bims-tremyl 2025-04-13 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2025–04–13
thirty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Distinct routes of clonal progression in SF3B1-mutant myelodysplastic syndromes.
Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.
TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia.
Identification of CD84 as a potent survival factor in acute myeloid leukemia.
Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.
Safety, tolerability, and pharmacokinetics of ASP1235 in relapsed or refractory acute myeloid leukemia: A phase 1 study.
Asciminib monotherapy in patients with chronic myeloid leukemia in chronic phase without BCR::ABL1T315I treated with at least 2 prior TKIs: Phase 1 final results.
Azacitidine, Venetoclax and Magrolimab in Newly Diagnosed and Relapsed Refractory Acute Myeloid Leukemia: Phase 1b/2 Study and Correlative Analysis.
Myeloid neoplasm inspired intensive therapy in VEXAS syndrome: A single-centre experience.
DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes.
Asciminib in combination with imatinib, nilotinib, or dasatinib in patients with chronic myeloid leukemia in chronic or accelerated phase: phase 1 study final results.
PD-1 Inhibition for Relapse after Allogeneic Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome.
Natural killer cells' functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes.
Patients with AML and an IDH2-R172 Mutation Exhibit a Unique Initial Response to Intensive Chemotherapy Induction.
Mechanisms of hematopoietic clonal dominance in VEXAS syndrome.
Project EVOLVE: An international analysis of postimmunotherapy lineage switch, an emergent form of relapse in leukemia.
A network-based approach to overcome BCR::ABL1-independent resistance in chronic myeloid leukemia.
Inflammatory signaling pathways play a role in SYK inhibitor resistant AML.
Elastic properties of leukemic cells linked to maturation stage and integrin activation.
Timing and trajectory of BCR::ABL1-driven chronic myeloid leukaemia.
Bcl7b and Bcl7c Subunits of BAF Chromatin Remodeling Complexes are Largely Dispensable for Hematopoiesis.
Bcl11a maintains hematopoietic stem cell function but accelerates inflammation-driven exhaustion during aging.
An unbiased genomewide screen uncovers 7 genes that drive hematopoietic stem cell fate from mouse embryonic stem cells.
Discovery of the first-in-class DOT1L PROTAC degrader.
Managing Myelofibrosis: Matching Advances in Treatments With Clinical Unmet Needs.
The mechanism of EZH2/H3K27me3 downregulating CXCL10 to affect CD8+ T cell exhaustion to participate in the transformation from myelodysplastic syndrome to acute myeloid leukaemia.
Breakthroughs of CAR T-cell therapy in acute myeloid leukemia: updates from ASH 2024.
Haematopoietic stem cell (HSC) graft cryopreservation effects on outcomes of patients with haematological malignancies: the multi-centre UK experience during COVID-19 pandemic.
Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors.
Fabp4 is essential for the maintenance of leukemia stem cells while sparing hematopoietic stem cells.
The effect of ibrutinib on the myeloid cell compartment in CNS lymphoma.

Blood Adv. 2025 Apr 06. pii: bloodadvances.2024014965. [Epub ahead of print]

Distinct routes of clonal progression in SF3B1-mutant myelodysplastic syndromes.

Martina Sarchi, Courtnee A Clough, Anna Gallì, Cristina Picone, Beatrice Ferrari, Edie I Crosse, Laura D Baquero Galvis, Claudia Fiducioso, Nelli Aydinyan, J Philip Creamer, Sara Pozzi, Elisabetta Molteni, Chiara Elena, Robert K Bradley, Luca Malcovati, Sergei Doulatov.

Myelodysplastic syndromes (MDS) are clonal stem cell disorders driven by heterogeneous genetic alterations leading to variable clinical course. MDS with splicing factor SF3B1 mutations is a distinct subtype with a favorable outcome. However, selected co-mutations induce poor prognosis and how these genetic lesions cooperate in human hematopoietic stem and progenitor cells (HSPCs) during disease progression is still unclear. Here, we integrated clinical and molecular profiling of patients with SF3B1 mutations with gene editing of primary and iPSC-derived human HSPCs to show that high-risk co-mutations impart distinct effects on lineage programs of SF3B1-mutant HSPCs. Secondary RUNX1 or STAG2 mutations were clinically associated with advanced disease and reduced survival. However, RUNX1 and STAG2 mutations induced opposing regulation of myeloid transcriptional programs and differentiation in SF3B1-mutant HSPCs. Moreover, high-risk RUNX1 and STAG2, but not low-risk TET2, mutations expanded distinct SF3B1-mutant HSPC subpopulations. These findings provide evidence that progression from low- to high-risk MDS involves distinct molecular and cellular routes depending on co-mutation patterns.

DOI: https://doi.org/10.1182/bloodadvances.2024014965
bioRxiv. 2025 Mar 26. pii: 2025.03.24.645017. [Epub ahead of print]

Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.

Gaurav Agarwal, Mateusz Antoszewski, Xueqin Xie, Yash Pershad, Uma P Arora, Chi-Lam Poon, Peng Lyu, Andrew J Lee, Chun-Jie Guo, Tianyi Ye, Laila Barakat Norford, Anna-Lena Neehus, Lucrezia Della Volpe, Lara Wahlster, Diyanath Ranasinghe, Tzu-Chieh Ho, Trevor S Barlowe, Arthur Chow, Alexandra Schurer, James Taggart, Benjamin H Durham, Omar Abdel-Wahab, Kathy L McGraw, James M Allan, Ruslan Soldatov, Alexander G Bick, Michael G Kharas, Vijay G Sankaran.

Somatic mutations that increase hematopoietic stem cell (HSC) fitness drive their expansion in clonal hematopoiesis (CH) and predispose to blood cancers. Although CH frequently occurs with aging, it rarely progresses to overt malignancy. Population variation in the growth rate and potential of mutant clones suggests the presence of genetic factors protecting against CH, but these remain largely undefined. Here, we identify a non-coding regulatory variant, rs17834140-T, that significantly protects against CH and myeloid malignancies by downregulating HSC-selective expression and function of the RNA-binding protein MSI2. By modeling variant effects and mapping MSI2 binding targets, we uncover an RNA network that maintains human HSCs and influences CH risk. Importantly, rs17834140-T is associated with slower CH expansion rates in humans, and stem cell MSI2 levels modify ASXL1-mutant HSC clonal dominance in experimental models. These findings leverage natural resilience to highlight a key role for post-transcriptional regulation in human HSCs, and offer genetic evidence supporting inhibition of MSI2 or its downstream targets as rational strategies for blood cancer prevention.

DOI: https://doi.org/10.1101/2025.03.24.645017
bioRxiv. 2025 Mar 27. pii: 2025.03.24.644993. [Epub ahead of print]

TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia.

Jeevitha D'Souza, Camille J Leung, Aishwarya C Ballapuram, Abigail S Lin, Alexa Rane Batingana, Adam J Lamble, Rhonda E Ries, Carolina E Morales, Charisa Cottonham, Pranav Gona, Li Fan, Xiaotu Ma, Kevin Shannon, Soheil Meshinchi, Benjamin S Braun, Benjamin J Huang.

Acute myeloid leukemia (AML) is a heterogeneous cancer that is associated with poor outcomes. Revumenib and other menin inhibitors have shown promising activity against AMLs with KMT2A -rearrangements or NPM1 mutations. However, mechanisms of de novo resistance have not yet been elucidated. We analyzed a panel of cell lines and generated an isogenic model to assess the impact of TP53 mutations on the response of AML cells to revumenib. TP53 mutations are associated with de novo resistance to revumenib, impaired induction of TP53 transcriptional targets, and deregulated expression of the BH3 proteins BCL-2 and MCL-1. The MCL-1 inhibitor MIK665, but not venetoclax, preferentially sensitized TP53 -mutant AML cells to revumenib. These data identify mutant TP53 as a potential biomarker for de novo resistance to revumenib, and provide a rationale to evaluate MCL-1 and menin inhibitor combinations in patients KMT2A -rearranged leukemias with TP53 mutations.

