bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–04–20
27 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis.
  2. Enhanced FLI1 accessibility mediates STAG2-mutant leukemogenesis.
  3. Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation.
  4. The ENHANCE-3 study: venetoclax and azacitidine plus magrolimab or placebo for untreated AML unfit for intensive therapy.
  5. Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.
  6. Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs.
  7. Prognostic Significance of Monocytic-like Phenotype in AML patients treated with Venetoclax and Azacytidine.
  8. IL1RAP is an immunotherapeutic target for normal karyotype triple-mutated acute myeloid leukemia.
  9. Reduced venetoclax exposure to 7 days vs standard exposure with hypomethylating agents in newly diagnosed AML patients.
  10. CD37 regulates the self-renewal of leukemic stem cells via integrin-mediated signaling in acute myeloid leukemia.
  11. A Phase 1 Study of FHD-286, a Dual BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, in Patients With Advanced Myeloid Malignancies.
  12. The Immune-Modulatory Function of Megakaryocytes in the Hematopoietic Niche of Myeloproliferative Neoplasms.
  13. DNMT3A mutations are unlikely to affect interferon alfa treatment outcomes in patients with polycythemia vera.
  14. A germline ETV6 mutation disrupts hematopoiesis via de novo creation of a nuclear export signal.
  15. Mutant CEBPA promotes tolerance to inflammatory stress through deficient AP-1 activation.
  16. GVHD prophylaxis in matched related stem cell transplantation: Why post-transplant cyclophosphamide can be recommended a study by the EBMT transplant complications working party.
  17. Polycythaemia vera.
  18. The impact of ABO compatibility on allogeneic hematopoietic cell transplantation outcomes: a contemporary and comprehensive study from the transplant complications working party of the EBMT.
  19. Impact of Clonal Hematopoiesis on Solid Tumor Progression Following Radiation Therapy.
  20. How I individualize treatment for chronic-phase CML.
  21. Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.
  22. BMAL1-depletion remodels ceramide metabolism to regulate ferroptosis and sorafenib chemosensitivity in acute myeloid leukemia.
  23. Prognostic scoring systems in chronic myeloid leukaemia.
  24. RUNX1 is a key inducer of human hematopoiesis controlling non-hematopoietic mesodermal development.
  25. Dysregulation of sphingolipid metabolism contributes to the pathogenesis of chronic myeloid leukemia.
  26. Real world outcomes of momelotinib in myelofibrosis patients with anemia: results from the MOMGEMFIN study.
  27. Canagliflozin May Increase Thromboembolic Events in Males With Erythrocytosis but Not in Females.
  1. Nature. 2025 Apr 16.
    Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis.
    Malgorzata Gozdecka, Monika Dudek, Sean Wen, Muxin Gu, Richard J Stopforth, Justyna Rak, Aristi Damaskou, Guinevere L Grice, Matthew A McLoughlin, Laura Bond, Rachael Wilson, George Giotopoulos, Vijaya Mahalingam Shanmugiah, Rula Bany Bakar, Eliza Yankova, Jonathan L Cooper, Nisha Narayan, Sarah J Horton, Ryan Asby, Dean C Pask, Annalisa Mupo, Graham Duddy, Ludovica Marando, Theodoros Georgomanolis, Paul Carter, Amirtha Priya Ramesh, William G Dunn, Clea Barcena, Paolo Gallipoli, Kosuke Yusa, Slavé Petrovski, Penny Wright, Pedro M Quiros, Christian Frezza, James A Nathan, Arthur Kaser, Siddhartha Kar, Konstantinos Tzelepis, Jonathan Mitchell, Margarete A Fabre, Brian J P Huntly, George S Vassiliou.
      Somatic DNMT3A R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk1,2. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3aR882H/+ HSPCs. Amongst the 640 vulnerability genes identified, many were involved in mitochondrial metabolism and metabolic flux analysis confirmed enhanced oxidative phosphorylation usage in Dnmt3aR882H/+ vs Dnmt3a+/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies. In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin, suppressed post-transplantation clonal expansion of Dnmt3aR882H/+, but not WT, LT-HSC. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank (UKB) participants revealed that individuals taking metformin had markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.
    DOI:  https://doi.org/10.1038/s41586-025-08980-6
  2. bioRxiv. 2025 Apr 03. pii: 2025.04.01.646632. [Epub ahead of print]
    Enhanced FLI1 accessibility mediates STAG2-mutant leukemogenesis.
    Jane J Xu, Viviana Scoca, Yi Chen, Yingqian A Zhan, Alexander Fisher, Eno-Obong Udoh, Sebastian Fernando, Besmira Alija, John Pantazi, Varun Sudunagunta, Edna Stewart, Anabella Maria D Galang, Mike Williams, Govind Bhagat, Claudia Gebhard, Valeria Visconte, Sarah Ondrejka, Ruud Delwel, Ming Hu, Richard Koche, Aaron D Viny.
      Transcription factors (TFs) influencing cell fate can be dysregulated in cancer. FLI1 is crucial for hematopoietic stem/progenitor cell (HSPC) function, with STAG2 regulating FLI1 target accessibility. STAG2 depletion enhances HSPC self-renewal, but its role in leukemic transformation is unclear. We uncovered that STAG2 loss maintains FLI1 target accessibility in murine HSPCs and enhances FLI1 binding in NPM1c leukemia. In our Stag2/Npm1c/+ murine model, myeloid-biased HSPCs with increased FLI1 accessibility are reservoirs for transformation, leading to a fully penetrant leukemia. STAG2 deleted NPM1c cell lines exhibit increased chromatin accessibility and chromatin-looping of key stem and leukemia genes including FLI1-target genes CD34 and MEN1. Similarly, enrichment for a CD34+ immunophenotype was observed in co-mutant leukemia patients. STAG2 deficient cells show increased chromatin-bound MENIN and increased sensitivity to MENIN inhibition. Our findings demonstrate that altered chromatin architecture can co-opt oncogenic TF signaling, such as FLI1, as a hallmark of leukemogenesis.
    Key Findings: Loss of STAG2 results in aberrant increased accessibility at FLI1 targets in mouse and human hematopoietic stem and progenitor cellsIncreased accessibility results in an increased fraction of chromatin-bound FLI1, which overlap with NPM1c targets in STAG2 NPM1c AML cellsStag2 Npm1c co-mutation leads to dysplastic murine AML phenotype arising from myeloid biased progenitors that exhibit increased Fli1 target accessibilityIn addition to higher chromatin-bound FLI1, co-mutant cells have higher chromatin-bound MENIN, including at the HOXA cluster, rendering cells highly sensitive to MENIN inhibition.
    Statement of Significance: Here, we identify enhanced FLI1 chromatin accessibility as a driver of stemness and leukemic transformation in STAG2 mutant leukemia. Through comprehensive in vivo and in vitro modeling, we demonstrate that altered chromatin architecture can co-opt oncogenic TF activity, like FLI1, to drive divergent leukemia development and therapeutic response.
