bims-tremyl 2025-10-05 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–10–05
27 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Long-term outcomes in FLT3-mutated acute myeloid leukemia after frontline hypomethylating agent, venetoclax and a FLT3 inhibitor.
Fetal context conveys heritable protection against MLL-rearranged AML that depends on MLL3.
Safety and Efficacy of Combining Midostaurin and Gemtuzumab Ozogamicin with Induction Chemotherapy in FLT3 mutated AML.
A comparative assessment of molecular-based prognostic models in CMML.
FLT3-ITD Induces CMTM6 and Enhances Immune Escape in Acute Myeloid Leukemia.
Regulation of metabolic adaptation and leukemia progression by MUSASHI2-DEPTOR-KIF11 axis.
Elevated clonal hematopoiesis in 9/11 first responders has distinct age-related patterns and relies on IL1RAP for clonal expansion.
MRC2 expression modulates metabolism in acute myeloid leukemia stem cells.
Hypomethylating Therapy With or Without Eltrombopag in Elderly Patients With Acute Myeloid Leukemia: Results From the Randomized, Placebo-Controlled Phase 2 DELTA Trial.
Base edited "universal" donor CAR T-cell strategies for acute myeloid leukaemia.
JAK2V617F Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones.
Misclassification of TP53 germline variants: implications for survival analysis in AML transplant studies.
Sirolimus and Cyclosporine With Post-Transplant Cyclophosphamide or Mycophenolate Mofetil as Graft-Versus-Host Disease Prophylaxis in Unrelated Donor Hematopoietic Cell Transplantation.
Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia.
Post-Transplant Cyclophosphamide Improves Survival in HLA-DPB1 Mismatched Unrelated Donor Allogeneic Transplantation.
Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation.
Dual Targeting of IKKβ and NR4A1 for AML Therapy.
Genome-wide analysis defines genetic determinants of MPN subtypes and identifies a sex-specific association at CDH22/CD40.
Clonal hematopoiesis driven by Dnmt3a mutations promotes metabolic disease development in mice.
Upfront Menin-inhibitor resistance in multiply pretreated leukemias.
Ivosidenib or venetoclax combined with hypomethylating agents in IDH1-mutated acute myeloid leukemia: a real-world study.
Acetyl-CoA carboxylase-1 inhibition increases regulatory T-Cell metabolism and graft-vs-host disease treatment efficacy via mitochondrial fusion.
Mechanisms of immune escape and extramedullary tropism in leukemia cutis.
Regulation of cell cycle by the novel GATA1/TAL1/Sphingomyelin Synthase 1 ( SGMS1 ) transcriptional axis. Implications for anti-leukemic strategies.
Diagnosis and management of adult telomere biology disorders.
Genetic landscape of DNMT3A R882H reveals mechanism of aberrant oligomerization.
RPS19 and RPL5 Haploinsufficient Models Reveal Divergent Ribosomal Subunit Controls of Fetal Hematopoiesis.

Haematologica. 2025 Oct 02.

Long-term outcomes in FLT3-mutated acute myeloid leukemia after frontline hypomethylating agent, venetoclax and a FLT3 inhibitor.

Nicholas J Short, Sanam Loghavi, Musa Yilmaz, Omer Karrar, Kunhwa Kim, Courtney D Dinardo, Tapan M Kadia, Manuel Maroun, Gautam Borthakur, Ghayas C Issa, Joseph Jabbour, Betul Oran, Elizabeth J Shpall, Uday Popat, Keyur P Patel, Mark Routbort, Marina Konopleva, Farhad Ravandi, Hagop Kantarjian, Naval Daver.

Triplet regimens with a hypomethylating agent, venetoclax and a FLT3 inhibitor yield high rates of response in newly diagnosed FLT3-mutated AML. However, the long-term outcomes and patterns of relapse with these triplet regimens are not well-established. In this retrospective analysis, 73 patients with newly diagnosed FLT3-mutated AML received a frontline FLT3 inhibitor-containing triplet regimen. The composite complete remission (CR) and CR with incomplete hematologic recovery (CRi) rate was 93%. Next-generation sequencing FLT3-ITD MRD negativity (sensitivity: 0.005%) was achieved in 60% of patients after cycle 2 and 90% after cycle 4. The estimated 3-year relapse-free survival (RFS) for FLT3-ITD-mutated and FLT3 TKD-mutated AML was 38% and 76%, respectively, and the 3-year overall survival (OS) was 45% and 76%, respectively. Neither age, NPM1 co-mutation, ELN 2022 risk, nor allogeneic stem cell transplantation in first remission significantly impacted OS. Baseline RAS pathway mutations were associated with poor long-term survival (3-year OS 22% versus 63% without RAS pathway mutation). FLT3 wild type relapses accounted for 65% of relapses, and new RAS pathway mutations were observed in 24% of relapses. Outcomes were poor after relapse (median OS of 6.1 months), particularly for those with persistently detectable FLT3 mutations. Triplet combinations of an HMA, venetoclax and a FLT3 inhibitor result in durable remission and encouraging long-term OS in older adults with newly diagnosed FLT3-mutated AML. However, better strategies to prevent FLT3 wild type relapses and to overcome RAS pathway-mediated resistance are still needed.

DOI: https://doi.org/10.3324/haematol.2025.288553
Blood. 2025 Oct 01. pii: blood.2025029686. [Epub ahead of print]

Fetal context conveys heritable protection against MLL-rearranged AML that depends on MLL3.

Jonny Mendoza-Castrejon, Wei Yang, Elisabeth D Denby, Helen C Wang, Emily B Casey, Rohini Muthukumar, Riddhi M Patel, Jihye Yoon, Yanan Li, J Michael White, Ran Chen, Luis Francisco Zirnberger Batista, Jeffrey A Magee.

MLL rearrangements (MLLr) are the most common cause of congenital and infant leukemias. MLLr arise prior to birth and can transform fetal/neonatal progenitors with the help of only a few additional cooperating mutations. Despite the low threshold for transformation, infant leukemias are rare, and congenital leukemias, which arise before birth, are even less common. These observations raise the question of whether mechanisms exist to suppress leukemic transformation during fetal life, thereby protecting the developing fetus from malignancy during a period of rapid hematopoietic progenitor expansion. To test this possibility, we used a mouse model of temporally controlled MLL::ENL expression to show that fetal MLL::ENL exposure establishes a heritable, leukemia-resistant state within hematopoietic progenitors that persists after birth. When we induced MLL::ENL expression prior to birth and transplanted hematopoietic stem and progenitor cells, very few recipient mice developed acute myeloid leukemia (AML) despite robust engraftment. When we induced MLL::ENL expression shortly after birth, all recipient mice developed a highly penetrant AML. Fetal MLL::ENL expression imposed a negative selective pressure on hematopoietic progenitors before birth followed by loss of self-renewal gene expression and enhanced myeloid differentiation after birth that precluded transformation. These changes did not occur when MLL::ENL expression initiated shortly after birth. The fetal barrier to transformation was enforced by the histone methyltransferase MLL3, and it could be overcome by cooperating mutations, such as NrasG12D. Heritable fetal protection against leukemic transformation may contribute to the low incidence of congenital and infant leukemias in humans.

