bims-tremyl 2026-09-20 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2026–09–20
23 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells.
Venetoclax Plus Hypomethylating Agent for 7- Versus 14- Versus 21- Versus 28-Day Cycles in Newly-Diagnosed Acute Myeloid Leukemia: ELN and Mayo Genetic Risk-Stratified Analysis in 540 Patients.
Intensive Chemotherapy and Tyrosine Kinase Inhibitor in Patients with De Novo BCR::ABL1+ Acute Myeloid Leukemia.
Markedly increased risk of myeloid neoplasia amongst clonal hematopoiesis carriers with multiple TET2 mutations.
Type 1 interferon perturbates clonal competition by reshaping human blood development.
GVHD prophylaxis with PTCy, ATG, PTCy+ATG, or no in vivo T-cell depletion in RIC matched-donor PBSC transplantation for AML and MDS.
Retrotransposable element derepression distinguishes DNMT3A-mutant from TET2-mutant clonal haematopoiesis.
The Impact of Induction With Azacitidine and Venetoclax Versus Intensive Chemotherapy on Outcomes After Allogeneic Hematopoietic Cell Transplantation for Newly Diagnosed Acute Myeloid Leukemia.
Clinical management of clonal hematopoiesis.
SRSF2 P95H induces monocytic priming of human hematopoietic stem and progenitor cells.
Outcomes of adult patients with Li-Fraumeni syndrome and myeloid neoplasms.
Canakinumab or emavusertib for anemia in lower-risk MDS: results of the CANFIRE and LUCAS phase 2, open-label, multicenter trials.
Acute Myeloid Leukemia With KMT2A Amplification: A TP53-Alteration-Enriched Subgroup Associated With Chromoanagenesis and Poor Prognosis.
Targeting BLVRB Overcomes Immunosuppression and Potentiates Immunotherapy in Monocytic Acute Myeloid Leukemia.
Glycosylation orchestrates megakaryocytic fate of hematopoietic stem cells via Wnt-MUC13 signaling.
Clinical evaluation of AI-assisted quantitative marrow fibrosis assessment using Continuous Indexing of Fibrosis (CIF).
Stabilization of the PP2A-B56α complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML.
Targeting CD38 with bispecific antibody XmAb 18968 in patients with relapsed/refractory acute myeloid leukemia and T-cell acute lymphoblastic leukemia.
Targeted genomic integration and rearrangement using prime assembly.
Optimizing venetoclax duration with hypomethylating agents for newly diagnosed acute myeloid leukemia: impact on response and survival.
Targeting lipid metabolic vulnerabilities with small-molecule inhibitors in acute myeloid leukemia: Emerging insights and therapeutic opportunities.
Generation of TWO iPSC lines (CRICKi025-A and CRICKi026-A) from healthy donor bone marrow mesenchymal stromal cells.
5-Azacytosine induces cytotoxicity via 5-methylcytosine depletion on chromatin-associated RNA in leukemia.

Blood. 2026 Sep 17. pii: blood.2026034181. [Epub ahead of print]

IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells.

Aykut Demir, Maximilian Mönnig, Nesrine Aroua, Eleni Besiridou, Valentin Schmidt, Kristina Müller, Simon Renders, Fabian Schulte, Alireza Pouya, Alexander Waclawiczek, Aino-Maija Leppä, Karolin Stumpf, Markus Sohn, Dominic Depke, Patrick Wuchter, Darja Karpova, Elisa Donato, Halvard Bonig, Carolin Andresen, Michael Büttner, Gernot Poschet, Daniel Hübschmann, Nicola Zamboni, Tim Sauer, Andreas Trumpp, Carsten Müller-Tidow, Simon Raffel.