DOI: https://doi.org/10.1101/2025.03.24.644993
J Clin Invest. 2025 Apr 08. pii: e176818. [Epub ahead of print]

Identification of CD84 as a potent survival factor in acute myeloid leukemia.

Yinghui Zhu, Mariam Murtadha, Miaomiao Liu, Enrico Caserta, Ottavio Napolitano, Le Xuan Truong Nguyen, Huafeng Wang, Milad Moloudizargari, Lokesh Nigam, Theophilus Tandoh, Xuemei Wang, Alex Pozhitkov, Rui Su, Xiangjie Lin, Marc Denisse Estepa, Raju Pillai, Joo Song, James F Sanchez, Yu-Hsuan Fu, Lianjun Zhang, Man Li, Bin Zhang, Ling Li, Ya-Huei Kuo, Steven Rosen, Guido Marcucci, John C Williams, Flavia Pichiorri.

  Acute myeloid leukemia (AML) is an aggressive and often deadly malignancy associated with proliferative immature myeloid blasts. Here, we identified CD84 as a critical survival regulator in AML. High levels of CD84 expression provided a survival advantage to leukemia cells, whereas CD84 downregulation disrupted their proliferation, clonogenicity and engraftment capabilities in both human cell lines and patient derived xenograft cells. Critically, loss of CD84 also markedly blocked leukemia engraftment and clonogenicity in MLL-AF9 and inv(16) AML mouse models, highlighting its pivotal role as survival factor across species. Mechanistically, CD84 regulated leukemia cells' energy metabolism and mitochondrial dynamics. Depletion of CD84 altered mitochondrial ultra-structure and function of leukemia cells, and it caused down-modulation of both oxidative phosphorylation and fatty acid oxidation pathways. CD84 knockdown induced a block of Akt phosphorylation and down-modulation of nuclear factor erythroid 2-related factor 2 (NRF2), impairing AML antioxidant defense. Conversely, CD84 over-expression stabilized NRF2 and promoted its transcriptional activation, thereby supporting redox homeostasis and mitochondrial function in AML. Collectively, our findings indicated that AML cells depend on CD84 to support antioxidant pro-survival pathways, highlighting a therapeutic vulnerability of leukemia cells.

Keywords:  Antigen; Bone marrow; Cancer immunotherapy; Cell biology; Hematology; Oncology

DOI:  https://doi.org/10.1172/JCI176818
Sci Adv. 2025 Apr 11. 11(15): eadu5511

Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.

James T Hagen, McLane M Montgomery, Raphael T Aruleba, Brett R Chrest, Polina Krassovskaia, Thomas D Green, Emely A Pacheco, Miki Kassai, Tonya N Zeczycki, Cameron A Schmidt, Debajit Bhowmick, Su-Fern Tan, David J Feith, Charles E Chalfant, Thomas P Loughran, Darla Liles, Mark D Minden, Aaron D Schimmer, Md Salman Shakil, Matthew J McBride, Myles C Cabot, Joseph M McClung, Kelsey H Fisher-Wellman.

OxPhos inhibitors have struggled to show a clinical benefit because of their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to acute myeloid leukemia (AML) mitochondria. Unlike healthy cells that couple respiration to ATP synthesis, AML mitochondria support inner-membrane polarization by consuming ATP. Matrix ATP consumption allows cells to survive bioenergetic stress. Thus, we hypothesized AML cells may resist chemotherapy-induced cell death by reversing the ATP synthase reaction. In support, BCL-2 inhibition with venetoclax abolished OxPhos flux without affecting mitochondrial polarization. In surviving AML cells, sustained mitochondrial polarization depended on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to down-regulations in the endogenous F1-ATPase inhibitor ATP5IF1. Knockdown of ATP5IF1 conferred venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. These data identify matrix ATP consumption as a cancer cell-intrinsic bioenergetic vulnerability actionable in the context of BCL-2 targeted chemotherapy.

DOI: https://doi.org/10.1126/sciadv.adu5511
Leuk Res. 2025 Apr 02. pii: S0145-2126(25)00050-5. [Epub ahead of print]152 107690

Safety, tolerability, and pharmacokinetics of ASP1235 in relapsed or refractory acute myeloid leukemia: A phase 1 study.

Monzr M Al Malki, Mark D Minden, Elizabeth Shima Rich, Jason E Hill, Stanley C Gill, Alan Fan, Christine E Fredericks, Amir T Fathi, Maher Abdul-Hay.

  Acute myeloid leukemia (AML) is an aggressive hematologic malignancy. Although new agents including targeted therapies for relapsed or refractory (R/R) AML have been introduced, poor outcomes remain, requiring the need for novel approaches. One novel approach is the use of antibody-drug conjugates (ADCs). We conducted an early phase clinical trial with ASP1235, an ADC targeting FMS-like tyrosine kinase 3. In total, 43 patients with R/R AML were treated with ASP1235. The most common adverse events (AEs) included elevated liver transaminase levels, ocular toxicity, and muscular weakness. Ocular treatment-emergent AEs (TEAEs) were observed in 53 % of patients; most were mild or moderate in severity. The most common ocular TEAEs were blurred vision, dry eye, keratitis, photophobia, and reduced visual acuity. Serious (grade ≥3) ocular TEAEs occurred in 16.3 % of patients, with only 1 patient experiencing grade 4 keratitis. Six patients achieved composite complete remission (complete remission [CR] + CR with incomplete hematologic recovery + CR with incomplete platelet recovery), 2 of whom proceeded to hematopoietic cell transplantation with long-term leukemia-free survival. This trial was registered at www.clinicaltrials.gov as #NCT02864290.

Keywords:  Acute myeloid leukemia (AML); Antibody-drug conjugate; FMS-like tyrosine kinase 3

DOI:  https://doi.org/10.1016/j.leukres.2025.107690
Leukemia. 2025 Apr 09.

Asciminib monotherapy in patients with chronic myeloid leukemia in chronic phase without BCR::ABL1T315I treated with at least 2 prior TKIs: Phase 1 final results.

Andreas Hochhaus, Dong-Wook Kim, Jorge E Cortes, Koji Sasaki, Michael J Mauro, Timothy P Hughes, Massimo Breccia, Moshe Talpaz, Hironobu Minami, Yeow Tee Goh, Daniel J DeAngelo, Fabian Lang, Oliver Ottmann, Michael C Heinrich, Valle Gomez Garcia de Soria, Philipp le Coutre, Gessami Sanchez-Olle, Meng Cao, Nathalie Pognan, Shruti Kapoor, Matthias Hoch, Delphine Rea.