    DOI:  https://doi.org/10.1101/2025.04.01.646632
  3. Nature. 2025 Apr 16.
    Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation.
    Amir Hosseini, Abhinav Dhall, Nemo Ikonen, Natalia Sikora, Sylvain Nguyen, Yuqi Shen, Maria Luisa Jurgensen Amaral, Alan Jiao, Felice Wallner, Philipp Sergeev, Yuhua Lim, Yuanqin Yang, Binje Vick, Kimihito Cojin Kawabata, Ari Melnick, Paresh Vyas, Bing Ren, Irmela Jeremias, Bethan Psaila, Caroline A Heckman, M Andrés Blanco, Yang Shi.
      Impaired differentiation is a hallmark of myeloid malignancies1,2. Therapies that enable cells to circumvent the differentiation block, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), are by and large curative in acute promyelocytic leukaemia3, but whether 'differentiation therapy' is a generalizable therapeutic approach for acute myeloid leukaemia (AML) and beyond remains incompletely understood. Here we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the WNT pathway antagonist GSK3 kinase4 (GSK3i) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumour burden and significantly extending survival in a patient-derived xenograft mouse model. Mechanistically, this combination promotes differentiation by activating genes in the type I interferon pathway via inducing expression of transcription factors such as IRF7 (LSD1i) and the co-activator β-catenin (GSK3i), and their selective co-occupancy at targets such as STAT1, which is necessary for combination-induced differentiation. Combination treatment also suppresses the canonical, pro-oncogenic WNT pathway and cell cycle genes. Analysis of datasets from patients with AML suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, this combination strategy rewires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and WNT-driven cancers beyond AML.
    DOI:  https://doi.org/10.1038/s41586-025-08915-1
  4. Blood. 2025 Apr 15. pii: blood.2024027506. [Epub ahead of print]
    The ENHANCE-3 study: venetoclax and azacitidine plus magrolimab or placebo for untreated AML unfit for intensive therapy.
    Naval G Daver, Paresh Vyas, Gerwin A Huls, Hartmut Döhner, Sebastien Maury, Jan Novak, Cristina Papayannidis, Carmen Martinez Chamorro, Pau Montesinos, Rabin Niroula, Pierre Fenaux, Jordi Esteve, Shang-Ju Wu, Adrien De Voeght, Jiri Mayer, Peter J M Valk, Lisa Johnson, Mei Dong, Ke Liu, Sowmya Banda Kuwahara, Kenneth Caldwell, Guru Subramanian Guru Murthy.
      Patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC) have limited treatment options. The phase 3 ENHANCE-3 study aimed to determine whether magrolimab (magrolimab arm) was superior to placebo (control arm) when either was combined with venetoclax and azacitidine. Adults with previously untreated AML who were ineligible for IC were randomized to receive magrolimab (1 mg/kg on days 1 and 4, 15 mg/kg on day 8, 30 mg/kg on days 11 and 15, then weekly for 5 weeks, then every 2 weeks) or placebo, venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg daily thereafter), and azacitidine (75 mg/m2 days 1-7) in 28-day cycles. The primary endpoint was overall survival (OS); key secondary endpoints included complete remission (CR) rate and safety. After randomization of 378 patients, the trial was stopped at a prespecified interim analysis due to futility. At final analysis, with median follow-up of 7.6 months (magrolimab arm) vs 7.4 months (control arm), median OS was 10.7 vs 14.1 months (HR, 1.178 [95% CI, 0.848-1.637]). The CR rate within 6 cycles was 41.3% vs 46.0%. Addition of magrolimab to venetoclax and azacitidine resulted in more fatal adverse events (19.0% vs 11.4%), primarily driven by grade 5 infections (11.1% vs 6.5%) and respiratory events (2.6% vs 0%). There were similar incidences of any-grade infections, febrile neutropenia, and neutropenia between arms. These results highlight the difficulty in improving outcomes for patients with AML ineligible for IC. This trial was registered at www.clinicaltrials.gov as #NCT05079230.
    DOI:  https://doi.org/10.1182/blood.2024027506
  5. Nat Commun. 2025 Apr 16. 16(1): 3306
    Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.
    Kira A Young, Mohsen Hosseini, Jayna J Mistry, Claudia Morganti, Taylor S Mills, Xiurong Cai, Brandon T James, Griffin J Nye, Natalie R Fournier, Veronique Voisin, Ali Chegini, Aaron D Schimmer, Gary D Bader, Grace Egan, Marc R Mansour, Grant A Challen, Eric M Pietras, Kelsey H Fisher-Wellman, Keisuke Ito, Steven M Chan, Jennifer J Trowbridge.
      The competitive advantage of mutant hematopoietic stem and progenitor cells (HSPCs) underlies clonal hematopoiesis (CH). Drivers of CH include aging and inflammation; however, how CH-mutant cells gain a selective advantage in these contexts is an unresolved question. Using a murine model of CH (Dnmt3aR878H/+), we discover that mutant HSPCs sustain elevated mitochondrial respiration which is associated with their resistance to aging-related changes in the bone marrow microenvironment. Mutant HSPCs have DNA hypomethylation and increased expression of oxidative phosphorylation gene signatures, increased functional oxidative phosphorylation capacity, high mitochondrial membrane potential (Δψm), and greater dependence on mitochondrial respiration compared to wild-type HSPCs. Exploiting the elevated Δψm of mutant HSPCs, long-chain alkyl-TPP molecules (MitoQ, d-TPP) selectively accumulate in the mitochondria and cause reduced mitochondrial respiration, mitochondrial-driven apoptosis and ablate the competitive advantage of HSPCs ex vivo and in vivo in aged recipient mice. Further, MitoQ targets elevated mitochondrial respiration and the selective advantage of human DNMT3A-knockdown HSPCs, supporting species conservation. These data suggest that mitochondrial activity is a targetable mechanism by which CH-mutant HSPCs gain a selective advantage over wild-type HSPCs.
    DOI:  https://doi.org/10.1038/s41467-025-57238-2
  6. Nature. 2025 Apr 16.
    Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs.
    Mohsen Hosseini, Veronique Voisin, Ali Chegini, Angelica Varesi, Severine Cathelin, Dhanoop Manikoth Ayyathan, Alex C H Liu, Yitong Yang, Vivian Wang, Abdula Maher, Eric Grignano, Julie A Reisz, Angelo D'Alessandro, Kira Young, Yiyan Wu, Martina Fiumara, Samuele Ferrari, Luigi Naldini, Federico Gaiti, Shraddha Pai, Grace Egan, Aaron D Schimmer, Gary D Bader, John E Dick, Stephanie Z Xie, Jennifer J Trowbridge, Steven M Chan.