Targeting metabolic dependencies of leukemic stem cells (LSC) may open avenues to improve outcomes of patients suffering from acute myeloid leukemia (AML). LSCs rely heavily on an active tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation whereas healthy hematopoietic stem and progenitor cells (HSPCs) possess more metabolic flexibility. Here, we identify the TCA cycle enzyme isocitrate dehydrogenase 3 (IDH3) as a critical and selective regulator of LSC maintenance. IDH3 is more abundant in LSCs compared to healthy HSPCs, and TCA cycle activity correlates with inferior clinical outcomes of AML patients. Knockdown of IDH3A, the catalytic subunit of the complex, impairs colony-forming potential and bone marrow organoid as well as in vivo engraftment of AML, while sparing healthy hematopoiesis. Mechanistically, IDH3A downregulation reduces TCA cycle flux and leads to accumulation of intracellular citrate, impairing both glycolysis and oxidative phosphorylation. The resulting bioenergetic crisis activates AMPK and suppresses mTORC1, leading to reduced translational activity and an imbalance of anti-apoptotic proteins. Consequently, IDH3A-KD cells show enhanced susceptibility to BCL2 inhibition by venetoclax in vitro and in vivo. In a clinical cohort, LSCs from patients resistant to venetoclax/azacitidine (Ven/Aza) exhibit transcriptomic programs indicative of active TCA cycle and glycolysis. We demonstrate that downregulation of IDH3A activity and subsequent citrate accumulation directly affect these pathways and shift AML stem cells towards a metabolic state of increased vulnerability. In summary, we establish IDH3 as a metabolic rheostat in LSCs and suggest targeting the IDH3A-citrate axis to overcome Ven/Aza resistance of AML patients.

DOI: https://doi.org/10.1182/blood.2026034181
Am J Hematol. 2026 Sep 17.

Venetoclax Plus Hypomethylating Agent for 7- Versus 14- Versus 21- Versus 28-Day Cycles in Newly-Diagnosed Acute Myeloid Leukemia: ELN and Mayo Genetic Risk-Stratified Analysis in 540 Patients.

Sudhesh Kumar, Momna Warraich, Mahnoor Fatima, Kristen McCullough, Aref Al-Kali, Hassan B Alkhateeb, Kebede H Begna, Abhishek A Mangaonkar, Antoine N Saliba, Mark R Litzow, William Hogan, Mithun Shah, Mrinal M Patnaik, Animesh Pardanani, Talha Badar, James Foran, Jeanne Palmer, Cecilia Arana Yi, Ayalew Tefferi, Naseema Gangat.

  Patients with newly-diagnosed acute myeloid leukemia (ND-AML) derive variable survival benefit from venetoclax (Ven) plus hypomethylating agent (HMA) therapy, and the optimal Ven duration across genetic risk groups remains undefined. Among 540 ND-AML patients receiving Ven-HMA at Mayo Clinic, outcomes were compared across Ven 7- (n = 33), 14- (n = 117), 21- (n = 96), and 28-day (n = 294) schedules during Cycle 1 and stratified by ELN 2024 and Mayo genetic risk groups. At a median follow-up of 37.7 months, allogeneic stem cell transplant (ASCT) rates were similar across Ven duration groups (15%, 18%, 18%, and 20% for 7-, 14-, 21-, and 28-day; p = 0.86). Median transplant-censored survival was comparable across Ven durations (13.3, 11.9, 16.8, and 13.2 months for 7, 14, 21, 28 days, respectively; p = 0.65), with outcomes driven by ELN risk (6.3, 11.5, 18.3 months for high, intermediate, low; p < 0.01) and Mayo genetic risk (6.9, 17.8 months, not reached; p < 0.01). Survival was comparable across Ven durations within ELN intermediate/low-risk and all Mayo risk groups. Among ELN high-risk patients, 14-day Ven was associated with inferior transplant-censored survival compared to 21- and 28-day schedules (p < 0.01). Notably, 30- and 60-day mortality were higher with shorter Ven schedules (7-day: 9%/18%; 14-day: 7%/15%) versus 28-day (2%/6%), which likely reflects treatment selection bias. In ND-AML, no significant difference in transplant-censored survival was observed across the 7-, 14-, 21-, and 28-day Ven schedules; prognosis was determined primarily by Mayo and ELN 2024 genetic risk rather than by Ven duration. Prospective trials are needed to establish risk-adapted Ven dosing strategies.

Keywords:  karyotype; mutations; remission; survival; venetoclax

DOI:  https://doi.org/10.1002/ajh.70500
Blood. 2026 Sep 18. pii: blood.2026033895. [Epub ahead of print]

Intensive Chemotherapy and Tyrosine Kinase Inhibitor in Patients with De Novo BCR::ABL1+ Acute Myeloid Leukemia.