DOI: https://doi.org/10.1182/blood.2025029686
Blood Adv. 2025 Sep 30. pii: bloodadvances.2025017244. [Epub ahead of print]

Safety and Efficacy of Combining Midostaurin and Gemtuzumab Ozogamicin with Induction Chemotherapy in FLT3 mutated AML.

Nigel H Russell, Jad Othman, Oliver Sebastian Cumming, Abin Thomas, Aditya Tedjaseputra, Nicola Potter, Jelena Jovanovic, Amanda Frances Gilkes, Leona Batten, Joanna Canham, Emily L Hinson, Manohursingh Runglall, Phoebe Aucken, Panagiotis Kottaridis, James Durrell Cavenagh, Claire Arnold, Sylvie D Freeman, Mike Dennis, Steven Knapper, Richard James Dillon.

Despite the use of FLT3 inhibitors, outcomes for patients with FLT3 mutated (FLT3mut) AML remain suboptimal because of high rates of relapse. We evaluated the safety and efficacy of the combination of daunorubicin, cytarabine (DA), gemtuzumab ozogamicin (GO) and midostaurin (DAGO+m) for younger patients with newly diagnosed FLT3mut AML in the UK NCRI AML19 trial. 195 patients were randomised to receive DA with either one or two doses of GO (DAGO1 and DAGO2). 77 had a FLT3 mutation (60 had FLT3-ITD) and received midostaurin for two weeks after each chemotherapy course and then as maintainance for one year unless transplanted. 39 patients received midostaurin with DAGO1 (DAGO1+m) and 38 with DAGO2 (DAGO2+m). Their median age was 51y (range 20-74) and 16 (20%) were aged >60y. The overall response rate (CR + CRi) was 91%. Day 30 and day 60 mortality was 0% with no increase in toxicity compared to patients treated contemporaneously with DAGO1 and DAGO2 without midostaurin. 2y overall survival was 77%. 2y event-free survival and cumulative incidence of relapse were 62% and 31% respectively. MRD clearance was enhanced compared to patients with FLT3-mutated AML treated with DAGO1 and DAGO2 without midostaurin. 81% of evaluable patients were NPM1 MRD negative by RT-qPCR in the peripheral blood after course 2 (76% with DAGO1+m and 86% with DAGO2+m), 79% were MRD negative in the bone marrow by FLT3-ITD NGS, and all patients had FLT3-MRD levels below 0.01%. DAGO+m appears safe and effective . DAGO2+m will now be evaluated in a randomised study (OPTIMISE-FLT3, ISRCTN 34016918). Trial: ISRCTN78449203.

DOI: https://doi.org/10.1182/bloodadvances.2025017244
Blood Neoplasia. 2025 Nov;2(4): 100116

A comparative assessment of molecular-based prognostic models in CMML.

Luis E Aguirre, Najla Al Ali, Somedeb Ball, Akriti G Jain, David A Sallman, Andrew T Kuykendall, Alison R Walker, Kendra Sweet, Jeffrey E Lancet, Eric Padron, Rami S Komrokji.

Several prognostic systems integrating clinical, cytogenetic, and molecular parameters have been developed to estimate risk and inform treatment in chronic myelomonocytic leukemia (CMML). Recently, the molecular International Prognostic Scoring System (IPSS-M) was introduced for risk stratification in myelodysplastic syndromes (MDS), demonstrating improved prognostic accuracy over the mutation-agnostic Revised International Prognostic Scoring System (IPSS-R) and potentially offering a novel tool for risk assessment in this population. We aimed to assess whether the applicability of the IPSS-M extends to CMML while providing a comprehensive comparison of all major molecular-based integrated models. Baseline clinical and molecular data were collected from 340 patients with CMML. The most frequent mutations were TET2, SRSF2, ASXL1, RUNX1, and NRAS. The IPSS-M stratified patients into 6 risk categories, with median overall survival (OS) of 18.5, 5.1, 3.9, 2.65, 1.7, and 1.1 years, corresponding to very low to very high risk disease (P < .001). Additionally, the 4-year cumulative incidence of acute myeloid leukemia evolution was 4.2%, 12.1%, 19.4%, 25.9%, 32.8%, and 26.7%, respectively (P = .008). Both CMML-specific prognostic scoring system (CPSS)-Mol and IPSS-M improved OS discrimination compared to the Mayo molecular and Groupe Francophone des Myélodysplasies models. CPSS-Mol outperformed CPSS, and IPSS-M was superior to IPSS-R. CPSS-Mol demonstrated the highest prognostic accuracy for predicting leukemic evolution, establishing it as the superior overall model. Importantly, IPSS-M was reliably applicable in CMML and displayed prognostic accuracy comparable to CPSS-Mol. Furthermore, all models retained predictive validity in patients receiving frontline hypomethylating agent therapy, suggesting that using the IPSS-M is unlikely to adversely affect outcomes when guiding treatment decisions, particularly in community settings in which CMML is often grouped with MDS.

DOI: https://doi.org/10.1016/j.bneo.2025.100116
Cancer Res. 2025 Oct 03.

FLT3-ITD Induces CMTM6 and Enhances Immune Escape in Acute Myeloid Leukemia.

Melissa Zwick, Bastian Zinkel, Corinna Spohr, Tamina Rückert, Sebastian Halbach, Khalid Shoumariyeh, Jonas Scheid, Anna-Sophia Baur, Lukas M Braun, Moritz Angel, Elisa Michaeli, Abhijeet Todkar, Annika Nelde, Melanie Märklin, Samuel J Holzmayer, Severin Dicks, Melanie Boerries, Sandra Duquesne, Alexandra Emilia Schlaak, Patricia Otto-Mora, Bertram Bengsch, Marcel Schiff, Sandra Kissel, Michael Selle, Marie Follo, Heidi Altmann, Desiree Kunadt, Anna-Lena Illert, Juliane S Walz, Gerd Walz, Justus Duyster, Johannes Schetelig, Tilman Brummer, Robert Zeiser, Natalie Köhler.

FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations are frequent in acute myeloid leukemia (AML) and are associated with a high risk of relapse. CKLF-like MARVEL transmembrane domain containing member 6 (CMTM6) stabilizes PD-L1 surface expression and modulates tumor immunity in solid cancer. In this study, we found a role for FLT3-induced CMTM6 in hematological malignancies. FLT3 drove CMTM6 and PD-L1 expression in AML cells, while FLT3 inhibition reduced expression of CMTM6 and PD-L1. In three distinct allogeneic hematopoietic cell transplantation mouse models, transplantation of Cmtm6 deficient FLT3-ITD+ leukemia cells resulted in prolonged survival, reduced leukemia burden, enhanced T cell effector function, and decreased expression of T cell exhaustion markers compared to Cmtm6 proficient FLT3-ITD+ leukemia cells. Furthermore, combination therapy with anti-PD-L1 and tandutinib significantly improved survival, suppressed leukemia cell expansion, and augmented the anti-leukemia T cell response in mice bearing FLT3-ITD+ leukemia. Mechanistically, protein-protein interaction of FLT3 and CMTM6 within their transmembrane domains, which was not phosphorylation dependent, enhanced CMTM6 stability in leukemia cells, while FLT3-ITD did not increase CMTM6 and PD-L1 expression at the RNA level. Furthermore, CMTM6 upregulation and protein interaction with FLT3 was validated in primary leukemia cells from two independent cohorts of patients with FLT3-ITD+ AML. Collectively, these findings uncover FLT3-mediated stabilization of CMTM6 in AML cells, which results in enhanced PD-L1 cell surface expression and leukemia immune escape.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0349
Leukemia. 2025 Oct 01.