      Clonal haematopoiesis arises when a haematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type HSCs, resulting in its clonal expansion. Individuals with clonal haematopoiesis are at increased risk of developing haematologic neoplasms and other age-related inflammatory illnesses1-4. Suppressing the expansion of mutant HSCs may prevent these outcomes; however, such interventions have not yet been identified. The most common clonal haematopoiesis driver mutations are in the DNMT3A gene, with arginine 882 (R882) being a mutation hotspot1-3,5-7. Here we show that mouse haematopoietic stem and progenitor cells (HSPCs) carrying the Dnmt3aR878H/+ mutation, equivalent to human DNMT3AR882H/+, have increased mitochondrial respiration compared with wild-type cells and are dependent on this metabolic reprogramming for their competitive advantage. Treatment with metformin, an anti-diabetic drug that inhibits mitochondrial respiration8, reduced the competitive advantage of Dnmt3aR878H/+ HSCs. Through a multi-omics approach, we found that metformin acts by enhancing methylation potential in Dnmt3aR878H/+ HSPCs and reversing the aberrant DNA CpG methylation and histone H3 K27 trimethylation profiles in these cells. Metformin also reduced the competitive advantage of human DNMT3AR882H HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against DNMT3A R882 mutation-driven clonal haematopoiesis in humans.
    DOI:  https://doi.org/10.1038/s41586-025-08871-w
  7. Blood Adv. 2025 Apr 18. pii: bloodadvances.2024015734. [Epub ahead of print]
    Prognostic Significance of Monocytic-like Phenotype in AML patients treated with Venetoclax and Azacytidine.
    Lin-Pierre Zhao, Typhaine Dumas-Rivero, Lauren Barette, Lorea Aguinaga, Arij Cheffai, Clementine Chauvel, Reinaldo Dal Bello, Emmanuel Raffoux, Emmanuelle Clappier, Matthieu Duchmann, Pierre Fenaux, Pierre Lemaire, Stephanie Mathis, Marie Sébert, Lionel Adès, Raphael A Itzykson.
      The prognostic impact of monocytic differentiation in AML patients receiving Venetoclax (Ven) and azacitidine (Aza) remains unclear. In a prospective cohort of 86 newly diagnosed AML patients treated with Ven-Aza, we used multiparametric flow cytometry (MFC) to define mono-blasts as AML blasts co-expressing ≥2 monocytic markers (CD4, CD36, CD64) per ELN guidelines. Patients with higher mono-blasts/CD45+ proportions had lower complete response rates (OR=0.24, p=0.005) and significantly shorter overall survival (OS, 4.0 versus 14.9 months, p=0.003). A ≥10% mono-blasts/CD45+ threshold, identified via maximally selected rank statistics, stratified patients into mono-blasthigh (≥10%) and mono-blastlow (<10%) groups. MFC reclassified 20% of FAB non-M4/5 and 15% of FAB M4/5 cases into mono-blasthigh and mono-blastlow groups, respectively. Multivariable analysis confirmed mono-blasthigh status as an independent adverse prognostic factor for OS (HR=1.95, p=0.023), with a particularly strong impact in ELN 2024 favorable-risk patients (HR=2.81, p=0.024). Our findings highlight monocytic differentiation, assessed via MFC, as a key predictor of Ven-Aza resistance and poor survival, independent of genetic classification. Given its availability in routine diagnostics, MFC-based monocytic assessment could improve AML risk stratification and treatment decisions in patients eligible for less intensive therapies.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015734
  8. Biomark Res. 2025 Apr 14. 13(1): 61
    IL1RAP is an immunotherapeutic target for normal karyotype triple-mutated acute myeloid leukemia.
    Arnaud Métois, Marie-Eve Bordeleau, Louis Theret, Azadeh Hajmirza, Ossama Moujaber, Jean-François Spinella, Jalila Chagraoui, Nadine Mayotte, Isabel Boivin, Éric Audemard, Léo Aubert, Véronique Lisi, Banafsheh Khakipoor, Azer Farah, Éric Bonneil, Alma Robert, Julie Lippens, Anna Moraitis, François Béliveau, Albert Feghaly, Geneviève Boucher, Richard Marcotte, Patrick Gendron, Pierre Thibault, Sébastien Lemieux, Guillaume Richard-Carpentier, Vincent-Philippe Lavallée, Josée Hébert, Philippe P Roux, Guy Sauvageau.
       BACKGROUND: Surface antigens of potential clinical significance remain under-characterized in AML. The European Leukemia Network classifies normal karyotype AML (NK-AML) mutated for NPM1 (NPM1c) as a distinct entity associated with favorable outcomes if not associated with FLT3-ITD mutation. A subset of NPM1c NK-AML shows additional mutations in 2 genes: FLT3 (FLT3-ITD) and DNMT3 A. These leukemias, also referred to as NK triple mutated AML (NKt-AML), are particularly difficult to eradicate with current treatment options. Therefore, novel therapies are necessary that use proteins specifically expressed at the surface.
    METHODS: In order to identify surface antigens for immunotherapy in NKt-AML, an extensive multi-omic analysis was conducted on primary AML samples. Surface proteome enrichment was performed on 100 primary AML samples, twelve of which were NKt-AML. Transcriptome analysis was carried out on the 691 primary AML samples, and single-cell RNA sequencing was conducted on 23 primary AML samples.
    RESULTS: Herein, using multi-omics data from the Leucegene collection, we identify IL1RAP as a promising antigen for this AML subgroup. We demonstrate that IL1RAP is expressed at the surface of primitive AML cells reminiscent of leukemic stem cells in NKt-AML primary human AML specimens, while showing relatively low expression levels in normal bone marrow HSCs. Furthermore, results indicate that elevated IL1RAP expression associates with poor overall and relapse-free survival in the Leucegene cohort of AML patients and predicts nonresponse to hematopoietic stem cell transplantation. Finally, we show that IL1RAP protein is internalized following exposure to specific antibodies, suggesting that IL1RAP represents an interesting target for antibody-drug conjugate development in NKt-AML.
    CONCLUSIONS: IL1RAP exhibits preferential expression within NKt-AML, correlating with diminished overall survival rates and diminished responsiveness to hematopoietic stem cell transplantation. Moreover, internalization of IL1RAP presents a promising avenue for immunotherapeutic intervention.
    Keywords:  Acute myeloid leukemia; Cancer; IL1RAP; Immunotherapy; Single cell; Surfaceome
    DOI:  https://doi.org/10.1186/s40364-025-00769-z
  9. Blood Cancer J. 2025 Apr 17. 15(1): 68
    Reduced venetoclax exposure to 7 days vs standard exposure with hypomethylating agents in newly diagnosed AML patients.