Sarah Bertoli, Niklas Landberg, Emilie Bérard, Camille Gondran, Laetitia Largeaud, Véronique Mansat-De Mas, Pierre-Yves Dumas, Arnaud Pigneux, Audrey Bidet, Sylvain Garciaz, Ludovic Gabellier, Gabrielle Roth Guepin, Corentin Orvain, Pierre Peterlin, Rudy Birsen, Magda Alexis, Martin Carré, Emmanuelle Tavernier, Marion Boissard Simonet, Chantal Himberlin, Marc Maynadié, Kamel Laribi, Cécile Moluçon Chabrot, Amine Belhabri, Samy Chraibi, Quentin Cabrera, Delphine Lebon, Emmanuel Raffoux, Thomas Cluzeau, Jean-Baptiste Micol, Mathieu Leclerc, Céline Berthon, Hervé Dombret, Gunnar Juliusson, Anna Robelius, Soren Lehmann, Martin Jädersten, Lovisa Vennström, Pau Montesinos, Carmen Botella, Juan Miguel Bergua Burgues, Raimundo Garcia, Josefina Serrano, Maria Luz Amigo, Patricia García Ramirez, Claudia Lucía Sossa-Melo, Juan Manuel Alonso-Domínguez, Hartmut Döhner, Konstanze Döhner, Daniela Späth, Michael Wm Kühn, Claudia Lengerke, Hans-Jörg Tischler, Christoph Röllig, Leo Ruhnke, Christian Thiede, Andreas Burchert, Hubert Serve, Carsten Müller-Tidow, Claudia D Baldus, Jurjen Versluis, Peter Jm Valk, Daniel Tuyet Kristensen, Anne Stidsholt Roug, Jiri Mayer, Mika Kontro, Pia Ettala, Vladimir Lj Lazarevic, Christian Récher.

To describe the impact of adding a tyrosine kinase inhibitor (TKI) to intensive chemotherapy (IC) on the outcome of de novo BCR::ABL1+ acute myeloid leukemia (AML), we retrospectively analyzed the data of 212 adult AML with ≥20% bone marrow blasts, BCR::ABL1+ or t(9;22)(q34.1;q11.2), no history of previous chronic myeloid leukemia and no prior exposure to BCR-ABL1 TKI. Eighty-nine patients were treated with IC alone and 123 with IC+TKI between 1999 and 2024. Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 52/77 patients (68%) with IC and 110/123 patients (89%) with IC+TKI (P<0.0001). With a median follow-up of 66.7 months, the median overall survival (OS) was 20.5 months with IC and not reached with IC+TKI. The 3-year and 5-year OS rates were 42.1% and 38.5% with IC and 70.9% and 62.9% with IC+TKI (P<0.0001) respectively. In multivariate analyses, the addition of TKI to IC was significantly and independently associated with an improved CR/CRi rate (odds ratio: 4.74 [95% confidence interval: 2.17-10.35]; P<0.001) and OS (hazard ratio: 0.40 [0.27-0.62]; P<0.001). Also, adding TKI to IC and alloHSCT in CR1 were independent prognostic factors for relapse-free survival (HR: 0.42; 95% CI: 0.23-0.75; P=0.004 and HR: 0.31; 95% CI: 0.17-0.55; P<0.0001). The outcome of de novo BCR::ABL1+ AML is strongly improved by the addition of a TKI to IC and should become the standard of care. The classification as adverse-risk should be reconsidered in the future ELN classification.

DOI: https://doi.org/10.1182/blood.2026033895
Blood Adv. 2026 Sep 18. pii: bloodadvances.2026020835. [Epub ahead of print]

Markedly increased risk of myeloid neoplasia amongst clonal hematopoiesis carriers with multiple TET2 mutations.

Fabio A Schwandt, Jake Tobin, Shreyashee Mallik, Rithin Nedumannil, Julian Ronnacker, William Grant Dunn, Veselin Manojlovic, Pedro M Quiros, Sean Wen, Malgorzata Gozdecka, Margarete A Fabre, Muxin Gu, George S Vassiliou.

DOI: https://doi.org/10.1182/bloodadvances.2026020835
Nat Genet. 2026 Sep 15.

Type 1 interferon perturbates clonal competition by reshaping human blood development.