Regulation of metabolic adaptation and leukemia progression by MUSASHI2-DEPTOR-KIF11 axis.

Tania Setiawan, Jabir Aliyu Muhammad, Nadya Marcellina, Lawrence Mario Wirawan, Nayoung Jun, Ita Novita Sari, Vivian G Oehler, Dong-Wook Kim, Hyog Young Kwon.

Amino acid homeostasis is critical for leukemic cell survival, with the mTOR pathway playing a central role in sensing and responding to nutrient availability. DEPTOR, a component and negative regulator of mTOR complexes, has been extensively studied in solid tumors and multiple myeloma, but its role in acute myeloid leukemia (AML) remains unclear. Here, we identify DEPTOR as a key regulator of leukemia progression through its interaction with KIF11. DEPTOR expression is transcriptionally induced by ATF4 and post-transcriptionally stabilized by MSI2, which binds to DEPTOR mRNA and prevents its degradation. DEPTOR is highly expressed in leukemia stem cells (LSCs) and is associated with poor clinical outcomes. Functionally, DEPTOR loss impairs leukemogenesis in both AML and blast phase chronic myeloid leukemia (bpCML) models, without affecting normal hematopoietic stem cells. Mechanistically, DEPTOR stabilizes KIF11 by preventing its ubiquitination and proteasomal degradation, thereby ensuring proper mTORC1 localization and metabolic adaptation during nutrient stress. Collectively, our findings establish the MSI2/DEPTOR/KIF11 axis as a critical driver of leukemogenesis and a promising therapeutic target for aggressive myeloid leukemias.

DOI: https://doi.org/10.1038/s41375-025-02768-3
Cancer Discov. 2025 Oct 01.

Elevated clonal hematopoiesis in 9/11 first responders has distinct age-related patterns and relies on IL1RAP for clonal expansion.

Divij Verma, Rachel Zeig-Owens, David G Goldfarb, Leah Kravets, Kith Pradhan, Bradley Rockwell, Srabani Sahu, Susheian Kelly, Orsi Giricz, Sakshi Jasra, Yiyu Zou, Colette Prophete, Lidiane S Torres, Srinivas Aluri, Samarpana Chakraborty, Rajni Kumari, Shanisha Gordon-Mitchell, Jingli Wang, Alexander J Silver, Taylor M South, Sarah D Olmstead, Charles B Hall, Simone Sidoli, Ryan Bender, Ola Landgren, Lee M Greenberger, Amittha Wickrema, Advaitha Madireddy, Aditi Shastri, Eric M Pietras, Lindsay M LaFave, Anna Nolan, Mitchell D Cohen, Michael R Savona, Ulrich Steidl, David J Prezant, Amit Verma.

Environmental exposures are linked to precancerous hematologic conditions, but studies in cohorts with well-defined exposures are limited. We sequenced blood samples from a large cohort of first-responders exposed to the aerosolized dust and carcinogens from the 9/11 World Trade Center (WTC) disaster and observed a significantly higher prevalence of clonal hematopoiesis (CH) mutations when compared to two sets of control cohorts after controlling for age, race, and sex. Younger exposed first-responders exhibited unconventional CH mutations, with defective DNA repair signatures. Leukemia risk was elevated (3.7% vs. 0.6%, OR=5.73) in WTC-exposed responders with CH versus without CH. Exposure to particulate matter collected from WTC site impaired healthy stem cell while expanding Tet2-mutant CH clones in mice. Inflammation sensor, IL1RAP, was overexpressed in murine CH, and genetic knockdown inhibited mutant clone growth in-vivo. This study links discrete environmental exposure to hematopoietic mutations and leukemia, identifying IL1RAP as a novel therapeutic target in CH.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1590
Cancer Lett. 2025 Sep 26. pii: S0304-3835(25)00640-8. [Epub ahead of print] 218068

MRC2 expression modulates metabolism in acute myeloid leukemia stem cells.

Taylor S Mills, Marlon Arnone, Elsa Görsch, Simone Poeschel, Stefan Winter, Jessica Kuebler, Lucca M Kimmich, Florian A Büttner, Jan Weller, Saskia S Rudat, Lucas Mix, Jan C Schroeder, Anna M Paczulla Stanger, Matthias Schwab, Claudia Lengerke.

  Leukemic stem cells (LSC) are well recognized for their essential roles in acute myeloid leukemia (AML) initiation and relapse. LSC can be distinguished from non-LSC AML cells by the expression of specific cell surface markers, but there is considerable phenotypic heterogeneity among LSC in AML. Here, using primary patient samples, we report that mannose receptor C-type 2 (MRC2) can be used to enrich for LSC across various AML subtypes. When compared to MRC2- AML cells isolated from the same patient samples, MRC2+ leukemic subpopulations show increased in vitro clonogenic capacity, a stemness transcriptomic signature, and enhanced leukemic capacity in mouse xenograft models. Further, we find that MRC2 is functional on AML cells, and enables their robust uptake of collagen, which supports their glycolytic metabolism. In sum these data highlight the use of functional surface markers to distinguish LSC in AML, and how they can yield insight into their unique characteristics.

Keywords:  MRC2; acute myeloid leukemia; glycolysis; leukemia stem cells; mannose receptor c-type2; metabolism

DOI:  https://doi.org/10.1016/j.canlet.2025.218068
Am J Hematol. 2025 Oct 02.

Hypomethylating Therapy With or Without Eltrombopag in Elderly Patients With Acute Myeloid Leukemia: Results From the Randomized, Placebo-Controlled Phase 2 DELTA Trial.

Katja Sockel, Christoph Röllig, Anke Mütherig, Martina Crysandt, Sven Zukunft, Regina Herbst, Richard Noppeney, Kerstin Schäfer-Eckardt, Martin Kaufmann, Uta Oelschlaegel, Frank Fiebig, Aristoteles Giagounides, Katharina Götze, Sebastian Scholl, Andreas Lück, Kathrin Rieger, Thomas Geer, Philipp Kiewe, Carsten Müller-Tidow, Hubert Serve, Claudia D Baldus, Ulrich Kaiser, Stefan Mahlmann, Burkhard Schmidt, Stefani Parmentier, Thomas Illmer, Ruth Seggewiss-Bernhardt, Alexander Kiani, Hartmut Linde, Heinz Dürk, Michael Kramer, Desiree Kunadt, Katharina Schmidt-Brücken, Ekaterina Balaian, Karolin Trautmann-Grill, Leo Ruhnke, Jan Moritz Middeke, Malte von Bonin, Gerhard Ehninger, Christian Thiede, Martin Bornhäuser, Johannes Schetelig, Uwe Platzbecker.