Asciminib is the first approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP). The present final analysis of the phase 1, open-label, nonrandomized trial (NCT02081378) assessed the long-term safety, tolerability, and antileukemic activity of asciminib in 115 patients with chronic myeloid leukemia in chronic phase without the BCR::ABL1T315I mutation who received asciminib 10-200 mg twice daily (BID) or 80-200 mg once daily (cutoff: March 14, 2023). Median exposure duration was 5.9 (range, 0-8.4) years; 60.9% of patients continued receiving asciminib through post-trial access. Grade ≥3 adverse events (AEs) occurred in 88 patients (76.5%). AEs led to treatment discontinuation, dose adjustment/interruption, or additional therapy in 15 (13.0%), 74 (64.3%), and 106 (92.2%) patients, respectively. Most first-ever AEs, particularly hematologic AEs, presented within the first year and no new safety signals emerged. Of 56 patients who achieved major molecular response, 50 maintained the response by cutoff; the Kaplan-Meier-estimated probability of maintaining this response for ≥432 weeks ( ≈ 8.3 years) was 88% (95% confidence interval, 78.2-97.0%). The recommended dose for expansion was determined at 40 mg BID. With up to 8.4 years of treatment, asciminib continued to demonstrate long-term safety and efficacy in this population.

DOI: https://doi.org/10.1038/s41375-025-02578-7
Clin Cancer Res. 2025 Apr 08.

Azacitidine, Venetoclax and Magrolimab in Newly Diagnosed and Relapsed Refractory Acute Myeloid Leukemia: Phase 1b/2 Study and Correlative Analysis.

Naval Daver, Jayastu Senapati, Hagop M Kantarjian, Bofei Wang, Patrick K Reville, Sanam Loghavi, Musa Yilmaz, Courtney D DiNardo, Tapan M Kadia, Mhd Yousuf Yassouf, Abhishek Maiti, Sankalp Arora, Guillermo Montalban Bravo, Guilin Tang, Gautam Borthakur, Koji Sasaki, Naveen Pemmaraju, Joie Alvarez, Graciela M Nogueras Gonzalez, Jing Ning, Ghayas C Issa, Marina Konopleva, Michael Andreeff, Farhad Ravandi, Guillermo Garcia-Manero, Hussein A Abbas.

PURPOSE: Magrolimab is a monoclonal antibody directed against macrophage checkpoint CD47 on myeloid leukemia cells that was pre-clinically synergistic with azacitidine-venetoclax, warranting further clinical evaluation.
PATIENTS AND METHODS: In this phase 1b/2 study the triplet combination of azacitidine, venetoclax and magrolimab was evaluated in adult patients with frontline (ineligible for intensive chemotherapy) and relapsed/refractory AML. Azacitidine was dosed at 75mg/m2 for 7 days, venetoclax at 400 mg/day for 28 days, and magrolimab (recommended phase 2 dose [RP2D]) as follows: 1 mg/kg dose on days 1 and 4, 15 mg/kg on day 8, 30 mg/kg on day 11, 15 and 22 (cycle 1), followed by 30 mg/kg weekly for cycle 2, then 30 mg/kg every 2 weeks cycle 3 and beyond. The primary endpoint was RP2D for phase 1b and rates of composite complete response (CRc) in phase 2.
RESULTS: The frontline cohort included 54 patients (median age 70.1 years); 35 (64.8%) were TP53 mutated (TP53mut). CRc was attained in 34 patients (63%); 49% in TP53mut and 90% in the TP53 wild-type patients. At a median follow-up of 27.9 months, the median event free survival (EFS) and overall survival (OS) was 6.6 months and 9.8 months respectively; for TP53mut patients the median EFS and OS was 5.9 and 7.6 months, while for TP53 wild type it was 9.6 months and 13 months respectively. CRc in the relapsed/refractory cohort (n=52) was 29% and median OS was 3.9 months. The regimen was well tolerated; infections were the most common ≥ grade 3 adverse event (75.4%) with no immune toxicities or deaths related to therapy. scRNAseq was performed on 27 longitudinal samples from 11 TP53mut patients (8 responders). Gene set enrichment analysis revealed enrichment of IFNγ and TNFα signaling in non-responders at baseline, while erythroid differentiation was associated with resistance. Patients at relapse also showed up-regulated CD47 expression and elevated leukemia regeneration score.
CONCLUSIONS: The triplet regimen was safe but did not lead to promising survival outcomes.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-0229
Br J Haematol. 2025 Apr 08.

Myeloid neoplasm inspired intensive therapy in VEXAS syndrome: A single-centre experience.

Maël Heiblig, Adriana Plesa, Juliet Tantot, Yvan Jamilloux, Hélène Labussière-Wallet, Pierre Sujobert.

  There is still no standard of care and unmet medical needs in refractory/advanced VEXAS (vacuoles in myeloid progenitors, E1 ubiquitin activating enzyme, X-linked, autoinflammatory manifestations and somatic) syndrome with or without associated haematological neoplasm. We report the clinical outcome of four multirefractory/advanced VEXAS patients treated with acute myeloid leukaemia-like therapeutic approaches. All patients responded to inflammatory/haematological VEXAS-related features, which were associated with measurable residual disease response (partial or complete). Prospective studies evaluating new and effective therapeutic strategies in order to reduce clonal burden in VEXAS patients are warranted.

Keywords:  VEXAS; acute leukaemia; venetoclax

DOI:  https://doi.org/10.1111/bjh.20067
Leukemia. 2025 Apr 09.

DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes.

Fadimana Kaya, Findlay Bewicke-Copley, Juho J Miettinen, Pedro Casado, Eve Leddy, Özgen Deniz, Vincent-Philippe Lavallée, Celine Philippe, Jiexin Zheng, Florian Grebien, Naeem Khan, Szilvia Krizsán, Joseph Saad, Alexis Nolin-Lapalme, Josée Hébert, Sébastien Lemieux, Eric Audemard, Janet Matthews, Marianne Grantham, Doriana Di Bella, Krister Wennerberg, Alun Parsons, John Gribben, James D Cavenagh, Sylvie D Freeman, Csaba Bödör, Guy Sauvageau, Jun Wang, Pilar Llamas-Sillero, Jean-Baptiste Cazier, David C Taussig, Dominique Bonnet, Pedro R Cutillas, Caroline A Heckman, Jude Fitzgibbon, Kevin Rouault-Pierre, Ana Rio-Machin.

The t(6;9)(p22.3;q34.1) translocation/DEK::NUP214 fusion protein defines a distinct subgroup of younger AML patients classified as a separate disease entity by the World Health Organization. DEK is a nuclear factor with multifunctional roles, including gene regulation, while its fusion partner, NUP214, plays a pivotal role in nuclear export by interacting with transport receptors such as XPO1. However, the precise mechanism by which DEK::NUP214 drives leukemia remains unclear. A comprehensive multi-omics comparison of 57 AML primary samples (including whole genome sequencing, targeted sequencing, transcriptomics, and drug screening with >500 compounds) revealed that t(6;9) cases display a selective response to XPO1 inhibitors (Selinexor & Eltanexor) and a distinct transcriptomic signature characterized by the overexpression of FOXC1 and HOX genes that are key leukemia mediators. CUT&RUN experiments demonstrated the direct binding of DEK::NUP214 to the promoters of FOXC1 and HOXA/B clusters. Strikingly, the expression of these genes and the binding of DEK::NUP214 to their regulatory regions were selectively reduced upon XPO1 inhibition in t(6;9) cells. Altogether, these results identified a novel function of DEK::NUP214 as an XPO1-dependent transcriptional activator of key leukemia drivers and provide a rationale to explore the use of XPO1 inhibitors in this patient population.

DOI: https://doi.org/10.1038/s41375-025-02593-8
Leukemia. 2025 Apr 09.

Asciminib in combination with imatinib, nilotinib, or dasatinib in patients with chronic myeloid leukemia in chronic or accelerated phase: phase 1 study final results.

Jorge E Cortes, Fabian Lang, Delphine Rea, Andreas Hochhaus, Massimo Breccia, Yeow Tee Goh, Michael C Heinrich, Timothy P Hughes, Jeroen J W M Janssen, Philipp le Coutre, Hironobu Minami, Koji Sasaki, Daniel J DeAngelo, Gessami Sanchez-Olle, Nathalie Pognan, Meng Cao, Matthias Hoch, Michael J Mauro.