Chhiring Lama, Danielle Isakov, Shira Rosenberg, Miguel Quijada-Álamo, Mirca S Saurty-Seerunghen, Sara Moein, Mathis Nozais, Tsega-Ab Abera, Olivia Sakaguchi, Mansi Totwani, Grace Freed, Leila Zaydon, Chi-Lam Poon, Neelang Parghi, Andrea Kubas-Meyer, Amy X Xie, Mohamed Omar, Daniel Choi, Franco Castillo-Tokumori, Ghaith Abu-Zeinah, Alicia Dillard, Saravanan Ganesan, Nathaniel D Omans, Neville Dusaj, Paulina Chamely, Eleni Mimitou, Peter Smibert, Heidi E Kosiorek, Amylou C Dueck, Rona Weinberg, Ronan Chaligne, Bridget Marcellino, Luigi Marchionni, Sanjay Patel, Paul Simonson, Dan A Landau, Elvin Wagenblast, Ronald Hoffman, Anna S Nam.

Inflammation accelerates evolutionary dynamics of hematopoietic stem cells (HSCs) in clonal hematopoiesis and myeloid neoplasms. We studied HSCs, progenitors and immune cells from patients with myeloproliferative neoplasms at baseline and following interferon-α (IFNα) treatment, the only therapy to deplete mutated stem cells. We deployed single-cell multiomics methods that distinguish the IFNα effects on mutated stem cells from the admixed wild-type HSCs, with respect to their differentiation, transcriptomes, immunophenotypes and chromatin accessibility. IFNα simultaneously activated HSCs into two polarized states: a lymphoid progenitor expansion associated with an anti-inflammatory state and an inflammatory myeloid progenitor state derived from HSCs. The augmented lymphoid differentiation balanced the typical myeloproliferative-neoplasm-induced myeloid bias, associated with normalized blood counts. Somatic mutations modified the effects of IFNα on HSC differentiation and cell cycle entry rates. Clonal fitness upon IFNα exposure was due to resistance of CALR- or JAK2-mutated stem cells to differentiate into inflammatory myeloid progenitors.

DOI: https://doi.org/10.1038/s41588-026-02751-3
Bone Marrow Transplant. 2026 Sep 12.

GVHD prophylaxis with PTCy, ATG, PTCy+ATG, or no in vivo T-cell depletion in RIC matched-donor PBSC transplantation for AML and MDS.

Tereza Coman, Stéphane Morisset, Raynier Devillier, Maud D'Aveni, Frederic Baron, Jacques Olivier Bay, Jean El-Cheikh, Karine Bilger, Claude-Eric Bulabois, Cristina Castilla-Llorente, Patrice Ceballos, Yves Chalandon, Sylvain Chantepie, Magalie Joris, Patrice Chevallier, Mustafa Alani, Jerôme Cornillon, Etienne Daguindeau, Edouard Forcade, Chama Mokeddem, Gaelle Guillerm, Hélène Labussiere, Philippe Lewalle, Mikael Loschi, Johan Maertens, Florent Malard, Jean-Valère Malfuson, Natacha Maillard, Jean Baptiste Mear, Stéphanie Nguyen-Quoc, Cécile Pivert, Xavier Poire, Marie-Thérèse Rubio, Felipe Suarez, Pascal Turlure, Alban Villate, Ibrahim Yakoub-Agha, Nicole Raus, Marie Robin, Anne Huynh, Mauricette Michallet.

Post-transplant cyclophosphamide (PTCy) has transformed graft-versus-host disease (GVHD) prophylaxis but its role in matched-donor reduced-intensity allogeneic hematopoietic cell transplantation (allo-HCT) remains uncertain. We retrospectively analyzed adults with AML or MDS reported to the French-Belgian-Swiss EBMT/SFGM-TC registry who received a first allo-HCT from a matched related (MRD) or matched unrelated donor (MUD) after reduced-intensity conditioning (RIC) with peripheral blood stem cells between 2014 and 2022. Among 3624 patients, GVHD prophylaxis comprised immunosuppressive agents without in vivo T cell depletion (NONE, n = 213), PTCy±immunosuppression (PTCy, n = 97), ATG±immunosuppression (ATG, n = 3 286), or PTCy+ATG±immunosuppression (PTCy+ATG, n = 28). In multivariable competing-risk models, PTCy was associated with a significant reduction of grade III-IV aGVHD compared to ATG (HR 0.44, p = 0.026). Both PTCy and ATG were associated with a lower incidence of extensive cGVHD vs NONE, without affecting NRM or relapse risk. With a median follow up of 16.6 months, the probability of 1-year OS, PFS and GRFS were 69.92%, 62.46% and 48.39%, regardless of donor type or GVHD prophylaxis group. These large, homogeneous registry data support PTCy as an effective alternative to ATG for GVHD prophylaxis in RIC MRD/MUD allo-HCT for AML/MDS, and provide a benchmark while ongoing randomized trials mature.