  Primary endpoint treatment-change-free survival (TCFS), defined as time from randomization to death or initiation of a new disease-modifying treatment in the phase 2 DELTA trial. AML, acute myeloid leukemia; EPAG, eltrombopag; HMA, hypomethylating agents; IC, intensive chemotherapy.

Keywords:  DELTA; elderly AML; eltrombopag; hypomethylating therapy; thrombocytopenia

DOI:  https://doi.org/10.1002/ajh.70091
Leukemia. 2025 Oct 01.

Base edited "universal" donor CAR T-cell strategies for acute myeloid leukaemia.

Renuka Kadirkamanathan, Christos Georgiadis, Arnold Kloos, Akshay Joshi, Annie Etuk, Roland Preece, Oliver Gough, Axel Schambach, Martin Sauer, Michael Heuser, Waseem Qasim.

Acute myeloid leukaemia (AML) is often aggressive and life-threatening with limited curative options. Immunotherapies including chimeric antigen receptor (CAR) T-cell approaches are under investigation, but high levels of disease heterogeneity remain a major hurdle to achieving durable responses. Targeting of multiple antigens may ensure complete immunological coverage of leukaemic blast populations, but such antigens are often also present on healthy haematopoietic populations. To address likely aplasia, strategies can be designed to bridge CAR T-cell therapies to allogeneic stem-cell transplantation (allo-SCT), as demonstrated in recent anti-CD7 CAR T-cell studies. Here we report that monotherapy using base edited "universal" donor CAR T cells against CD33, CLL-1, or CD7 delivered inhibition of AML in immunodeficient mice when antigen expression was homogenous, but combined use of BE-CAR33 and BE-CARCLL-1 T cells was required to address heterogenous CLL-1-/+CD33-/+ disease. We also demonstrate that removal of shared CD7 antigens enabled compatibility of BE-CAR33 and BE-CARCLL-1 with BE-CAR7 T cells, including in a patient-derived xenograft (PDX) model of AML. Therapeutic strategies envisage 'pick and mix' applications of base edited "universal" CAR T cells in combination determined by patient-specific antigen profiles. Such approaches also offer the possibility of deep, cell-based, de-bulking and conditioning ahead of allo-SCT and subsequent donor-derived reconstitution.

DOI: https://doi.org/10.1038/s41375-025-02720-5
bioRxiv. 2025 Sep 25. pii: 2025.09.23.678057. [Epub ahead of print]

JAK2V617F Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones.

Tyler M Parsons, Aishwarya Krishnan, Infencia Xavier Raj, Andrew L Young, David R O'Leary, Jason Arand, Maggie Cox, Stephen T Oh, Grant A Challen.

Myeloproliferative neoplasms (MPNs) are hematological diseases predominantly driven by the JAK2 V617F mutation. Progression from chronic-phase MPN to secondary acute myeloid leukemia (sAML) is a severe complication that dramatically worsens disease prognosis. While progression to sAML is classically linked to MPN clones acquiring additional mutations, the absence of JAK2 V617F in some cases of post-MPN sAML cases suggests alternative mechanisms of transformation. Utilizing patient samples and in vivo modeling, we establish that leukemic clones can emerge independently of JAK2 -mutant cells and undergo positive selection in the pro-inflammatory MPN environment, leading to parallel disease evolution. Genetic and pharmacological inhibition of IL-12 and TNFα mitigates this competitive advantage. Our data establish a new paradigm and show that disease progression in MPN can arise from parallel acute myeloid leukemia (pAML) clones.

DOI: https://doi.org/10.1101/2025.09.23.678057
Leukemia. 2025 Sep 28.

Misclassification of TP53 germline variants: implications for survival analysis in AML transplant studies.

Léa Rodriguez, François Delhommeau, Thierry Soussi.

DOI: https://doi.org/10.1038/s41375-025-02772-7
J Clin Oncol. 2025 Oct 03. JCO2501238

Sirolimus and Cyclosporine With Post-Transplant Cyclophosphamide or Mycophenolate Mofetil as Graft-Versus-Host Disease Prophylaxis in Unrelated Donor Hematopoietic Cell Transplantation.

Masumi Ueda Oshima, Phuong T Vo, Michael Boeckh, Michelle E Bouvier, Paul A Carpenter, Marco Mielcarek, Effie W Petersdorf, Rainer Storb, Ted Gooley, Brenda M Sandmaier.

PURPOSE: To determine whether sirolimus (SIR) and cyclosporine (CSP) combined with post-transplantation cyclophosphamide (PTCy), after nonmyeloablative or reduced-intensity conditioning unrelated donor hematopoietic cell transplantation (HCT), would be more effective than SIR, CSP, and mycophenolate mofetil (MMF) in reducing the risk of chronic graft-versus-host disease (cGVHD) without increasing risk of recurrent malignancy.
METHODS: In a Phase II trial of HLA-matched or mismatched unrelated donor mobilized blood HCT (ClinicalTrials.gov identifier: NCT03246906), adults with hematologic malignancies ineligible for myeloablative HCT were randomly assigned 1:1 to GVHD prophylaxis with SIR/CSP/PTCy (50 mg/kg once daily on days +3, +4) or SIR/CSP/MMF. The primary end point was 1-year chronic GVHD-free relapse-free survival (CRFS).
RESULTS: One hundred forty-five patients were randomly assigned and transplanted. Median follow-up among survivors was 3.0 (range, 0.6-7.0) years. Comparing PTCy-based with non-PTCy-based immunosuppression, estimated 1-year CRFS was 73% (95% CI, 61% to 82%) versus 48% (95% CI, 36% to 59%), translating into a hazard ratio (HR) for CRFS failure of 0.46 (95% CI, 0.26 to 0.79; P = .005) for PTCy. Probabilities of acute GVHD (aGVHD) grades II-IV and III-IV, respectively, were 40% versus 42% and 6% versus 10%. One-year estimates for secondary end points were as follows: moderate-to-severe cGVHD, 3% (95% CI, 1% to 9%) versus 33% (95% CI, 22% to 44%); relapse, 15% versus 15%; progression-free survival, 75% versus 78%; survival, 86% versus 86%; and nonrelapse mortality, 10% versus 7%. The HR of ≥grade 3 infections with PTCy versus non-PTCy was 2.65 (95% CI, 1.41 to 4.97; P = .003).
CONCLUSION: After HLA-matched or mismatched unrelated donor mobilized blood HCT, replacing MMF with PTCy, when used in combination with SIR and CSP, significantly reduced risk of cGVHD, without increasing risks of aGVHD or relapse. Thus, the combination of PTCy and SIR/CSP may have synergistic cGVHD-protective effects warranting further study.

DOI: https://doi.org/10.1200/JCO-25-01238
Nat Cancer. 2025 Oct 03.

Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia.

Carl Sandén, Niklas Landberg, Pablo Peña-Martínez, Hanna Thorsson, Shruti Daga, Noelia Puente-Moncada, Maria Rodriguez-Zabala, Sofia von Palffy, Marianne Rissler, Vladimir Lazarevic, Gunnar Juliusson, Mats Ohlin, Axel Hyrenius-Wittsten, Christina Orsmark-Pietras, Henrik Lilljebjörn, Helena Ågerstam, Thoas Fioretos.