Data from in vitro and animal studies suggest that asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), synergizes with adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) to prevent emergence of and overcome resistance. Combination therapy may provide new treatment options for patients with chronic myeloid leukemia (CML) with suboptimal responses to ATP-competitive TKI monotherapy. Preliminary analysis of asciminib combined with nilotinib, imatinib, or dasatinib in a phase 1 dose-escalation study suggested promising efficacy and safety for patients with CML in chronic phase or accelerated phase treated with prior ATP-competitive TKIs; herein, we present final results from the 3 combination therapy arms. Asciminib, in combination with ATP-competitive TKIs, demonstrated rapid efficacy offset by a decreased tolerability compared with asciminib monotherapy. Based on these safety, tolerability, and preliminary efficacy results, asciminib 40 mg twice daily (BID) plus nilotinib 300 mg BID, asciminib 40 or 60 mg once daily (QD) plus imatinib 400 mg QD, and asciminib 80 mg QD plus dasatinib 100 mg QD were identified as recommended doses for expansion. The maximum tolerated dose was reached at asciminib 60 mg QD plus imatinib 400 mg QD and was not reached with asciminib plus nilotinib or dasatinib.

DOI: https://doi.org/10.1038/s41375-025-02592-9
Blood Adv. 2025 Apr 08. pii: bloodadvances.2024015200. [Epub ahead of print]

PD-1 Inhibition for Relapse after Allogeneic Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome.

John M Magenau, David G Frame, Mary Mansour Riwes, John Joseph Maciejewski, Sarah Anand, Attaphol Pawarode, Anamarija M Perry, Marcus J Geer, Thomas M Braun, Monalisa Ghosh, Pavan Reddy.

Relapse of AML and MDS remains the primary source of mortality after allogeneic transplantation (HCT). Targeting PD-1 is an approach for reversing T cell exhaustion and restoring the graft-versus-leukemia (GVL) effect that has logistical advantages versus donor lymphocyte infusion. In a prospective phase 1B clinical trial, pembrolizumab monotherapy was administered every three weeks to sixteen AML (n=12) and MDS (n=4) patients in relapse after HCT to assess Graft-versus-Host Disease (GVHD), clinical response and survival. The median time to relapse after HCT was 5.5 months and the median pre-treatment bone marrow blast percentage was 21.5%. The overall response rate (ORR) was 31.3% for patients receiving pembrolizumab monotherapy, consisting of three complete remissions (18.8%) and two partial remissions (13.5%). The median duration of response was 610 days. A significantly greater proportion of patients with mixed CD3 chimerism had clinical response compared to those with full donor chimerism (50% vs. 0%; p=0.03). Immune toxicities were frequent with 37.5% patients developing severe (grade III-IV) GVHD after pembrolizumab, of which the majority had resistance to corticosteroids and contributed to death in four patients (25%). The one-year overall survival was 37.5% and event-free survival was 31.3%. For AML, one-year overall survival was 50.0%. In this trial, PD-1 inhibition led to durable remissions in a third of patients experiencing early relapse after HCT suggesting this approach may augment the GVL response. Responses were exclusively observed in the setting of mixed CD3 donor chimerism. Immune toxicities (GVHD) were a barrier to successful treatment outcome. NCT03286114.

DOI: https://doi.org/10.1182/bloodadvances.2024015200
Nat Commun. 2025 Apr 11. 16(1): 3450

Natural killer cells' functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes.

Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Bijender Kumar, Natthakan Thongon, Feiyang Ma, Kelly S Chien, Yi J Kim, Hui Yang, Sanam Loghavi, Roselyn Tan, Vera Adema, Zongrui Li, Tomoyuki Tanaka, Hidetaka Uryu, Rashmi Kanagal-Shamanna, Gheath Al-Atrash, Rafael Bejar, Pinaki Prosad Banerjee, Sophia Lynn Cha, Guillermo Montalban-Bravo, Max Dougherty, Maria Claudina Fernandez Laurita, Noelle Wheeler, Baosen Jia, Eirini P Papapetrou, Franco Izzo, Daniela E Dueñas, Salome McAllen, Yiqian Gu, Gabriele Todisco, Francesca Ficara, Matteo Giovanni Della Porta, Abhinav Jain, Koichi Takahashi, Karen Clise-Dwyer, Stephanie Halene, Maria Teresa Sabrina Bertilaccio, Guillermo Garcia-Manero, May Daher, Simona Colla.

Dissecting the preneoplastic disease states' biological mechanisms that precede tumorigenesis can lead to interventions that can slow down disease progression and/or mitigate disease-related comorbidities. Myelodysplastic syndromes (MDS) cannot be cured by currently available pharmacological therapies, which fail to eradicate aberrant hematopoietic stem cells (HSCs), most of which are mutated by the time of diagnosis. Here, we sought to elucidate how MDS HSCs evade immune surveillance and expand in patients with clonal cytopenias of undetermined significance (CCUS), the pre-malignant stage of MDS. We used multi-omic single-cell approaches and functional in vitro studies to show that immune escape at disease initiation is mainly mediated by mutant, dysfunctional natural killer (NK) cells with impaired cytotoxic capability against cancer cells. Preclinical in vivo studies demonstrated that injecting NK cells from healthy donors efficiently depleted CCUS mutant cells while allowing normal cells to regenerate hematopoiesis. Our findings suggest that early intervention with adoptive cell therapy can prevent or delay the development of MDS.

DOI: https://doi.org/10.1038/s41467-025-58662-0
Blood Adv. 2025 Apr 08. pii: bloodadvances.2024015324. [Epub ahead of print]

Patients with AML and an IDH2-R172 Mutation Exhibit a Unique Initial Response to Intensive Chemotherapy Induction.

Meira Yisraeli Salman, Alexander R Terry, Andriy Derkach, David Nemirovsky, Kuo-Kai Chin, Yannis K Valtis, Leora Boussi, Theresa Spivey, Wenbin Xiao, Christopher A Famulare, Jenna R Ciervo, Jacob M Rowe, Martin S Tallman, Eytan M Stein.

The utility of a mid-cycle bone marrow biopsy (BMB) for early assessment of response in patients with acute myeloid leukemia (AML) after intensive chemotherapy (IC) induction is contested. Even when challenged, there is little consideration as to the possibility of different response dynamics among genetically defined subgroups. Clinical observations led to the hypothesis that patients with AML and mutations in IDH2-R172 (R172-m) exhibit particularly slow blast reduction following IC induction. The purpose of this study was to analyze response kinetics of patients with R172-m to IC and compare the dynamics to patients with AML and IDH2-R140 mutations (R140-m). A retrospective single-center analysis was conducted among patients with newly diagnosed IDH2-mutated AML who received IC induction. Dynamics of blast reduction were compared and correlated with outcomes. 52 patients were identified; 33 with R140-m and 19 with R172-m. Patients with R172-m had significantly higher mid-cycle BMB median blast count (70% versus 5%, p<0.001), and their BMBs were slightly more cellular (p=0.045). Among the R140-m, 58% had ≤5% blasts versus 0 of the R172-m. Furthermore, it took significantly longer for patients with R172-m to achieve blast clearance (≤5% blasts in BMB) compared to those with R140-m (p=0.017). However, there was no difference in overall survival between the two groups, and outcomes were similar and favorable. This type of slow blast reduction has only previously been described in patients with acute promyelocytic leukemia. These findings suggest judicial application of re-induction strategies in this subgroup and warrant further investigation.