DOI: https://doi.org/10.1038/s41409-026-03033-6
Geroscience. 2026 Sep 16.

Retrotransposable element derepression distinguishes DNMT3A-mutant from TET2-mutant clonal haematopoiesis.

Maroof Hasan, Sylvia Durandeau, I Richard Thompson, Hanae Roussotte, Yi-Ting Tsai, Nogayhan Seymen, Sila Gerlevik, Nicholas Bianchini, Khadijeh Alishah, Merilyn M Albuquerque, Jen Lewis, Laarni Bonganay, Niels Asger Jakobsen, Bernd Zeisig, Sheeba Irshad, Paresh Vyas, Eric C W So, Alfredo Iacoangeli, Xuesen Zheng, Sarah Mackie, Kai Yi Mok, Viktoria Uksaite, Louis-Francois Handfield, Giorgio Napolitani, James Carmichael, Ghulam J Mufti, Anita K Gandhi, Rajasekhar N V S Suragani, Lynn Quek, Mohammad M Karimi.

  Clonal haematopoiesis (CH) is driven by somatic mutations in haematopoietic stem cells that generate clonal populations detectable in peripheral blood and is present in 10-20% of individuals over the age of 65. Mutations in DNMT3A and TET2 are the most common drivers and have been linked to inflammatory phenotypes and increased risk of haematologic and cardiovascular disease. However, the cell-intrinsic mechanisms connecting these mutations to inflammatory signalling remain incompletely understood. Because retrotransposable elements (RTEs) are epigenetically regulated and can activate innate immune pathways when derepressed, we hypothesised that RTE reactivation may represent a mutation-specific mechanism linking clonal haematopoiesis driver mutations to inflammatory pathways. We analysed RTE expression and clonal burden in peripheral blood mononuclear cell (PBMC) samples from 56 individuals with CH and 12 non-CH controls using integrated genomic and transcriptomic approaches, with complementary validation by TARGET-seq across haematopoietic lineages. High variant allele frequency (VAF; > 10%) DNMT3A-mutant clones exhibited widespread derepression of RTEs, particularly LINE and LTR families, whereas TET2-mutant clones showed a trend towards reduced RTE expression relative to controls. Transcriptomic analyses revealed that DNMT3A high-variant allele frequency clones with elevated RTE expression were enriched for inflammatory signalling pathways, including TNF-α/NF-κB signalling, interferon responses, and senescence-associated signatures. In contrast, TET2-mutant clones lacked these RTE-associated inflammatory signatures and instead showed enrichment of oxidative phosphorylation, reactive oxygen species signalling, and a mechanistic target of rapamycin complex 1 pathway. These findings were reproduced in an independent cohort. Collectively, our results highlight mutation-specific inflammatory mechanisms in clonal haematopoiesis and provide a foundation for future functional and preclinical studies to determine whether modulation of RTE activity can influence the inflammatory phenotype of DNMT3A-mutant CH and represent a potential therapeutic strategy.

Keywords:   DNMT3A ; TET2 ; Ageing; Clonal haematopoiesis; Inflammation; RNA sequencing; Retrotransposable elements

DOI:  https://doi.org/10.1007/s11357-026-02510-6
J Hematol. 2026 Aug;15(4): 179-187

The Impact of Induction With Azacitidine and Venetoclax Versus Intensive Chemotherapy on Outcomes After Allogeneic Hematopoietic Cell Transplantation for Newly Diagnosed Acute Myeloid Leukemia.

Baldeep Wirk, Rami Hawila.