    Christophe Willekens, Alexandre Bazinet, Samy Chraibi, Alex Bataller, Justine Decroocq, Naszrin Arani, Benjamin Carpentier, Caitlin Rausch, Delphine Lebon, Abhishek Maiti, Nicolas Gauthier, Nicholas Short, Sarah Bonnet, Koji Sasaki, Sabine Khalife-Hachem, Mahesh Swaminathan, Jean-Baptiste Micol, Florence Pasquier, Christophe Marzac, Damien Roos-Weil, Laurent Pascal, Naval Daver, Tapan Kadia, Didier Bouscary, Farhad Ravandi, Arnaud Pages, Hagop Kantarjian, Stéphane De Botton, Courtney DiNardo.
      Hypomethylating agent (HMA) plus venetoclax (VEN) regimens are standard of care in patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. While the VEN label recommends continuous 28-day cycles, shortened VEN durations may induce similar response rates and improve tolerability. It is unknown how a VEN exposure reduced to 7 days during cycles compares to standard HMA + VEN. We retrospectively compared newly diagnosed AML patients treated with azacitidine (AZA) x 7 days plus VEN x 7 days ("7 + 7" regimen) from the first cycle (n = 82) vs patients treated with standard dose HMA + VEN (std-HMA/VEN) (n = 166). Composite complete remission rate was similar between cohorts (72% vs 72%; p = 0.95) and a median number of cycles to best response was 2 with "7 + 7" vs 1 with std-HMA/VEN (p = 0.03). Concerning toxicity, platelet transfusion rates during cycle 1 as well as early mortality at 8-weeks (6% vs 16%; p = 0.03) were lower in "7 + 7" cohort. Finally, the median OS was 11.2 months (2-year 28%) with "7 + 7" vs 10.3 months (2-year 34%) with "std-HMA/VEN" (p = 0.75). In summary, acknowledging limitations of a retrospective comparison, a shortened course of VEN used for 7 days every 28 days resulted in similar response rates and survival when compared to standard VEN exposure.
    DOI:  https://doi.org/10.1038/s41408-025-01269-x
  10. Stem Cell Reports. 2025 Apr 05. pii: S2213-6711(25)00080-3. [Epub ahead of print] 102476
    CD37 regulates the self-renewal of leukemic stem cells via integrin-mediated signaling in acute myeloid leukemia.
    Jinyuan Lu, Lixin Lv, Xiaoxue Tian, Zheng Li, Yuting Ma, Nannan Li, Jian Wang, Guangming Wang, Yu Zeng, Wenjun Zhang, Jun Xu, Aibin Liang.
      Leukemic stem cells (LSCs) are a small subset of leukemia cells that drive leukemia initiation and maintenance. Herein, we report that CD37, a member of transmembrane 4 superfamily (TM4SF), regulates the survival of acute myeloid leukemia (AML) cells as well as the self-renewal of AML LSCs. The downregulation of CD37 retarded proliferation and increased apoptosis in human AML cell lines THP-1 and OCI-AML2. Deficiency of CD37 in vivo had a minimal effect on normal hematopoiesis but significantly impeded leukemia maintenance and propagation, which led to increased apoptosis and decreased cell cycle entry in AML blasts as well as impaired colony formation and declined frequency of AML LSCs in the serial transplantation. Furthermore, CD37 interacted with integrin α4β7 and activated the phosphatidylinositol 3-kinase (PI3K)-AKT pathway mediated by integrin signaling. Our study provides novel insights for targeted therapy of AML, indicating CD37 as a safe and effective target for immunotherapy.
    Keywords:  CD37; acute myeloid leukemia; integrin; leukemic stem cell; tetraspanin
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102476
  11. Clin Cancer Res. 2025 Apr 16.
    A Phase 1 Study of FHD-286, a Dual BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, in Patients With Advanced Myeloid Malignancies.
    Courtney D DiNardo, Amir T Fathi, Ashwin Kishtagari, Kapil N Bhalla, Alfonso Quintás-Cardama, Sarah A Reilly, Caroline Almon, Caitlin Patriquin, Salah Nabhan, Kathleen Healy, Denice Hickman, Michael P Collins, Alexis Khalil, Dillon Corrigan, Tina Zhao, Jessica Piel, Kelly Lyons, Kim Horrigan, Virna Schuck, Paul Martin, GiNell Elliott, David L Lahr, Mia Bosinger, Katie D'Aco, Gromoslaw Aleksander Smolen, Murphy Hentemann, Sanam Loghavi, Samuel Agresta, Michael R Savona, Eytan M Stein.
       PURPOSE: Safety and preliminary clinical activity of FHD-286, a dual BRG1/BRM inhibitor, were evaluated in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.
    PATIENTS AND METHODS: In this multicenter, open-label, phase 1, dose escalation study (NCT04891757), patients received FHD-286 orally once daily (QD) at 2.5, 5, 7.5, and 10 mg.
    RESULTS: Forty patients (median age 65.5 years; 85% with adverse genetic status; 65% with ≥3 prior therapy lines) received FHD-286 for 28 days (median). FHD-286 was not tolerated at 10 mg QD. Across all doses, treatment-related adverse events (TRAEs) were predominantly Grade 1-2, most commonly dry mouth (27.5%) and increased alanine aminotransferase (20%). Dose-limiting Grade 3 hyperbilirubinemia and Grade 3 muscular weakness occurred at 5 and 10 mg QD, respectively. The most common serious TRAE was differentiation syndrome (DS) (10%). An independent committee retrospectively adjudicated DS in 15% of patients (five Grade 3, one Grade 4). FHD-286 plasma exposure increased with dose and accumulated with continuous dosing. Exposures were typically higher with concomitant CYP3A4 inhibitors. Myeloid differentiation and leukemic burden reduction were observed across cytogenetic and mutational backgrounds, notably in patients with enhancer-driven genotypes. There were no objective responses.
    CONCLUSIONS: DS was the most frequent serious TRAE. While antileukemic activity was observed, no objective responses were achieved and disease progression frequently occurred within 1-2 treatment cycles. Blast reductions were reported across cytogenetic and mutational profiles, coupled with myeloid differentiation via BRG1/BRM inhibition. This novel mechanism warrants further investigation of FHD-286 in combination with other agents in myeloid malignancies.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-3790
  12. bioRxiv. 2025 Apr 03. pii: 2025.04.01.646152. [Epub ahead of print]
    The Immune-Modulatory Function of Megakaryocytes in the Hematopoietic Niche of Myeloproliferative Neoplasms.
    Sandy Lee, Xiaoxi Yang, Kyla Masarik, Tameena Ahmed, Lei Zheng, Huichun Zhan.
      Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by dysregulated megakaryopoiesis and neoplastic hematopoietic stem cell (HSC) expansion. Using a murine model with MK-specific JAK2V617F expression, we establish an MPN aging model where mutant MKs drive HSC expansion and a progressive decline in wild-type HSC function. Compared to wild-type MKs, JAK2V617F MKs exhibit heightened inflammation and innate immune activation with aging, including increased antigen presentation, elevated pro-inflammatory cytokines, skewed T cell populations, and impaired T cell functions in the marrow niche. Enhanced MK immunomodulatory function is linked to mutant cell expansion and MPN progression in a chimeric murine model with co-existing wild-type and JAK2V617F mutant HSCs. LINE-1 (long-interspersed element-1), a retrotransposon linked to innate immune activation and aging, is upregulated in mutant MKs during aging in murine models. We validated that LINE-1-encoded protein ORF1p is expressed in marrow MKs in 12 of 13 MPN patients but absent in control samples from patients undergoing orthopedic surgery (n=5). These findings suggest that MKs reprogram the marrow immune microenvironment, impairing normal HSC function while promoting neoplastic expansion in MPNs. LINE-1 activation in mutant MKs may be a key driver of immune dysregulation in MPNs.
    Key Points: JAK2V617F mutant MKs reprogram the marrow immune microenvironment to promote neoplastic HSC expansion in MPNs.LINE-1 activation in diseased MKs triggers chronic inflammation and immune dysfunction in MPNs.
    DOI:  https://doi.org/10.1101/2025.04.01.646152
  13. Blood. 2025 Apr 15. pii: blood.2024027528. [Epub ahead of print]
    DNMT3A mutations are unlikely to affect interferon alfa treatment outcomes in patients with polycythemia vera.
    Ghaith Abu-Zeinah, Katie Erdos, Neville Lee, Yara Ganom, Christoph Klade, Kurt Krejcy, Heinz Gisslinger, Richard T Silver, Joseph Michael Scandura.
      DNMT3A mutations in polycythemia vera (PV) patients were heterogenous and not enriched in interferon-alpha (IFN)-treated patients. DNMT3A mutations had no detectable impact on hematologic response, molecular response or survival outcomes.
    DOI:  https://doi.org/10.1182/blood.2024027528
  14. Sci Adv. 2025 Apr 18. 11(16): eadu4058
    A germline ETV6 mutation disrupts hematopoiesis via de novo creation of a nuclear export signal.
    Michael McConville, Toby Thomas, Ryan Beckner, Benjamin Kroger, Catherine Valadez, Yuh Min Chook, Stephen Chung, Glen Liszczak.
      Germline mutations in the transcriptional regulator ETV6 are a root cause of familial inherited thrombocytopenia and predispose carriers to myelodysplastic syndromes and acute leukemias. Here, we report that the ETV6 P214L mutation creates an XPO1-dependent nuclear export signal to cause protein mislocalization. Strategies to disrupt XPO1 nuclear export activity fully restore ETV6 P214L protein nuclear localization and transcription regulation activity, establishing XPO1-dependent mislocalization as a critical mechanism underscoring ETV6 P214L dysfunction. Mechanistic insight inspired the design of "humanized" ETV6 mice in which the germline P214L mutation is sufficient to elicit severe defects in thrombopoiesis and hematopoietic stem cell maintenance and survival in animals. These studies define a unique mechanism by which the ETV6 P214L mutation exerts a dominant negative effect on protein function and reveal critical mutation-dependent disruptions to hematopoiesis that underlie disease phenotypes.
    DOI:  https://doi.org/10.1126/sciadv.adu4058
  15. Nat Commun. 2025 Apr 12. 16(1): 3492
    Mutant CEBPA promotes tolerance to inflammatory stress through deficient AP-1 activation.
    Maria Cadefau-Fabregat, Gerard Martínez-Cebrián, Lucía Lorenzi, Felix D Weiss, Anne-Katrine Frank, José Manuel Castelló-García, Eric Julià-Vilella, Andrés Gámez-García, Laura Yera, Carini Picardi Morais de Castro, Yi-Fang Wang, Felix Meissner, Alejandro Vaquero, Matthias Merkenschlager, Bo T Porse, Sergi Cuartero.
      The CEBPA transcription factor is frequently mutated in acute myeloid leukemia (AML). Mutations in the CEBPA gene, which are typically biallelic, result in the production of a shorter isoform known as p30. Both the canonical 42-kDa isoform (p42) and the AML-associated p30 isoform bind chromatin and activate transcription, but the specific transcriptional programs controlled by each protein and how they are linked to a selective advantage in AML is not well understood. Here, we show that cells expressing the AML-associated p30 have reduced baseline inflammatory gene expression and display altered dynamics of transcriptional induction in response to LPS, consequently impacting cytokine secretion. This confers p30-expressing cells an increased resistance to the adverse effects of prolonged exposure to inflammatory signals. Mechanistically, we show that these differences primarily arise from the differential regulation of AP-1 family proteins. In addition, we find that the impaired function of the AP-1 member ATF4 in p30-expressing cells alters their response to ER stress. Collectively, these findings uncover a link between mutant CEBPA, inflammation and the stress response, potentially revealing a vulnerability in AML.
    DOI:  https://doi.org/10.1038/s41467-025-58712-7
  16. Leukemia. 2025 Apr 17.
    GVHD prophylaxis in matched related stem cell transplantation: Why post-transplant cyclophosphamide can be recommended a study by the EBMT transplant complications working party.
    Olaf Penack, Mouad Abouqateb, Christophe Peczynski, William Boreland, Malek Benakli, Nicolaus Kröger, Igor Wolfgang Blau, Didier Blaise, Jaime Sanz, Matthias Eder, Hakan Ozdogu, Dominik Schneidawind, Annoek E C Broers, Gerald G Wulf, Alberto Mussetti, Ivan Moiseev, Charlotte Graham, Hélène Schoemans, Zinaida Peric.
      Rabbit anti-thymocyte globulin (rATG) reduced chronic GVHD after matched related donor (MRD) allogeneic stem cell transplantation (alloSCT) from 69% to 32% in a randomized trial and is the recommended standard in Europe. Post-transplantation Cyclophosphamide (PTCy) is an emerging alternative but lacks such solid data in MRD alloSCT. We therefore analyzed outcomes of rATG (n = 4140) vs. PTCy (n = 1069) in adult patients with hematologic malignancies undergoing MRD alloSCT between 2017 and 2021 in the EBMT database. The provided hazard ratios (HR) and P-values are adjusted for potential risk factors using multivariate analysis. Results are given at 2 years after alloSCT for all endpoints except for acute GVHD (100 days). The main difference was a lower relapse incidence after PTCy vs. rATG (26.2% vs. 32.8%; HR 0.78 [CI 95%: 0.66-0.92], p = 0.003). Interaction analyses confirmed the consistency of this result across different disease risk index and conditioning intensity subgroups. Other major transplant outcomes showed no significant differences: non-relapse mortality, overall survival, progression-free survival, GVHD-free relapse-free survival, incidence and severity of acute GVHD as well as chronic GVHD. In summary, PTCy results in comparable GVHD and survival outcomes but lower relapse rates compared to rATG. We conclude that PTCy can be recommended in MRD alloSCT.