DOI: https://doi.org/10.1182/bloodadvances.2024015324
Nat Med. 2025 Apr 07.

Mechanisms of hematopoietic clonal dominance in VEXAS syndrome.

Raffaella Molteni, Martina Fiumara, Corrado Campochiaro, Roberta Alfieri, Guido Pacini, Eugenia Licari, Alessandro Tomelleri, Elisa Diral, Angelica Varesi, Alessandra Weber, Pamela Quaranta, Luisa Albano, Chiara Gaddoni, Luca Basso-Ricci, Davide Stefanoni, Laura Alessandrini, Sara Degl'Innocenti, Francesca Sanvito, Gregorio Maria Bergonzi, Andrea Annoni, Maddalena Panigada, Eleonora Cantoni, Daniele Canarutto, Stephanie Z Xie, Angelo D'Alessandro, Raffaella Di Micco, Alessandro Aiuti, Fabio Ciceri, Giacomo De Luca, Lorenzo Dagna, Marco Matucci-Cerinic, Ivan Merelli, Simone Cenci, Serena Scala, Giulio Cavalli, Luigi Naldini, Samuele Ferrari.

Clonal dominance characterizes hematopoiesis during aging and increases susceptibility to blood cancers and common nonmalignant disorders. VEXAS syndrome is a recently discovered, adult-onset, autoinflammatory disease burdened by a high mortality rate and caused by dominant hematopoietic clones bearing somatic mutations in the UBA1 gene. However, pathogenic mechanisms driving clonal dominance are unknown. Moreover, the lack of disease models hampers the development of disease-modifying therapies. In the present study, we performed immunophenotype characterization of hematopoiesis and single-cell transcriptomics in a cohort of nine male patients with VEXAS syndrome, revealing pervasive inflammation across all lineages. Hematopoietic stem and progenitor cells (HSPCs) in patients are skewed toward myelopoiesis and acquire senescence-like programs. Humanized models of VEXAS syndrome, generated by inserting the causative mutation in healthy HSPCs through base editing, recapitulated proteostatic defects, cytological alterations and senescence signatures of patients' cells, as well as hematological and inflammatory disease hallmarks. Competitive transplantations of human UBA1-mutant and wild-type HSPCs showed that, although mutant cells are more resilient to the inflammatory milieu, probably through the acquisition of the senescence-like state, wild-type ones are progressively exhausted and overwhelmed by VEXAS clones, overall impairing functional hematopoiesis and leading to bone marrow failure. Our study unveils the mechanism of clonal dominance and provides models for preclinical studies and preliminary insights that could inform therapeutic strategies.

DOI: https://doi.org/10.1038/s41591-025-03623-9
Blood. 2025 Apr 07. pii: blood.2024026655. [Epub ahead of print]

Project EVOLVE: An international analysis of postimmunotherapy lineage switch, an emergent form of relapse in leukemia.

Sara K Silbert, Alexander W Rankin, Chloe N Hoang, Alexandra Semchenkova, Regina M Myers, Elena Zerkalenkova, Hao-Wei Wang, Alexandra E Kovach, Constance M Yuan, Dana Delgado Colon, Loic Vasseur, Alex Bataller, Samuel John, Kaylyn Utley Lyons, Barbara D Friedes, Anna Alonso-Saladrigues, Hisham Abdel-Azim, Estelle Balducci, Ahmed Aljudi, Marie Balsat, D Nathan Biery, Aghiad Chamdin, Bill H Chang, Raymund S Cuevo, Barbara De Moerloose, David S Dickens, Ulrich A Duffner, Nicolas Duployez, Firas El Chaer, Michelle Ann Elliott, Gabriele Escherich, Sneha Fernandes, Mandi R Fitzjohn, Zhubin J Gahvari, Stephan A Grupp, Rui Rochelle He, Cynthia Harrison, Christopher Bruce Hergott, Emily M Hsieh, Annette S Kim, Dennis John Kuo, Daniel P Larson, Benjamin J Lee, Thibaut Tl Leguay, R Coleman Lindsley, Abhishek A Mangaonkar, Kerstin Mezger, Holly L Pacenta, Jing Pan, Marlie R M Provost, Latika Puri, Sunil Sudhir Raikar, Armando Jose Martinez, Isabella Quijada Bristol, Kyle Daniel Murphy, Lauren Reiman, Michele S Redell, Kelly Reed, Gabrielle Roth Guepin, Jeremy D Rubinstein, Süreyya Savaşan, Kristian T Schafernak, Alexandra McLean Stevens, Aimee C Talleur, Naomi Torres Carapia, Jacques Vargaftig, Anant Vatsayan, Matthias Wölfl, Lipng Zhao, Susana Rives, Vanessa A Fabrizio, Koji Sasaki, Ibrahim Aldoss, Nicolas Boissel, Susan R Rheingold, Kara L Davis, Sara Ghorashian, Elad Jacoby, Alexander Popov, Adam Joseph Lamble, Nirali N Shah.

Lineage switch (LS), defined as the immunophenotypic transformation of acute leukemia, has emerged as a mechanism of relapse following antigen-targeted immunotherapy which is associated with dismal outcomes. Through an international collaborative effort, we identified cases of LS following a host of antigen-targeted therapies (e.g., CD19, CD22, CD38 and CD7), described how LS was diagnosed, reviewed treatment approaches, and analyzed overall outcomes for this form of post-immunotherapy relapse. Collectively, 75 cases of LS were evaluated, including 53 (70.7%) cases of B-ALL to AML, 17 (22.7%) cases of B-ALL to mixed phenotypic acute leukemia (MPAL)/acute leukemias of ambiguous lineage (ALAL), and 5 (6.7%) cases of rare LS presentation (i.e., T-cell ALL to AML). An additional 10 cases with incomplete changes in immunophenotype, referred to as "lineage drift" were also described. With a primary focus on the 70 cases of LS from B-ALL to AML or MPAL/ALAL, LS emerged at a median of 1.5 months (range, 0-36.5 months) post-immunotherapy, with 81.4% presenting with LS within the first 6 months from the most proximal immunotherapy. While the majority involved KMT2A rearrangements (n=45, 64.3%), other rare cytogenetic and/or molecular alterations were uniquely observed. Treatment outcomes were generally poor with < 40% remission rates. The median overall survival following LS diagnosis was 4.8 months. Outcomes were similarly poor for those with rare immunophenotypes of LS or "lineage drift." This global initiative robustly categorizes lineage changes post-immunotherapy and, through enhanced understanding, establishes a foundation for improving outcomes of LS.

DOI: https://doi.org/10.1182/blood.2024026655
Cell Commun Signal. 2025 Apr 10. 23(1): 179

A network-based approach to overcome BCR::ABL1-independent resistance in chronic myeloid leukemia.

Valeria Bica, Veronica Venafra, Giorgia Massacci, Simone Graziosi, Sara Gualdi, Gessica Minnella, Federica Sorà, Patrizia Chiusolo, Maria Elsa Brunetti, Gennaro Napolitano, Massimo Breccia, Dimitrios Mougiakakos, Martin Böttcher, Thomas Fischer, Livia Perfetto, Francesca Sacco.