   Background: Induction with azacitidine and venetoclax (AZA-VEN) is standard therapy for patients 75 years or older or those with comorbidities that preclude intensive chemotherapy (IC) for acute myeloid leukemia (AML). Data on the impact of AZA-VEN on allogeneic hematopoietic cell transplant (HCT) outcomes in younger, fit patients are limited.
Methods: In a single-center retrospective study, we examined adult patients with newly diagnosed AML receiving either AZA-VEN or IC (cytarabine and anthracycline) to attain first complete remission (CR) before allogeneic HCT with posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis between 2023 and 2025.
Results: The median age in the AZA-VEN (N = 14) and IC (N = 17) groups was similar (67 years (62-69) vs. 63 years (54-66), P = 0.13). The AZA-VEN group had more adverse-risk AML (93% vs. 41%, P = 0.001). Otherwise, there were no significant differences in Hematopoietic Cell Transplantation Comorbidity Index, secondary AML incidence, minimal residual disease (MRD) status, or donor types between the two cohorts. The AZA-VEN and IC cohorts had similar 1-year overall survival (69.2%, 95% confidence interval (CI) (48.2-99.5) vs. 75%, 95% CI (56.5-99.7), P = 0.73), 1-year relapse-free survival (57.1%, 95% CI (36.3-89.9) vs. 64.7%, 95% CI (45.5-91.9), P = 0.67), 1-year GVHD-free relapse-free survival (57.1%, 95% CI (36.3-89.9) vs. 64.7% 95% CI (45.5-91.9), P = 0.67), 1-year cumulative incidence of relapse (14.3% vs. 11.8%, P = 0.84), 1-year cumulative incidence of non-relapse mortality (28.5% vs. 23.5%, P = 0.76), 1-year cumulative incidence of grade 3-4 acute GVHD (14.3% vs. 5.9%, P = 0.46), and 1-year cumulative incidence of chronic GVHD (7.1% vs. 11.8 %, P = 0.67). On multivariable Cox analysis, there was no significant impact of treatment cohort (AZA-VEN vs. IC), MRD, adverse-risk genetics, acute GVHD, Hematopoietic Cell Transplantation Comorbidity Index, or age on overall survival.
Conclusions: In newly diagnosed AML, AZA-VEN and IC induction yield comparable outcomes after allogeneic HCT, regardless of age or adverse genetics, warranting prospective studies.

Keywords:  Acute myeloid leukemia; Allogeneic hematopoietic cell transplantation; Azacitidine; Intensive chemotherapy; Venetoclax

DOI:  https://doi.org/10.14740/jh2217
Cancer. 2026 Sep 15. 132(18): e70588

Clinical management of clonal hematopoiesis.

Kelly S Chien, Guillermo Garcia-Manero.

  Clonal hematopoiesis, particularly clonal hematopoiesis of indeterminate potential and clonal cytopenia of undetermined significance, is an age-related premalignant condition characterized by the expansion of hematopoietic clones carrying somatic mutations. Because of the accessibility of peripheral blood, it has been increasingly detected, even in otherwise healthy individuals. Although often asymptomatic, specific clonal hematopoiesis-associated mutations and clonal features are associated with an increased risk of progression to hematologic malignancies, including myelodysplastic syndromes and acute myeloid leukemia. Beyond malignant transformation, clonal hematopoiesis also has systemic implications and has been linked to a variety of nonmalignant conditions, such as cardiovascular and inflammatory disease. In this review, we focus on the clinical management of clonal hematopoiesis, including approaches to diagnosis, tools for risk stratification, and strategies for surveillance and comorbidity mitigation. In the absence of consensus guidelines and approved therapies, management remains individualized, underscoring the need for continued research and clinical trials to guide evidence-based care and improve patient outcomes.

Keywords:  CCUS; CHIP; clonal hematopoiesis

DOI:  https://doi.org/10.1002/cncr.70588
Leukemia. 2026 Sep 14.

SRSF2 P95H induces monocytic priming of human hematopoietic stem and progenitor cells.

Johannes Foßelteder, Gabriel Pabst, Andrea Raicht, Tommaso Sconocchia, Angelika Schlacher, Lisa Auinger, Daniel Martinez-Krams, Asiri Ediriwickrema, Katarina Vizar-Cisarova, Peter Schlenke, Annkristin Heine, Heinz Sill, Armin Zebisch, Ravindra Majeti, Andreas Reinisch.