    DOI:  https://doi.org/10.1038/s41375-025-02619-1
  17. Nat Rev Dis Primers. 2025 Apr 17. 11(1): 26
    Polycythaemia vera.
    Claire N Harrison, Tiziano Barbui, Prithviraj Bose, Jean-Jacques Kiladjian, John Mascarenhas, Mary Frances McMullin, Ruben Mesa, Alessandro M Vannucchi.
      Polycythaemia vera (PV) is a haematological malignancy in the myeloproliferative neoplasm family. PV is typically characterized by erythrocytosis and often leukocytosis and thrombocytosis1. Clinical features include reduced life expectancy due to hazards of thrombosis (often in atypical sites), haemorrhage and transformation to myelofibrosis and less frequently to a form of acute myeloid leukaemia called blast phase. Almost two decades ago, the JAK2V617F mutation in exon 14 of JAK2 was described, and is known to be present in more than 95% of patients with PV. Testing for the JAK2V617F mutation is used in the diagnosis of PV, and the quantity of the mutation (that is, the variant allele frequency) is linked to prognosis and the risk of complications. As such, reduction of JAK2V617F variant allele frequency is currently being evaluated as a treatment target. Recommendations for PV treatment include control of vascular risk factors, therapeutic phlebotomy and low-dose aspirin in all patients. Currently, patients at higher risk of thrombosis (aged over 60 years and/or with a history of thrombosis) are offered cytoreductive agents. Hydroxyurea or interferons remain the preferred first-line cytoreductive agents, with the JAK1 and JAK2 inhibitor, ruxolitinib, currently approved for the treatment of patients who are resistant to, or intolerant of, hydroxyurea. Future recommendations might be to treat the majority of patients with these agents as long-term benefits of treatment begin to emerge.
    DOI:  https://doi.org/10.1038/s41572-025-00608-3
  18. Bone Marrow Transplant. 2025 Apr 17.
    The impact of ABO compatibility on allogeneic hematopoietic cell transplantation outcomes: a contemporary and comprehensive study from the transplant complications working party of the EBMT.
    Mustafa Güven, Christophe Peczynski, William Boreland, Didier Blaise, Régis Peffault de Latour, Ibrahim Yakoub-Agha, Tobias Gedde-Dahl, Urpu Salmenniemi, Edouard Forcade, Jakob Passweg, Patrice Chevallier, Loron Sandrine, Stephan Mielke, Annoek Broers, Patrice Ceballos, Jennifer Byrne, Cristina Castilla-Llorente, Johan Maertens, Anne Huynh, Raffaella Cerretti, Claude Eric Bulabois, Gwendolyn van Gorkom, Charles Crawley, Charlotte Graham, Alberto Mussetti, Hélène Schoemans, Olaf Penack, Ivan Moiseev, Zinaida Peric.
      The role of ABO blood group system mismatch on allogeneic hematopoietic cell transplantation (allo-HCT) outcomes is controversial since current publications of large datasets are lacking. We retrospectively analyzed 30,487 patients transplanted between 2010 and 2021 using the EBMT registry to assess ABO incompatibility's effect on non-relapse mortality (NRM), overall survival (OS), progression-free survival (PFS), relapse incidence (RI), acute GvHD (aGvHD), chronic GvHD (cGvHD), and neutrophil engraftment. Transplantations were classified as ABO-compatible (56.3%), major (18.1%), minor (20.1%), and bidirectional (5.5%) incompatibilities. Mainly peripheral blood stem cells (PBSC) were used as the cell source in 85.6% of cases. Multivariate analysis found no significant association between compatibility status, with the compatible group serving as the reference, and NRM, OS, PFS, RI or cGvHD. The incidence of non-engraftment was significantly higher in the major (HR 1.04, 95% CI 1.01-1.07, p = 0.021) and bidirectional (HR 1.09, 95% CI 1.03-1.15, p = 0.003) incompatibilities. At the same time, the risk of severe aGvHD grades III-IV was lower in the major incompatibility group (HR 0.85, 95% CI 0.77-0.94, p = 0.001). Our large contemporary study, showing no major impact on outcomes, suggests that the ABO blood group system should not be a primary consideration in donor selection for PBSC-based allo-HCT.
    DOI:  https://doi.org/10.1038/s41409-025-02580-8
  19. JCO Precis Oncol. 2025 Apr;9 e2400548
    Impact of Clonal Hematopoiesis on Solid Tumor Progression Following Radiation Therapy.
    Jacqueline J Tao, Jeremy Setton, Pablo Sánchez Vela, Anton M Safonov, Elizabeth A Comen, Lior Z Braunstein, Jorge S Reis-Filho, Nadeem Riaz, Simon N Powell, Ross L Levine, Larry Norton, Pedram Razavi, Atif J Khan.
       PURPOSE: Clonal hematopoiesis (CH) has been shown to adversely affect outcomes in patients with nonhematologic cancers. However, the effects of CH on response to specific treatments, including radiation therapy (RT), are unknown.
    METHODS: We analyzed patients with solid tumors harboring nonpathogenic somatic or germline ATM mutations (n = 144) and FAT1 mutations (n = 270) who received RT and underwent prospective tumor and matched WBC sequencing using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets assay. CH variants were detected in blood samples using a well-validated CH variant detection pipeline. We compared irradiated tumor progression in patients with and without CH. Nonpathogenic ATM mutations and FAT1 mutations have previously been shown not to be associated with response to RT.
    RESULTS: The final cohort consisted of 412 patients who underwent 811 total courses of RT. One hundred sixty-one patients (39.1%) had CH; the most frequently mutated genes were DNMT3A (25.6%), PPM1D (6.2%), TET2 (5.8%), and TP53 (5.0%). Fine-Gray competing-risks analysis, with death treated as a competing event, showed no difference in irradiated tumor progression between patients with and without CH (hazard ratio, 1.09 [95% CI, 0.72 to 1.66]; P = .68). Similarly, subanalyses of CH variant allele frequency and CH mutations in putative cancer drivers did not reveal an association with RT response.
    CONCLUSION: We found no difference in irradiated tumor progression between patients with and without CH. Further studies are warranted to examine the potential clinical implications of CH on treatment responsiveness of solid tumors.
    DOI:  https://doi.org/10.1200/PO-24-00548
  20. Blood. 2025 Apr 16. pii: blood.2024026508. [Epub ahead of print]
    How I individualize treatment for chronic-phase CML.
    Ariel Monet Leyte-Vidal, Neil P Shah.