   BACKGROUND: About 40% of relapsed or non-responder tumors exhibit therapeutic resistance in the absence of a clear genetic cause, suggesting a pivotal role of intracellular communication. A deeper understanding of signaling pathways rewiring occurring in resistant cells is crucial to propose alternative effective strategies for cancer patients.
METHODS: To achieve this goal, we developed a novel multi-step strategy, which integrates high sensitive mass spectrometry-based phosphoproteomics with network-based analysis. This strategy builds context-specific networks recapitulating the signaling rewiring upon drug treatment in therapy-resistant and sensitive cells.
RESULTS: We applied this strategy to elucidate the BCR::ABL1-independent mechanisms that drive relapse upon therapy discontinuation in chronic myeloid leukemia (CML) patients. We built a signaling map, detailing - from receptor to key phenotypes - the molecular mechanisms implicated in the control of proliferation, DNA damage response and inflammation of therapy-resistant cells. In-depth analysis of this map uncovered novel therapeutic vulnerabilities. Functional validation in patient-derived leukemic stem cells revealed a crucial role of acquired FLT3-dependency and its underlying molecular mechanism.
CONCLUSIONS: In conclusion, our study presents a novel generally applicable strategy and the reposition of FLT3, one of the most frequently mutated drivers of acute leukemia, as a potential therapeutic target for CML relapsed patients.

Keywords:  BCR:ABL1-independent resistance; Chronic myeloid leukemia; Computational strategy; Drug repurposing; FLT3; Phosphoproteomics; Signaling pathways

DOI:  https://doi.org/10.1186/s12964-025-02185-0
Sci Rep. 2025 Apr 05. 15(1): 11673

Inflammatory signaling pathways play a role in SYK inhibitor resistant AML.

Sarah Tausch, Christina Villinger, Gabriela Alexe, Daniel J Urban, Min Shen, Dominique Jahn, Jonas Vischedyk, Sebastian Scheich, Hubert Serve, Matthew D Hall, Kimberly Stegmaier, Thomas Oellerich, Anjali Cremer.

  Trials have shown promising clinical activity of the selective SYK inhibitor entospletinib in patients with high expressing HOXA9/MEIS1 acute leukemias. As the development of resistance mechanisms is a common problem in the use of targeted drugs, we performed a chemical library screen to identify drug sensitivities in SYK inhibitor resistant AML cells. We identified that SYK inhibitor resistant cells displayed an increased sensitivity to glucocorticoids. Glucocorticoids are potent immunosuppressants which work in part by inhibiting the transcription of cytokine genes. RNA sequencing of entospletinib resistant cells revealed a strong enrichment of inflammatory response and TNFα signaling via NF-κB gene sets in comparison to naive cells. Naive AML cells treated with entospletinib showed a strong downregulation of the same gene sets which were upregulated in the resistant state. Our data suggest that inflammatory signaling pathways play a role in entospletinib resistant AML cells.

Keywords:  Acute myeloid leukemia cells; Glucocorticoids; Inflammatory pathways; Resistance

DOI:  https://doi.org/10.1038/s41598-025-96660-w
iScience. 2025 Apr 18. 28(4): 112150

Elastic properties of leukemic cells linked to maturation stage and integrin activation.

Ceri J Richards, Albertus T J Wierenga, Annet Z Brouwers-Vos, Emmanouil Kyrloglou, Laura S Dillingh, Patty P M F A Mulder, Georgios Palasantzas, Jan Jacob Schuringa, Wouter H Roos.

  Acute myeloid leukemia (AML) remains challenging to cure. In addition to mutations that alter cell functioning, biophysical properties are modulated by external cues. In particular, membrane proteins that interact with the bone marrow niche can induce cellular changes. Here, we develop an atomic force microscopy (AFM) approach to measure non-adherent AML cell mechanical properties. The Young's modulus of the AML cell line, THP-1, increased in response to retronectin, whereas knock-out of the adhesion protein ITGB1 resulted in no response to retronectin. Confocal microscopy revealed different actin cytoskeleton morphologies for wild-type and ITGB1 knock-out cells exposed to retronectin. These results indicate that ITGB1 mediates stimuli-induced cellular mechanoresponses through cytoskeletal changes. We next used AFM to investigate the elastic properties of primary AML cells and found that more committed cells had lower Young's moduli than immature AMLs. Overall, this provides a platform for investigating the molecular mechanisms involved in leukemic cell mechanoresponse.

Keywords:  Biomechanics; Health sciences; Natural sciences

DOI:  https://doi.org/10.1016/j.isci.2025.112150
Nature. 2025 Apr 09.

Timing and trajectory of BCR::ABL1-driven chronic myeloid leukaemia.

Aleksandra E Kamizela, Daniel Leongamornlert, Nicholas Williams, Xin Wang, Kudzai Nyamondo, Kevin Dawson, Michael Spencer Chapman, Jing Guo, Joe Lee, Karim Mane, Kate Milne, Anthony R Green, Timothy Chevassut, Peter J Campbell, Patrick T Ellinor, Brian J P Huntly, E Joanna Baxter, Jyoti Nangalia.

Mutation of some genes drives uncontrolled cell proliferation and cancer. The Philadelphia chromosome in chronic myeloid leukaemia (CML) provided the very first such genetic link to cancer1,2. However, little is known about the trajectory to CML, the rate of BCR::ABL1 clonal expansion and how this affects disease. Using whole-genome sequencing of 1,013 haematopoietic colonies from nine patients with CML aged 22 to 81 years, we reconstruct phylogenetic trees of haematopoiesis. Intronic breaks in BCR and ABL1 were not always observed, and out-of-frame exonic breakpoints in BCR, requiring exon skipping to derive BCR::ABL1, were also noted. Apart from ASXL1 and RUNX1 mutations, extra myeloid gene mutations were mostly present in wild-type cells. We inferred explosive growth attributed to BCR::ABL1 commencing 3-14 years (confidence interval 2-16 years) before diagnosis, with annual growth rates exceeding 70,000% per year. Mutation accumulation was higher in BCR::ABL1 cells with shorter telomere lengths, reflecting their excessive cell divisions. Clonal expansion rates inversely correlated with the time to diagnosis. BCR::ABL1 in the general population mirrored CML incidence, and advanced and/or blast phase CML was characterized by subsequent genomic evolution. These data highlight the oncogenic potency of BCR::ABL1 fusion and contrast with the slow and sequential clonal trajectories of most cancers.

DOI: https://doi.org/10.1038/s41586-025-08817-2
Exp Hematol. 2025 Apr 03. pii: S0301-472X(25)00060-8. [Epub ahead of print] 104769

Bcl7b and Bcl7c Subunits of BAF Chromatin Remodeling Complexes are Largely Dispensable for Hematopoiesis.

Pierre Priam, Veneta Krasteva, Alexandre Polsinelli, Laurence Côté, Francis Dilauro, Thérèse-Marie Poinsignon, Pierre Thibault, Julie A Lessard.

  Chromatin remodelers have emerged as prominent regulators of hematopoietic cell development and potential drivers of various human hematological malignancies. ATP-dependent BAF chromatin remodeling complexes, related to yeast SWI/SNF, determine gene expression programs and consequently contribute to the self-renewal, commitment, and lineage-specific differentiation of hematopoietic stem cells and progenitors. Here, we investigated the elusive biological function of the core Bcl7b and Bcl7c subunits of BAF complexes in hematopoietic tissue. Our analysis of mouse constitutive knockout alleles revealed that both Bcl7b and Bcl7c are dispensable for animal survival and steady-state adult hematopoiesis. Bcl7b and Bcl7c double knockout (dKO) mice can maintain long-term hematopoiesis with no observable effect on the hematopoietic stem cell (HSC) compartment. Moreover, we show that Bcl7b/Bcl7c dKO HSCs are capable of normal multi-lineage hematopoietic reconstitution after competitive serial transplantation. Collectively, these studies suggest that the Bcl7b and Bcl7c subunits of BAF complexes are dispensable for normal hematopoiesis.

