https://doi.org/10.1111/bjh.19421
  43. bioRxiv. 2024 Mar 04. pii: 2024.02.29.582846. [Epub ahead of print]
    Leukemia aggressiveness is driven by chromatin remodeling and expression changes of core regulators.
    Gracia Bonilla, Alexander Morris, Sharmistha Kundu, Anthony Ducasse, Nathan E Jeffries, Kashish Chetal, Emma E Yvanovich, Rana Barghout, David Scadden, Michael K Mansour, Robert E Kingston, David B Sykes, Francois E Mercier, Ruslan I Sadreyev.
      Molecular mechanisms driving clonal aggressiveness in leukemia are not fully understood. We tracked and analyzed two mouse MLL-rearranged leukemic clones independently evolving towards higher aggressiveness. More aggressive subclones lost their growth differential ex vivo but restored it upon secondary transplantation, suggesting molecular memory of aggressiveness. Development of aggressiveness was associated with clone-specific gradual modulation of chromatin states and expression levels across the genome, with a surprising preferential trend of reversing the earlier changes between normal and leukemic progenitors. To focus on the core aggressiveness program, we identified genes with consistent changes of expression and chromatin marks that were maintained in vivo and ex vivo in both clones. Overexpressing selected core genes (Smad1 as aggressiveness driver, Irx5 and Plag1 as suppressors) affected leukemic progenitor growth in the predicted way and had convergent downstream effects on central transcription factors and repressive epigenetic modifiers, suggesting a broader regulatory network of leukemic aggressiveness.
    DOI:  https://doi.org/10.1101/2024.02.29.582846
  44. Mol Cell. 2024 Mar 11. pii: S1097-2765(24)00176-X. [Epub ahead of print]
    Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1.
    Tristen Wright, Meghan E Turnis, Christy R Grace, Xiao Li, Lauren A Brakefield, Yong-Dong Wang, Haiyan Xu, Ewa Kaminska, Leslie K Climer, Tresor O Mukiza, Chi-Lun Chang, Tudor Moldoveanu, Joseph T Opferman.
      MCL-1 is essential for promoting the survival of many normal cell lineages and confers survival and chemoresistance in cancer. Beyond apoptosis regulation, MCL-1 has been linked to modulating mitochondrial metabolism, but the mechanism(s) by which it does so are unclear. Here, we show in tissues and cells that MCL-1 supports essential steps in long-chain (but not short-chain) fatty acid β-oxidation (FAO) through its binding to specific long-chain acyl-coenzyme A (CoA) synthetases of the ACSL family. ACSL1 binds to the BH3-binding hydrophobic groove of MCL-1 through a non-conventional BH3-domain. Perturbation of this interaction, via genetic loss of Mcl1, mutagenesis, or use of selective BH3-mimetic MCL-1 inhibitors, represses long-chain FAO in cells and in mouse livers and hearts. Our findings reveal how anti-apoptotic MCL-1 facilitates mitochondrial metabolism and indicate that disruption of this function may be associated with unanticipated cardiac toxicities of MCL-1 inhibitors in clinical trials.
    Keywords:  MCL-1; acyl-coenzyme A synthetase; apoptosis; fatty acid; metabolism; mitochondria; β-oxidation
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.035
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