      Chronic myeloid leukemia (CML) has served as a paradigm for the development of effective initial and next-generation targeted therapies. The availability of five effective and generally well-tolerated BCR::ABL1 tyrosine kinase inhibitors for the treatment of newly diagnosed chronic phase CML offers patients and their treating physicians a welcome luxury of choice. The long-term outlook for newly diagnosed chronic phase CML patients is excellent, with expected survival similar to age-matched controls. However, most patients are expected to require lifelong treatment. As a result, important considerations when choosing frontline treatment include not only treatment efficacy, but also response durability, tolerability, maximizing quality of life, avoidance of serious and irreversible toxicities, the ease of treatment administration and increasingly, the cost of treatment to the patient as well as to society.
    DOI:  https://doi.org/10.1182/blood.2024026508
  21. Cell Rep Methods. 2025 Apr 08. pii: S2667-2375(25)00063-3. [Epub ahead of print] 101027
    Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.
    Liam P Kelley, Song-Hua Hu, Sarah A Boswell, Peter K Sorger, Alison E Ringel, Marcia C Haigis.
      Mitochondrial stress arises from a variety of sources, including mutations to mitochondrial DNA, the generation of reactive oxygen species, and an insufficient supply of oxygen or fuel. Mitochondrial stress induces a range of dedicated responses that repair damage and restore mitochondrial health. However, a systematic characterization of transcriptional and metabolic signatures induced by distinct types of mitochondrial stress is lacking. Here, we defined how primary human fibroblasts respond to a panel of mitochondrial inhibitors to trigger adaptive stress responses. Using metabolomic and transcriptomic analyses, we established integrated signatures of mitochondrial stress. We developed a tool, stress quantification using integrated datasets (SQUID), to deconvolute mitochondrial stress signatures from existing datasets. Using SQUID, we profiled mitochondrial stress in The Cancer Genome Atlas (TCGA) PanCancer Atlas, identifying a signature of pyruvate import deficiency in IDH1-mutant glioma. Thus, this study defines a tool to identify specific mitochondrial stress signatures, which may be applied to a range of systems.
    Keywords:  CP: Metabolism; CP: Systems biology; cancer metabolism; integrated multi-omics; integrated stress response; metabolomics; mitochondria; mitochondrial stress response; mitochondrial unfolded protein response; stress signatures
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101027
  22. iScience. 2025 Apr 18. 28(4): 112054
    BMAL1-depletion remodels ceramide metabolism to regulate ferroptosis and sorafenib chemosensitivity in acute myeloid leukemia.
    Hong Zheng, Zhi Lin, Dan Wang, Jing Zhang, Ting Zeng, Jie Shen, Jia-Da Li, Minghua Yang.
      Acute myeloid leukemia (AML) is a hematologic malignancy with a poor prognosis. We discovered that BMAL1 is a ferroptosis suppressor. Furthermore, it was also found to be overexpressed in AML patients, affecting the cell cycle and promoting tumor cell growth and progression. In this study, we further validated the association of BMAL1 with the progression and survival outcomes of AML. Lipidomic revealed that the levels of ceramide increased in AML cells following the depletion of BMAL1. Ceramide facilitated ferroptosis in AML cells. ASAH2 played a key role in this process. BMAL1 could not directly regulate ASAH2 but instead through IKZF2. Elevated levels of ceramide promoted the degradation of the ferroptosis protection molecule GPX4, ultimately promoting ferroptosis. Furthermore, ceramide treatment has been demonstrated to enhance the responsiveness of AML cells to sorafenib. In summary, this study elucidates that BMAL1 depletion remodels ceramide metabolism to regulate the sensitivity of AML cells to ferroptosis and targeted drug sorafenib.
    Keywords:  Cancer; Cell biology; Lipidomics; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112054
  23. Leukemia. 2025 Apr 15.
    Prognostic scoring systems in chronic myeloid leukaemia.
    Michael Lauseker, Verena S Hoffmann, Markus Pfirrmann.
      Prognostic scores are an important tool in medical statistics. In chronic myeloid leukaemia (CML), prognostic models have existed for many years, enabling the classification of patients into groups that can be clearly differentiated in terms of their prognosis. However, over time, the focus of these models has shifted from solely survival outcomes to a broader range of diverse endpoints. This review explores the development and applications of these scores, offering recommendations for their use, and looks ahead to potential future advancements in the field. As the landscape of CML treatment evolves with newer therapeutic options, it is crucial to adapt prognostic models to reflect not only survival rates but also other important clinical milestones such as molecular remission, progression-free survival, and CML-related survival. The continued refinement of these tools, alongside international validation efforts, will be essential in providing clinicians with more accurate and individualized patient prognostication, ultimately improving therapeutic decision-making and patient outcomes.
    DOI:  https://doi.org/10.1038/s41375-025-02606-6
  24. Stem Cells. 2025 Apr 12. pii: sxaf019. [Epub ahead of print]
    RUNX1 is a key inducer of human hematopoiesis controlling non-hematopoietic mesodermal development.
    Zahir Shah, Cuihua Wang, Hanif Ullah, Hao You, Elena S Philonenko, Olga V Regan, Pavel Volchkov, Yong Dai, Jianhua Yu, Igor M Samokhvalov.
      The RUNX1/AML1 transcription factor is one of the key regulators of definitive hematopoietic development in mice. However, its role in early human hematopoiesis remains poorly investigated. In this study, we integrated a tdTomato reporter cassette into the RUNX1 locus of human pluripotent stem cells (hPSCs) to monitor and block the expression of the gene during hPSC differentiation. This approach demonstrated that expression of RUNX1 starts early in mesodermal specification focusing later on hemogenic endothelium (HE) and nascent hematopoietic cells. Lack of RUNX1 halted the development of CD43+ and CD235-CD45+ hematopoietic cells, preventing the production of clonogenic hematopoietic progenitors including the multilineage ones. The abrogation of RUNX1 resulted in the failure of definitive lineages, specifically T and NK cells. Remarkably, we instead observed the accumulation of RUNX1-null HE cells at the stage of blood cell generation. Moreover, the loss of the gene biased the development toward the lineage of CD43-CD146+CD90+CD73+ mesenchymal cells. RNA-seq analysis of RUNX1-null cells revealed the downregulation of top-level hematopoietic transcription factor genes and the reciprocal upregulation of genes associated with non-hematopoietic cells of mesodermal origin. Forced expression of RUNX1c in differentiating RUNX1-null hPSCs effectively rescued the development of CD45+ myeloid cells and megakaryocytes. Our data demonstrate that RUNX1 is a top hematopoietic inducer that simultaneously controls the expansion of non-hematopoietic lineages.
    Keywords:  RUNX1; development; hematopoiesis; hemogenic endothelium; mesenchymal cells
    DOI:  https://doi.org/10.1093/stmcls/sxaf019
  25. Cell Death Dis. 2025 Apr 13. 16(1): 282
    Dysregulation of sphingolipid metabolism contributes to the pathogenesis of chronic myeloid leukemia.