Keywords:  BAF complexes; Bcl7b; Bcl7c; chromatin remodeling; hematopoiesis

DOI:  https://doi.org/10.1016/j.exphem.2025.104769
Sci Immunol. 2025 Apr 11. 10(106): eadr2041

Bcl11a maintains hematopoietic stem cell function but accelerates inflammation-driven exhaustion during aging.

Jing Wang, Linlin Zhang, Xinyu Cui, Xiang Xu, Rui Guo, Kairui Li, Li Zhang, Bing Xu, Cizhong Jiang, Yong Yu.

Preserving hematopoietic stem cell (HSC) functionality is essential for maintaining healthy blood and the immune system throughout life. HSC function declines with age; however, the underlying mechanisms are not fully understood. Using an inducible mosaic mouse model to overexpress the transcription factor Bcl11a in the hematopoietic compartment, we found that an aging-related increase in Bcl11a mitigated HSC functional decline, promoted IL-1β production in the bone marrow (BM), and accelerated HSC attrition in a non-cell-autonomous manner. Aging-related inflammation in the BM enhanced Bcl11a and Fc receptor (FcR) expression in HSCs, and FcR signaling induced HSC differentiation. This was counteracted by Bcl11a through repression of Fcer1g. Bcl11a up-regulation promoted IL-1β production in BM myeloid cells, driving inflammation and HSC deterioration. Deletion of Fcer1g, or blocking IL-1β signaling, eliminated this non-cell-autonomous effect on HSC decline. These findings demonstrate that Bcl11a plays a dual role in HSCs during aging not only by cell-intrinsically preserving HSC function but also by promoting BM inflammation and HSC dysfunction.

DOI: https://doi.org/10.1126/sciimmunol.adr2041
Blood. 2025 Apr 10. pii: blood.2024027742. [Epub ahead of print]

An unbiased genomewide screen uncovers 7 genes that drive hematopoietic stem cell fate from mouse embryonic stem cells.

Luis Galan Palma, Gayathri M Kartha, Maria Maqueda, Mercedes Barrero, Eric Canton, Arnau Iglesias, Jessica Gonzalez Miranda, Patricia Herrero Molinero, Raul Torres-Ruíz, Bernhard Payer, Clara Bueno, Pablo Menendez, Lluis Espinosa, Anna Bigas.

Hematopoietic Stem Cells (HSCs) possess the ability to long-term reconstitute all the blood lineages and generate all blood cell types. As such, the in vitro generation of HSCs remains a central goal in regenerative medicine. Despite many efforts and recent advancements in the field, there is still no robust, reproducible and efficient protocol for generating bona-fide HSCs in vitro. This suggests that certain regulatory elements have yet to be uncovered. Here, we present a novel and unbiased approach to identifying endogenous components to specify HSCs from pluripotent stem cells. We performed a genome-wide CRISPR activator screening during mesodermal differentiation from mouse embryonic stem cells (mESCs). Following in vitro differentiation, mesodermal KDR+ precursors were transplanted into primary and secondary immunodeficient NSG mice. This approach led to the identification of seven genes (Spata2, Aass, Dctd, Eif4enif1, Guca1a, Eya2, Net1) that, when activated during mesoderm specification, induce the generation of hematopoietic stem and progenitor cells (HSPCs). These cells are capable of serial engraftment and multilineage output (erythroid, myeloid and T and B lymphoid) in vivo. Single-cell RNA sequencing further revealed that activating these seven genes biases the embryoid bodies towards intraembryonic development, instead of extraembryonic, increasing the number of mesodermal progenitors that can generate HSCs. Our findings underscore the importance of differentiation during the first germ layer specification to generate definitive blood stem cells.

DOI: https://doi.org/10.1182/blood.2024027742
Eur J Med Chem. 2025 Apr 02. pii: S0223-5234(25)00360-5. [Epub ahead of print]291 117595

Discovery of the first-in-class DOT1L PROTAC degrader.

Hyerin Yim, Renhong Sun, Zhongli Xu, Huen Suk Kim, Minjeong Kim, Tao Cao, Ling Xie, Xian Chen, H Ümit Kaniskan, Jian Jin.

  DOT1L is the lysine methyltransferase responsible for histone H3 lysine 79 (H3K79) methylation and plays a crucial role in leukemia progression. Furthermore, DOT1L has biological functions that are independent of its methyltransferase activity. Therefore, targeting and degrading DOT1L with PROteolysis TArgeting Chimeras (PROTACs) could represent a promising therapeutic strategy. Here, we report the discovery of the first-in-class DOT1L PROTAC degrader, compound 13 (MS2133), which potently induces DOT1L degradation in a concentration- and time-dependent manner, without affecting DOT1L mRNA expression. The DOT1L degradation induced by 13 requires binding to the E3 ligase von Hippel-Lindau (VHL) and DOT1L and occurs through the ubiquitin-proteasome system. 13 is selective for DOT1L over other methyltransferases and effectively inhibits the growth of mixed lineage leukemia-rearranged (MLL-r) leukemia cells while having no toxicity on normal cells. Overall, 13 is a valuable chemical biology tool for further studying functions of DOT1L and a potential therapeutic for DOT1L-dependent cancers.

Keywords:  DOT1L; Degrader; Leukemia; Methyltransferase; PROTAC

DOI:  https://doi.org/10.1016/j.ejmech.2025.117595
Hematol Oncol. 2025 Mar;43 Suppl 1 e70053

Managing Myelofibrosis: Matching Advances in Treatments With Clinical Unmet Needs.

Chan Tze Wei, Hein Than, Feng-Ju Huang, Gauri Billa, Lai Heng Lee.

  Myelofibrosis (MF) is characterized by anemia, constitutional symptoms, hepatosplenomegaly and bone marrow fibrosis, and is associated with poor survival. The janus kinase inhibitor (JAKi) ruxolitinib has been the mainstay of treatment for over a decade. Despite demonstrated symptomatic and quality of life improvement, unmet clinical needs persist. A literature review identified promising novel targeted treatment options in MF using pre-set selection criteria (available Phase 2 or 3 data, minimum enrollment of 50 patients, trial end date within the last 5 years). Available data for novel and approved therapies were extracted, tabulated, and analyzed for clinical relevancy. From an initial shortlist of 48, 16 retained molecules were selected for inclusion. Other JAKi (pacritinib, momelotinib, jaktinib) address treatment-related cytopenia, expanding the therapeutic utility of this class of agents to patients with baseline anemia or thrombocytopenia. Novel candidates exploit multiple molecular pathways, and offer the potential to improve the management of MF-associated cytopenia (imetelstat, pelabresib, navitoclax, selinexor, luspatercept, sotatercept, elritercept, LCL161, bomedemstat) and recover bone marrow fibrosis (imetelstat, pelabresib, navitoclax and bomedemstat). It remains to be seen if these newer agents can induce any remission in MF and enable patients to come off therapy, but the future is beginning to look much brighter.

Keywords:  anemia; bone marrow fibrosis; janus kinase inhibitors; myelofibrosis; myeloproliferative neoplasm; splenomegaly

DOI:  https://doi.org/10.1002/hon.70053
Br J Haematol. 2025 Apr 09.

The mechanism of EZH2/H3K27me3 downregulating CXCL10 to affect CD8+ T cell exhaustion to participate in the transformation from myelodysplastic syndrome to acute myeloid leukaemia.

Zhuanzhen Zheng, Wenjing Wang, Mengjing Feng, Xiuhua Chen, Fanggang Ren, Yanfei Hou.

  Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) link to unfavourable prognoses. We explored the mechanism of enhancer of zeste homologue 2/histone H3 of lysine 27 (EZH2/H3K27me3) downregulating C-X-C motif chemokine 10 (CXCL10) to affect CD8+ T-cell exhaustion, participating in MDS-to-AML transformation. NHD13 mice were treated with GSK126 (EZH2 inhibitor) and CXCL10 neutralizing antibody, with transformation time, blood cell counts and CD8+ T cell determined. SKM-1 cells treated with short hairpin-EZH2, overexpressing-EZH2, GSK126 and CXCL10 were co-cultured with CD8+ T cells. EZH2, CXCL10, H3K27me3 and EZH2 levels and EZH2 enzyme activity were assessed. CD8+ T-cell cytotoxicity, exhaustion, apoptosis and SKM-1 cell malignant behaviours were evaluated. In vivo, EZH2 inhibition upregulated CXCL10, decelerating MDS to AML transformation and delaying CD8+ T-cell exhaustion. EZH2 inhibition elevated peripheral blood cells, alleviated splenomegaly, reduced CD8+ T cells, elevated CD8+ T cytotoxicity and abated CD8+ T-cell exhaustion in NHD13 mice. CXCL10 neutralizing antibody accelerated AML transformation by inhibiting CD8+ T-cell exhaustion via EZH2. In vitro, EZH2 overexpression facilitated CD8+ T-cell exhaustion and SKM-1 cell malignant behaviours. EZH2-mediated H3K27me3 curbed CXCL10 transcription and secretion. Collectively, EZH2/H3K27me3 downregulates CXCL10 to facilitate CD8+ T-cell exhaustion, accelerating transformation from MDS to AML.

Keywords:  CD8+ T cells; C‐X‐C motif chemokine 10; acute myeloid leukaemia; enhancer of zeste homologue 2; histone H3 of lysine 27; histone methylation; immune escape; myelodysplastic syndrome

DOI:  https://doi.org/10.1111/bjh.20066
Exp Hematol Oncol. 2025 Apr 11. 14(1): 57

Breakthroughs of CAR T-cell therapy in acute myeloid leukemia: updates from ASH 2024.

Haixiao Zhang, Hong-Hu Zhu.

While chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape for lymphoid malignancies, its greatest challenge remains in the treatment of acute myeloid leukemia (AML). Its success in AML has been limited by the ideal target antigen, myelosuppression, and immunosuppressive leukemia microenvironment. The 2024 ASH Meeting highlighted several cutting-edge advancements in AML-directed CAR T therapies, including clinical trials targeting CD33, CD123, CLL1, CD19, and IL1RAP, as well as novel engineering strategies such as dual-targeting CARs, inhibitory CAR designs, and genome-editing approaches to enhance safety and efficacy. Here, we summarize key findings from both clinical and preclinical studies, offering insights into the evolving landscape of CAR T-cell therapy for AML.

DOI: https://doi.org/10.1186/s40164-025-00651-6
Transplant Cell Ther. 2025 Apr 07. pii: S2666-6367(25)01114-5. [Epub ahead of print]

Haematopoietic stem cell (HSC) graft cryopreservation effects on outcomes of patients with haematological malignancies: the multi-centre UK experience during COVID-19 pandemic.

Dr Ruta Barkauskiene, Dr Angharad Pryce, Rachel Pearce, Prof John A Snowden, Dr Ram Malladi, Dr Victoria Potter, Julia Lee, Marie Wilson, Prof Nicola Cooper, Prof Jane F Apperley, Dr Chloe Anthias, Prof Antonio Pagliuca, Dr Rachel Pawson, Dr Robert Danby.

  The effects of graft cryopreservation on patient outcomes in allogeneic haematopoietic cell transplantation (HCT) remains unclear. In our multicentre UK study, outcomes of 926 adults receiving allogeneic cryopreserved peripheral blood stem cell (PBSC) graft for a malignant haematological indication between June 2020 and September 2021 were compared to 1491 adults with haematological malignancy transplanted June 2018 - September 2019 with fresh PBSC grafts. There were short delays in median platelet and neutrophil engraftment with cryopreserved HSC grafts: 18 vs 15 days (p<0.01) for platelets and 14 vs 13 days (p<0.01) for neutrophils in the cryopreserved and fresh historical control groups, respectively. Reassuringly, primary graft failure rates were similar (p=0.48). Relapse rates (RR) were higher (p=0.03) but non-relapse mortality (NRM) was lower (p<0.01) in the cryopreserved group at 12-month follow-up. There was no statistical difference in overall survival between the groups (p=0.52). Cryopreservation of allogeneic HSC grafts remains an important 'quality' consideration in HCT practice. Advancement of our clinical and scientific understanding of this aspect of laboratory processing of HCT grafts is essential in relation not only to the pandemic but also for its use in other clinical and logistical settings where fresh donations are not feasible.

Keywords:  Cryopreservation; allogeneic stem cell transplantation

DOI:  https://doi.org/10.1016/j.jtct.2025.03.018
Cell Death Discov. 2025 Apr 06. 11(1): 147

Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors.

Jorge Antonio Elias Godoy Carlos, Mauricio Temotheo Tavares, Keli Lima, Larissa Costa de Almeida, Karoline de Barros Waitman, Leticia Veras Costa-Lotufo, Roberto Parise-Filho, João Agostinho Machado-Neto.

Epigenetic modifications significantly influence gene expression and play crucial roles in various biological processes, including carcinogenesis. This study investigates the effects of novel purine-benzohydroxamate compounds, particularly 4 f, as hybrid kinase/histone deacetylase (HDAC) inhibitors in hematological malignancies, focusing on acute myeloid leukemia (AML). Our results demonstrate that these compounds selectively reduce cell viability in blood cancer cells, with inhibitory concentration values indicating higher potency against neoplastic cells compared to normal leukocytes. Mechanistically, 4 f induces apoptosis and cell cycle arrest, promoting differentiation in leukemia cells, while effectively inhibiting HDAC activity. Furthermore, 4 f enhances the therapeutic efficacy of venetoclax, a BCL2 inhibitor, in AML models sensitive and resistant to this drug. The combination treatment significantly increases apoptosis and reduces cell viability, suggesting a synergistic effect that may overcome drug resistance. This study provides valuable insights into the potential of HDAC inhibitors, particularly 4 f, as a promising therapeutic strategy for treating resistant hematological malignancies. Our findings underscore the importance of further exploring hybrid kinase/HDAC inhibitors in combination therapies to improve outcomes in patients with acute leukemias and other hematological malignancies.

DOI: https://doi.org/10.1038/s41420-025-02446-4
Leukemia. 2025 Apr 10.

Fabp4 is essential for the maintenance of leukemia stem cells while sparing hematopoietic stem cells.

Cheng Xing, Huifang Zhang, Mengqiu Zheng, Qian Lu, Yujia Tao, Shina Xu, Yang Xiao, Long Liang, Haodong Xu, Shuqian Xu, Hongling Peng, Yue Sheng.

DOI: https://doi.org/10.1038/s41375-025-02568-9
Leukemia. 2025 Apr 10.

The effect of ibrutinib on the myeloid cell compartment in CNS lymphoma.

Julia C Kuehn, Nicolas N Neidert, Junyi Zhang, Jurik Mutter, Stefan Alig, Christian Klingler, Fabian Hummel, Lavanya Ranganathan, Sabine Bleul, Jürgen Beck, Marco Prinz, Maximilian Diehn, Ash Alizadeh, Justus Duyster, Roman Sankowski, Dieter H Heiland, Florian Scherer.

DOI: https://doi.org/10.1038/s41375-025-02600-y