Immunotherapy has shown limited success in acute myeloid leukemia (AML), indicating an incomplete understanding of the underlying immunoregulatory mechanisms. Here we identify an immune evasion mechanism present in 60% of AML cases, wherein primitive AML cells aberrantly express the lymphoid surface protein SLAMF6 (signaling lymphocyte activation molecule family member 6). Knockout of SLAMF6 in AML cells enables T cell activation and highly efficient killing of leukemia cells in coculture systems, demonstrating that SLAMF6 protects AML cells from recognition and elimination by the immune system in a mode analogous to the programmed cell death protein-ligand (PDL1/PD1) axis. Targeting SLAMF6 with an antibody against the SLAMF6 dimerization site inhibits the SLAMF6-SLAMF6 interaction and induces T cell activation and killing of AML cells both in vitro and in humanized in vivo models. In conclusion, we show that aberrant expression of SLAMF6 is a common and targetable immune escape mechanism that could pave the way for immunotherapy in AML.

DOI: https://doi.org/10.1038/s43018-025-01054-6
Transplant Cell Ther. 2025 Oct 01. pii: S2666-6367(25)01480-0. [Epub ahead of print]

Post-Transplant Cyclophosphamide Improves Survival in HLA-DPB1 Mismatched Unrelated Donor Allogeneic Transplantation.

Shannon R McCurdy, Scott R Solomon, Brian C Shaffer, Meilun He, Yung-Tsi Bolon, Amanda G Blouin, Alla Keyzner, Francisco A Socola, Uroosa Ibrahim, Jun Zou, Hana Safah, Nakhle Saba, Shahinaz Gadalla, Miguel-Angel Perales, Sophie Paczesny, Steven G E Marsh, Effie W Petersdorf, Tao Wang, Stephanie J Lee, Ephraim J Fuchs.

BACKGROUND: HLA-DPB1 mismatching is common in unrelated donor (URD) hematopoietic cell transplantation (HCT) and increases graft-versus-host disease (GVHD) when using methotrexate and tacrolimus (MTX/Tac)-based GVHD prophylaxis. Historically, national and international guidelines recommended prioritizing HLA-DPB1 matching in URD selection. The impact of HLA-DPB1 matching in URD HCT when using post-transplantation cyclophosphamide (PTCy) has been understudied.
OBJECTIVES: Our primary endpoint was the association of GVHD-prophylaxis strategy with overall survival (OS) after T cell-replete 12/12 HLA-matched or permissive or non-permissive (NP) mismatch (MM) at HLA-DPB1 (defined by the T-cell-epitope groups model) URD HCT.GVHD-free, relapse-free survival (GRFS) was our key secondary endpoint.
STUDY DESIGN: This was a retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Recipients underwent a first HCT from 2015-2020 for acute leukemia or myelodysplastic syndrome using either HLA-DPB1 NP MM (n=329), permissive MM (n=992), or 12/12 HLA-matched (n=300) URD with PTCy ± mycophenolate mofetil and/or a calcineurin inhibitor, or HLA-DPB1 NP MM (n=709), permissive MM (n=2,395), or 12/12 HLA-matched (n=911) URD with MTX/Tac.
RESULTS: HLA-DPB1 NP MM with MTX/Tac was associated with higher treatment-related mortality (TRM) (hazard ratio [HR]: 1.64, 1.08-2.49, p=0.019), lower relapse (HR: 0.73, 0.59-0.92, p=0.0073), inferior OS (HR: 1.27, 1.03 -1.57, p=0.023), and worse GRFS (HR: 1.61, 1.34-1.94, p<0.0001) when compared with PTCy. Adjusted 1-yr estimates for GRFS were 54% (95% confidence interval [CI]: 49-60%) for PTCy and 40% (CI: 37-44%) for MTX/Tac. For permissive MM URD HCT, MTX/Tac was associated with inferior GRFS (HR 1.54, CI: 1.36-1.76, p<0.0001) when compared with PTCy. When using PTCy, there were no significant differences in these outcomes for HLA-DPB1 NP MM, HLA-DPB1 permissive MM, or 12/12 HLA-matched URD HCT.
CONCLUSIONS: PTCy should be the preferred GVHD prophylaxis strategy for HLA-DPB1 MM URD HCT. Furthermore, within PTCy platforms, survival is comparable across HLA-DPB1 match and thus NP mismatching at HLA-DPB1 should not be a determinant in URD selection.

DOI: https://doi.org/10.1016/j.jtct.2025.09.048
Cell Rep. 2025 Sep 30. pii: S2211-1247(25)01150-7. [Epub ahead of print]44(10): 116379

Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation.

Tiffany E Leesang, John P Brabson, Yoon Sing Yap, Daniela A Barbieri, Abigail S Klimas, Joey Pinzone, Emily L Ahearn, Minh Q Lam, Peter D Lyon, Anna Swirski, Nicholas B Wolfe, Yuichiro Nakata, Helena Gomes Dos Santos, Ramin Shiekhattar, Lluis Morey, Panayiotis I Vlantis, Maria E Figueroa, Namrata Chandhok, Felipe Beckedorff, Aristeidis G Telonis, Luisa Cimmino.

  Enhancing ten-eleven translocation 2 (TET2) activity through genetic or pharmacologic approaches, such as ascorbate supplementation, can slow myeloid malignancy progression. However, ascorbate alone may be insufficient to fully activate TET2 in malignant cells due to pharmacokinetic constraints and the need for chromatin remodeling to enable effective cellular reprogramming. Here, we identify a novel mechanism to enhance TET2 activity via all-trans retinoic acid (ATRA), which induces retinoic acid receptor alpha (RARA)-mediated TET2 transcription in myeloid leukemia cells and synergizes with ascorbate to promote DNA hydroxymethylation and chromatin remodeling at key myeloid differentiation loci. Using Tet1/2/3-deficient mice and primary human acute myeloid leukemia (AML) models, we show that ATRA plus ascorbate more effectively induces differentiation, inhibits leukemia stem cell self-renewal in a TET2-dependent manner, and sensitizes AML cells to targeted therapies in vivo, leading to improved survival. These findings support the combined use of ATRA and ascorbate as a strategy to enhance TET2 activity for the treatment of myeloid malignancies.

Keywords:  5hmC; CP: Cancer; CP: Genomics; TET2; ascorbate; differentiation therapy; myeloid leukemia; retinoic acid

DOI:  https://doi.org/10.1016/j.celrep.2025.116379
bioRxiv. 2025 Sep 27. pii: 2025.09.24.678355. [Epub ahead of print]

Dual Targeting of IKKβ and NR4A1 for AML Therapy.

Chandra K Maharjan, Yi Liu, Yufeng Xiao, Bristy R Podder, Tyler H Montgomery, Lei Wang, Myung-Chul Kim, Zeng Jin, Seyedehalaleh Anvar, Alexandra M Stevens, Ryan Kolb, Chen Zhao, Zhijian Qian, Jatinder Lamba, Guangrong Zheng, Weizhou Zhang.