    Yinyin Xie, Qinghua Zeng, Zhiwei Chen, Jiachun Song, Fuhui Wang, Dan Liu, Xiaojian Sun, Yuanliang Zhang, Qiuhua Huang.
      Chronic myeloid leukemia (CML) is primarily driven by the BCR::ABL1 oncoprotein, which has potent tyrosine kinase activity. BCR::ABL1 has been shown to facilitate several metabolic processes, including glycolysis, lipid synthesis, and protein synthesis in vitro. However, the altered metabolic profile in vivo remains poorly understood. Using Scl/tTA-BCR::ABL1 mice as a model, we conducted an analysis of plasma metabolites at different stages following BCR::ABL1 induction. Metabolites involved in sphingolipid and thiamine metabolism were significantly altered at the early stage of CML, while the tricarboxylic acid (TCA) cycle metabolites were altered during disease progression. Among these metabolic changes, sphingolipid metabolism is of particular significance. Inhibition of sphingolipid metabolism had a more pronounced effect on the growth and survival fate of K562 cells compared to thiamine metabolism inhibition. Furthermore, knockdown of sphingosine kinase 1 (SPHK1) resulted in extensive metabolic remodeling, affecting lipid, energy, and heme metabolism. Pharmacological targeting of sphingolipid metabolism appeared to attenuate the development of CML. Our study also demonstrated that BCR::ABL1 triggers ERK-dependent phosphorylation of SphK1, leading to aberrant activation of sphingolipid metabolism, which in turn has a positive feedback effect on BCR/ABL expression. These findings highlight the dominant role of sphingolipid metabolism in BCR::ABL1-induced metabolic reprogramming in CML.
    DOI:  https://doi.org/10.1038/s41419-025-07594-0
  26. Blood Cancer J. 2025 Apr 17. 15(1): 67
    Real world outcomes of momelotinib in myelofibrosis patients with anemia: results from the MOMGEMFIN study.
    Lucía Pérez-Lamas, Adrián Segura Diaz, Regina García Delgado, Alberto Álvarez-Larrán, María Alicia Senin, Elvira Mora, María Laura Fox, Irene Pastor Galan, Gemma Azaceta, Sara Garrido Paniagua, Raúl Pérez Lopez, Diana Margarita Trejos Carvajal, Anna Angona, Carmen Albo López, Pablo Lorente Alegre, Miriam Vara, Juan Antonio Vera Goñi, Dunia De Miguel Llorente, Ángeles Fernández Rodríguez, Alberto Marín Sanchez, Adriana Hernando Megido, María Teresa Gómez Casares, Ruth Stuckey, Gonzalo Carreño-Tarragona, Natalia De Las Heras Rodriguez, Blanca Xicoy, Manuel Pérez Encinas, Raquel Mata Serna, Lucia Núñez Martin-Buitrago, Francisca Ferrer Marín, Neus Amer Salas, Carolina Guillén Rienda, Patricia Velez, Laura Lamarca Eraso, Sandra Martín, Iryna Luts Khoroz, Erik De Cabo López, Angela Gil, Sofía Martín-Consuegra Ramos, Fernando Marco De Lucas, María José Otero Martinez-Fornes, María Luisa Martín Mateos, Teresa Arquero, Elena Cabezudo Pérez, Luis Antonio López Gómez, Ángela Martínez Hellin, Aurelia Tejedor, Esther Herrera de Pablo, María Isabel Mata Vazquez, Inmaculada Castillo Valero, María José Fernández, Carlos Aguilar, Marta Santaliestra, Antonio García Menchon, Begoña Navas Elorza, María Antonia Duran, María Pérez Sala, Teresa Hernández Santamaría, Ma Ángeles Muñoz Jarreño, Julio Dávila-Valls, Williana Torres Jiménez, Joan Alfons Gonzálvez Fernández, Hugo Alexander Torres Mantilla, Teresa Cobo Rodríguez, Aitor Abuin Blanco, Francisco Pérez, Santiago Osorio Prendes, Paola Beneit Villena, Raisa Peralta, Federico Herrera, Eloi Cañamero Giro, Reyes Jiménez Bárcenas, Mercedes Gasior Kabat, Sonia González De Villambrosia, Mariana Teresa Tercero-Mora Rodriguez, Marina Menéndez Cuevas, Beatriz Cuevas Ruiz, Marta Fonseca-Santos, Sonia Garcés Piquer, Rosalía De La Puerta, Álvaro Lorenzo Vizcaya, Juan Carlos Hernández Boluda, Valentín García Gutiérrez.
      
    DOI:  https://doi.org/10.1038/s41408-025-01275-z
  27. Blood Adv. 2025 Apr 16. pii: bloodadvances.2025016320. [Epub ahead of print]
    Canagliflozin May Increase Thromboembolic Events in Males With Erythrocytosis but Not in Females.
    Yohei Doi, Takayuki Hamano, Osamu Yamaguchi, Yoshitaka Isaka.
      Sodium-glucose cotransporter 2 (SGLT2) inhibitors are increasingly recognized as a common cause of drug-induced erythrocytosis. SGLT2 inhibitor-induced erythropoiesis may increase blood viscosity and precipitate thromboembolism, particularly in patients with pre-existing erythrocytosis. We conducted a post hoc, pooled analysis of patient-level data from the randomized, double-blind, placebo-controlled CANVAS Program and CREDENCE trials, which assessed the safety and efficacy of canagliflozin in patients with type 2 diabetes. The primary outcome, a composite of myocardial infarction (MI), stroke, and any thromboembolism, was evaluated using sex-specific Cox models, with baseline hematocrit as an effect modifier. Among participants with available baseline hematocrit values (98.5% [14,321/14,543]), 35% were female. Canagliflozin significantly increased hematocrit levels compared to placebo even in patients with erythrocytosis (males >49%, females >48%) and raised the proportion of individuals with erythrocytosis at 1 year (males: 16.9% vs. 5.5%; females: 5.2% vs. 1.0%). Overall, canagliflozin did not alter the risk of the primary outcome in either males (hazard ratio [HR] 0.97; 95% CI, 0.86-1.10) or females (HR 0.95; 95% CI, 0.78-1.15). However, in males, baseline hematocrit levels modified the treatment effect on the primary outcome, whether assessed categorically (anemia, normal, erythrocytosis) or continuously with fractional polynomial (FP) analysis (P interaction <0.05). FP analysis showed treatment benefits in anemic males but harm in those with erythrocytosis, primarily driven by an increased risk of MI. Meanwhile, no heterogeneity was seen in females for these outcomes. In conclusion, canagliflozin may pose a safety concern for thromboembolism in males with erythrocytosis at baseline, warranting further investigations. NCT01032629, NCT01989754, and NCT02065791.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016320
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