Acute myeloid leukemia (AML) is a common and aggressive blood cancer with the highest lethality rate among all leukemia subtypes. The cure rate of available therapeutic options is very low, underscoring an urgent need to develop novel and effective AML therapeutics. Here we identify IKKβ and NR4A1 as two closely related drivers of AML progression and develop a proteolysis targeting chimera (PROTAC) drug that has dual degradation activity against IKKβ and NR4A1. IKKβ and its downstream nuclear factor-κB (NF-κB) signaling are aberrantly activated in around 40% AML patients. However, nearly all IKKβ inhibitors have failed prior clinical trials due to their serious side effects such as neutrophilia and systematic inflammation. As opposed to the previously reported tumor suppressive role in AML, we found that NR4A1 promotes AML pathogenesis in a context-dependent manner. Here we designed, synthesized, and validated several celastrol-based PROTACs, with one lead compound A9 that effectively kills several AML cell lines and primary human AML cells via the degradation of IKKβ and NR4A1. At the mechanistic level, A9 degrades both targets through cereblon (CRBN) E3 ligase-mediated proteasomal system by forming ternary complexes with the target proteins and CRBN. More importantly, A9 attenuates AML disease progression in a clinically relevant KMT2A::MLLT3 mouse model and doesn't induce neutrophilia in vivo - a common side effect of IKKβ inhibitors. Our results reveal a potentially novel strategy to treat intractable and aggressive AMLs in the clinic.
Key Points: IKKβ and NR4A1 are clinically relevant mediators of AML pathogenesis.A novel celastrol-based PROTAC can effectively degrade both IKKβ and NR4A1 to disrupt AML pathogenesis.

DOI: https://doi.org/10.1101/2025.09.24.678355
Blood. 2025 Sep 30. pii: blood.2025028489. [Epub ahead of print]

Genome-wide analysis defines genetic determinants of MPN subtypes and identifies a sex-specific association at CDH22/CD40.

William J Tapper, Ahmed A Z Dawoud, Joannah Score, Andrew J Chase, E Joanna Baxter, Joanne Ewing, Louise Wallis, Paola Guglielmelli, Dolors Colomer, Beatriz Bellosillo, Monste Gomez, Juan Carlos Hernandez-Boluda, Carlos Besses, Francisco Cervantes, Steffen Koschmieder, Anthony R Green, Andreas Reiter, Alessandro M Vannucchi, Claire N Harrison, Nicholas C P Cross.

To identify genetic variants that influence myeloproliferative neoplasm (MPN) phenotype, we undertook a two-stage case-only genome-wide association study using cohorts from the UK (including UK Biobank), Spain, Germany and Italy. MPN subtype [essential thrombocythemia (ET); polycythemia vera (PV)] were compared to each other, to healthy controls and stratified analyses was performed based on chromosome 9p aberrations, JAK2 V617F mutation burden and sex. The ET versus PV analysis identified known associations: (i) at HBS1L-MYB that increased ET risk (PMETA=7.93x10-6, OR=1.28) and reduced PV risk (PMETA=9.43x10-5, OR=0.81) and (ii) at GFI1B-GTF3C5 that predisposed to PV only (PMETA=1.43x10-9, OR=1.38). Two further linked intronic SNPs, rs2425786 and rs2425788, at CDH22/CD40 were significant in females only (PMETA=2.67x10-8) with predisposition to PV (PMETA=0.0006, OR=1.3) and reduction of ET risk (PMETA=7.82x10-5, OR=0.75). Associations with JAK2, TERT, ATM, TET2, PINT, GFI1B and SH2B3 were confirmed (PMETA<5x10-8) and nine further loci were replicated (PMETA<0.05). A polygenic risk score consisting of 48 SNPs from 31 loci demonstrated moderate discriminative performance for ET and PV (AUC=0.718) and was improved by optimization for disease subtype (AUCET=0.724 and AUCPV=0.755). Overall, our results reveal that multiple germline variants influence MPN phenotype with HBS1L-MYB and a novel sex-specific association with CDH22/CD40 being the strongest determinants.

DOI: https://doi.org/10.1182/blood.2025028489
J Clin Invest. 2025 Sep 30. pii: e197100. [Epub ahead of print]

Clonal hematopoiesis driven by Dnmt3a mutations promotes metabolic disease development in mice.

Bowen Yan, Qingchen Yuan, Marco M Buttigieg, Prabhjot Kaur, Annalisse R McKee, Daniil E Shabashvili, Caitlyn Vlasschaert, Alexander G Bick, Michael J Rauh, Olga A Guryanova.



Keywords:  Diabetes; Hematology; Inflammation; Metabolism; Mouse models; Obesity

DOI:  https://doi.org/10.1172/JCI197100
Exp Hematol. 2025 Sep 28. pii: S0301-472X(25)00557-0. [Epub ahead of print] 105268

Upfront Menin-inhibitor resistance in multiply pretreated leukemias.

Leila Mahdavi, Fatemeh Alikarami, Haley Goodrow, Alexandra Lenard, Simone S Riedel, Clara Libbrecht, Isabel Bowser, Sarah K Tasian, Catherine D Falkenstein, Bryan Manning, Sarah Skuli, Martin P Carroll, Gerald Wertheim, Sheng F Cai, Gerard McGeehan, Sixiang Yu, Junwei Shi, Hongbo M Xie, Kathrin M Bernt.

Inhibitors of the Menin-KMT2A interaction are promising agents for the treatment of KMT2A-rearranged (KMT2A-r) leukemias. We evaluated Menin inhibition in patient derived xenografts of KMT2A-r leukemias with high-risk features. Three AMLs with high-risk fusion partners (MLLT10, MLLT4) and two infant ALL samples were sensitive to Menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated KMT2A::AFF1 ALL samples were much less sensitive compared to cells obtained earlier in the same patients' disease course. Since none of the patients had been treated with a Menin inhibitor, resistance in these highly pretreated samples was acquired in the absence to Menin inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy towards the canonical targets in the Menin-inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple co-mutations, including RAS pathway and TP53 mutations, although neither was sufficient to induce Menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patients; inactivation of KMT2C/D has been reported to result in Menin inhibitor resistance, and KMT2C-edited cells from this patient were selected for in VTP containing growth conditions. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data supports using Menin-inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred.

DOI: https://doi.org/10.1016/j.exphem.2025.105268
Blood Neoplasia. 2025 Nov;2(4): 100152

Ivosidenib or venetoclax combined with hypomethylating agents in IDH1-mutated acute myeloid leukemia: a real-world study.

Curtis A Lachowiez, B Douglas Smith, Alexander Joseph Ambinder, Gary Binder, Anne Angiolillo, Ravi Potluri, Eros Papademetriou, Thomas W LeBlanc.

Approximately 10% of patients with newly diagnosed acute myeloid leukemia (ND-AML) harbor the isocitrate dehydrogenase 1 gene mutation (mIDH1). In this real-world study evaluating ivosidenib (IVO) + hypomethylating agents (HMAs; n = 181) vs venetoclax (VEN) + HMAs (n = 99) in patients with mIDH1 ND-AML, those treated with IVO+HMA had higher rates of complete remission (CR; 42.5% vs 26.3%; P = .007), higher rates of composite CR + CR with incomplete platelet count recovery (63.0% vs 48.5%; P = .019), shorter median time to best response (3.3 vs 4.1 months; P = .006), and improved 6-month event-free survival (55.8% vs 38.4%; P = .006). Most patients treated with VEN received well under 28 days of VEN per cycle, likely due to anticipation of toxicity; outcomes with this short-schedule VEN were proportionately worse with fewer days of exposure per cycle. The between-group rate of grade ≥3 adverse events was similar within 30 days of treatment initiation, except for higher rates of febrile neutropenia for VEN+HMA vs IVO+HMA (8.1% vs 1.7%; P = .008). These findings support results from the phase 3 AGILE trial demonstrating IVO+HMA's efficacy and favorable toxicity profile in patients with mIDH1 ND-AML. IVO + azacitidine should be considered as the preferred standard of care treatment regimen in this patient subgroup.

DOI: https://doi.org/10.1016/j.bneo.2025.100152
J Clin Invest. 2025 Sep 30. pii: e182480. [Epub ahead of print]

Acetyl-CoA carboxylase-1 inhibition increases regulatory T-Cell metabolism and graft-vs-host disease treatment efficacy via mitochondrial fusion.

Cameron McDonald-Hyman, Ethan G Aguilar, Ewoud B Compeer, Michael C Zaiken, Stephanie Y Rhee, Fathima A Mohamed, Jemma H Larson, Michael L Loschi, Christopher Lees, Govindarajan Thangavelu, Margaret L Sleeth, Kyle D Smith, Jennifer S Whangbo, Jerome Ritz, Tim D Sparwasser, Roddy S O'Connor, Peter A Crawford, Jeffrey C Rathmell, Leslie S Kean, Robert Zeiser, Keli L Hippen, Michael L Dustin, Bruce R Blazar.

  Regulatory T-cells (Treg) are critical for maintaining immune homeostasis, and their adoptive transfer can treat murine inflammatory disorders. In patients, Treg therapies have been variably efficacious. Therefore, new strategies to enhance Treg therapeutic efficacy are needed. Treg predominantly depend upon oxidative phosphorylation (OXPHOS) for energy and suppressive function. Fatty acid oxidation (FAO) contributes to Treg OXPHOS and can be important for Treg "effector" differentiation, but FAO activity is inhibited by coordinated activity of isoenzymes acetyl-CoA Carboxylase-1 and -2 (ACC1/2). Here, we show that small molecule inhibition or Treg-specific genetic deletion of ACC1 significantly increases Treg suppressive function in vitro and in mice with established chronic GVHD. ACC1 inhibition skewed Treg towards an "effector" phenotype and enhanced FAO-mediated OXPHOS, mitochondrial function, and mitochondrial fusion. Inhibiting mitochondrial fusion diminished the effect of ACC1 inhibition. Reciprocally, promoting mitochondrial fusion, even in the absence of ACC1 modulation, resulted in a Treg functional and metabolic phenotype similar to ACC1 inhibition, indicating a key role for mitochondrial fusion in Treg suppressive potency. Ex vivo expanded, ACC1 inhibitor treated human Treg similarly augmented suppressor function as observed with murine Treg. Together, these data suggest that ACC1 manipulation may be exploited to modulate Treg function in patients.

Keywords:  Bone marrow transplantation; Immunology; Metabolism; Mitochondria; T cells

DOI:  https://doi.org/10.1172/JCI182480
Blood. 2025 Sep 30. pii: blood.2025029121. [Epub ahead of print]

Mechanisms of immune escape and extramedullary tropism in leukemia cutis.

Livius Penter, Katie Maurer, Nicoletta Cieri, Wesley Lu, Haoxiang Lyu, Mischa Selig, Maria Joosten, Jana Ihlow, Shuqiang Li, Kenneth J Livak, Lars Bullinger, Jerome Ritz, Pavan Bachireddy, Matthew S Davids, Jacqueline S Garcia, Robert J Soiffer, Catherine J Wu.

The mechanisms that lead to extramedullary tropism of acute myeloid leukemia (eAML) remain obscure and no specific therapeutic approaches for this entity exist. As the long-term survival of eAML is poor, a deeper understanding of the immune microenvironment and leukemia phenotypes underlying this entity is warranted. Here, we performed bulk and single-cell transcriptome profiling of 23 eAML biopsies from 10 patients with isolated extramedullary disease in skin and subcutaneous tissue. Unlike normal healthy skin, we found leukemia cutis to be heavily immune-infiltrated; in cases of extramedullary relapse following allogeneic stem cell transplantation, >90% of T/NK cells were donor-derived. eAML-associated T cells expressed a clear signature of T cell exhaustion, dissimilar to leukemia-associated immune populations in bone marrow relapse (n=7), but related to acute and chronic skin inflammation. Further, HLA class II was down-regulated in 4 of 7 leukemia cutis specimens, consistent with an immune escape phenotype in cases of eAML. Extramedullary and bone marrow-resident leukemia cells differed with regard to the expression of 8 homing receptor molecules (ICAM1 (encoding CD54), PECAM1 (CD31), ITGA4, ITGA6, ITGAL, ITGB4, ITGA5, and ITGAV). Serial samples obtained from one leukemia cutis case throughout consecutive immune checkpoint blockade with ipilimumab followed by nivolumab showed a consistently high degree of overlap between local and circulating T cell receptor (TCR) sequences, suggesting that only a minority of eAML-associated T cells are leukemia-specific. Our analysis reveals eAML to associate with complex changes in leukemia and T cell gene expression profiles that suggest multiple potential avenues for therapeutic targeting.

DOI: https://doi.org/10.1182/blood.2025029121
bioRxiv. 2025 Jan 22. pii: 2025.01.19.633812. [Epub ahead of print]

Regulation of cell cycle by the novel GATA1/TAL1/Sphingomyelin Synthase 1 ( SGMS1 ) transcriptional axis. Implications for anti-leukemic strategies.

Yasharah Raza, Sitapriya Moorthi, Gui-Qin Yu, Sam Chiappone, Caterina Vacchi-Suzzi, Chiara Luberto.

Sphingomyelin Synthase 1 (gene name: SGMS1 ) participates in regulation of sphingolipid levels by synthesizing sphingomyelin from ceramide and phosphatidylcholine. Evidence have supported SGMS1's functions in regulating proliferation, cell cycle, cell death and migration. While its functions have begun to be explored, very little is known about upstream regulators. Here, we demonstrate that SGMS1 is a direct gene target of the GATA1-TAL1 transcriptional complex in K562 erythroleukemic cells. A predicted GATA1 consensus DNA binding sequence was identified with in a newly characterized alternative SGMS1 promoter (TSS-7 promoter) and ChIP analysis confirmed GATA1 occupancy on the promoter. Down-regulation of GATA1 in K562 cells significantly decreased SGMS1 expression and enzymatic activity, and ChIP-Seq analysis from ENCODE showed colocalized peaks for GATA1 and TAL1 ( a well-established GATA1 DNA binding partner) on the SGMS1 gene. Analysis of publicly available datasets shows that elevated GATA1, TAL1 and SGMS1 expression not only clusters GATA1 positive chronic myelogenous leukemia cells (like K562), but also selectively identifies acute erythrocytic and megakaryocytic leukemias (M6 and M7 AML, respectively). Microarray gene expression analysis after down-regulation of SGMS1 in M6 AML Hel cells revealed alteration of genes regulating G2/M check point and mitotic spindle formation. This phenotype was functionally confirmed by the significant delay in G2/M cell cycle progression of cells with SGMS1 downregulation and sensitization to the clinically relevant anti-mitotic agent, Taxol. Altogether, these results identify SGMS1 as a novel target of GATA1/TAL1 transcriptional complex and they support a role for the GATA1/TAL1/SGMS1 axis in regulating transit through G2/M. Importantly, results also point to combination of anti-mitotic agents and inhibition of SGMS1 as a potential novel therapeutic approach against the aggressive and resilient M6 AMLs.
KEY POINTS: The Sphingomyelin Synthase 1 gene ( SGMS1 ) is a novel direct target of GATA1 and TAL1. High SGMS1 levels are associated with high GATA1/TAL1 expression and regulate cell cycle progression through the G2/M checkpoint in GATA1 + erythroleukemic Acute Myeloid Leukemia Hel cells. High SGMS1 is associated with lower probability of survival of patients with Acute Myeloid Leukemia and down-regulation of SGMS1 co-operates with microtubule targeting agents to induce cytotoxicity in GATA1 positive AML Hel cells.

DOI: https://doi.org/10.1101/2025.01.19.633812
Haematologica. 2025 Oct 02.

Diagnosis and management of adult telomere biology disorders.

Madeline Franke, Alejandro Ferrer, Mrinal M Patnaik.

Telomere biology disorders (TBDs) comprise a heterogenous group of inherited conditions characterized by impaired telomere maintenance, resulting in abnormal telomere lengths and/or telomere dysfunction. The clinical spectrum of TBDs is broad, spanning bone marrow failure, pulmonary fibrosis, liver disease, and an increased predisposition to malignancy, complicating timely diagnosis and management. In this review, we explore the evolving clinical landscape and diagnostic strategies for TBDs, while highlighting the diverse phenotypic presentations. We further examine the role of telomere dysfunction in driving cancer development and clonal hematopoiesis. Finally, we discuss current and emerging therapeutic approaches for TBDs, emphasizing the need for individualized and multidisciplinary management to optimize patient outcomes.

DOI: https://doi.org/10.3324/haematol.2025.287739
bioRxiv. 2025 Sep 25. pii: 2025.09.24.678339. [Epub ahead of print]

Genetic landscape of DNMT3A R882H reveals mechanism of aberrant oligomerization.

Emma M Garcia, Olivia R Lavidor, Shaunak Raval, Nicholas Z Lue, Jessica K Liang, Maeve McFadden, Derek D Hwang, Marcanthony U Zepeda, Luke W Chen, Steven A Carr, Malvina Papanastasiou, Brian B Liau.

DNA methyltransferase 3A (DNMT3A) is a de novo DNA methyltransferase that is recurrently mutated in hematological malignancies and developmental disorders. The most prevalent mutation, R882H, compromises DNMT3A activity in a dominant-negative manner, but its precise biochemical mechanism has been debated. Here, we use paired deep mutational scanning of the wild-type and R882H-mutant proteins to systematically identify mutations on a massively parallel scale that modify DNMT3A activity by suppressing, phenocopying, or selectively rescuing the dominant-negative effect of R882H. By leveraging the mutational depth and unbiased nature of the paired genetic landscapes, we uncover two distinct mechanisms that can rescue DNMT3A R882H activity, providing novel insights into the function of the R882 hotspot. First, by analyzing the effects of combinatorial mutations in the target recognition domain (TRD), we reveal that its crosstalk with the ADD regulatory domain modulates DNMT3A DNA binding and enzymatic activity, partially compensating for R882H-induced loss-of-function. Second, pairwise analysis of variant effects across the two genetic backgrounds supports the notion that R882H promotes aberrant macro-oligomerization of DNMT3A via its central dimerization interface, which accounts for its dominant-negative effect. Critically, we show that the R882 position exhibits a distinct dominant-negative signature in the genetic landscape, where positively charged residues at this position safeguard against aberrant macro-oligomerization. By performing hydrogen-deuterium exchange mass spectrometry (HDX-MS) on DNMT3A mutants, we show that R882H dramatically alters the protein dynamics of DNMT3A, rigidifying its central dimerization interface to promote oligomerization. Our data support a new model in which R882H removes the critical function of R882, where the arginine attenuates the pre-organization of the interface and subsequent oligomerization at a supramolecular assembly hotspot 1 . Altogether, we map the genetic landscape underpinning the DNMT3A R882H hotspot mutation, illuminating the unexpected molecular mechanism of macro-oligomerization that drives its dominant-negative effect.

DOI: https://doi.org/10.1101/2025.09.24.678339
Res Sq. 2025 Sep 26. pii: rs.3.rs-7563799. [Epub ahead of print]

RPS19 and RPL5 Haploinsufficient Models Reveal Divergent Ribosomal Subunit Controls of Fetal Hematopoiesis.

Lionel Blanc, Yuefeng Tang, Te Ling, Rashid Mehmood, Alexis Bertrand, Julien Papoin, Mushran Khan, Riaz Rao, Jianing Xu, Vincent Schulz, James Palis, Laurie Steiner, Betsy Barnes, YongRui Zou, Philippe Marambaud, Robert Signer, Irene Roberts, Deena Iskander, Leonard Zon, Senthil Bhoopalan, Mitchell Weiss, Jeffrey Lipton, Patrick Gallagher, Narla Mohandas, Naomi Taylor, Sebastien Durand, John Crispino.

Diamond Blackfan anemia syndrome (DBAS) is a congenital ribosomopathy caused by haploinsufficiency of ribosomal proteins (RPs), but how RP stoichiometry and activity regulates erythroid development remains enigmatic. Using novel in vivo models, we uncover strikingly divergent functions for the small and large ribosomal subunit proteins RPS19 and RPL5 in fetal hematopoiesis. While RPL5 haploinsufficiency causes hematopoietic stem and progenitor cell (HSPC) accumulation and prenatal lethality via p53-mediated ferroptosis of mature erythroid progenitors, RPS19 haploinsufficiency leads to HSPC depletion and impaired erythroid expansion through p53-dependent apoptosis. The latter is accompanied by translational and transcriptional dysregulation, including the upregulation of RUNX1 , which is also observed in RPS- haploinsufficient DBAS patients. Importantly, Runx1 deletion in RPS19-haploinsufficient mice partially rescues HSPC numbers. These findings reveal subunit-specific RP functions in controlling fetal hematopoiesis and demonstrate how imbalanced RP stoichiometry disrupts developmental programs, providing crucial mechanistic insights into DBAS pathogenesis and the basis for its clinical heterogeneity.

DOI: https://doi.org/10.21203/rs.3.rs-7563799/v1