DOI: https://doi.org/10.1038/s41375-026-03127-6
Cancer. 2026 Oct 01. 132(19): e70613

Outcomes of adult patients with Li-Fraumeni syndrome and myeloid neoplasms.

Jayastu Senapati, Hiam M Abdel-Salam, Vladislav D Jdanov, Sanam Loghavi, Ashley Woodson, Jessica Corredor, Gautam Borthakur, Naval G Daver, Tapan M Kadia, Koichi Takahashi, Yesid Alvarado, Naveen Pemmaraju, Uday R Popat, Elizabeth J Shpall, Farhad Ravandi, Florencia McAllister, Najat C Daw, Guillermo Garcia-Manero, Banu K Arun, Courtney D DiNardo.

   BACKGROUND: Li-Fraumeni syndrome (LFS) is an inherited cancer predisposition syndrome. Hematologic malignancies are not considered LFS defining tumors, however, both acute lymphoblastic leukemia and therapy-related myeloid neoplasms (MNs) in LFS are described. Treatment approaches and outcomes of MN in LFS need further evaluation.
METHODS: The authors performed a retrospective analysis to understand treatment approaches and outcomes in patients with LFS who developed an MN.
RESULTS: Among 190 patients with LFS between February 2001 and February 2026 with a history of at least one neoplasm, 14 (7%) had an MN. Median age at MN diagnosis was 43 years (range, 25-73) and 11 (79%) patients were female. Overall, eight (57%) patients had myelodysplastic syndrome (MDS), five (36%) had acute myeloid leukemia (AML), and one (7%) had T-myeloid mixed phenotype acute leukemia (MPAL). With frontline therapy, six (75%) patients with MDS and one (17%) patient with AML achieved an overall response. Considering all lines of therapy received, cumulatively six (75%) patients with MDS and five (83%) patients with AML/MPAL achieved an overall response. At a median follow-up of 28.8 months, the median overall survival (OS) was 18.2 months, and 1-year and 2-year OS rates were 77% and 17%, respectively. Five patients (two MDS, two AML, and one MPAL) underwent hematopoietic stem cell transplantation during their MN therapy with a median OS of 19.3 months.
CONCLUSION: Although short-lived responses to leukemia-directed therapy are common, long-term survival in most patients with LFS developing MN are poor. Additional research and understanding of the mechanisms to prevent MN and to improve MN treatment in LFS are needed.

Keywords:  AML; Li‐Fraumeni syndrome; MDS; survival outcomes; venetoclax

DOI:  https://doi.org/10.1002/cncr.70613
Commun Med (Lond). 2026 Sep 16. pii: 486. [Epub ahead of print]6(1):

Canakinumab or emavusertib for anemia in lower-risk MDS: results of the CANFIRE and LUCAS phase 2, open-label, multicenter trials.

Anne Sophie Platzbecker, Katharina Zoldan, Dominic Brauer, Philipp Kiewe, Daniel Sasca, Katja Sockel, Thomas Illmer, Aristoteles Giagounidis, Daniel Nowak, Kathrin Rieger, Friederike Wortmann, Katharina Götze, Martin Schmidt-Hieber, Karin Mayer, Ursula Vehling-Kaiser, Rudolf Weide, Stefan Mahlmann, Jens Przybilla, Susanne Melzer, Michael Cross, Marie Schneider, Dirk Hasenclever, Klaus H Metzeler, Uwe Platzbecker.

BACKGROUND: Dysregulated innate immune signaling promotes inflammatory suppression of hematopoietic stem and progenitor cell function, contributing to ineffective erythropoiesis in myelodysplastic neoplasms (MDS). The phase 2, open-label CANFIRE and LUCAS trials aimed to determine the efficacy and safety of canakinumab or emavusertib, respectively, in patients with lower-risk MDS (LR-MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN).
METHODS: Patients in CANFIRE were refractory, intolerant to, or ineligible for erythropoiesis-stimulating agent (ESA) treatment and received canakinumab 200 mg subcutaneously every 21 days for up to eight cycles within the first six months of treatment. Patients in LUCAS were either refractory or intolerant to ESAs (cohort A) or ESA-naïve with serum erythropoietin levels >200 U/L (cohort B); all patients received emavusertib 200-300 mg orally twice daily for 21 days in up to four 28-day cycles. The primary endpoint for both trials was hematologic improvement-erythroid per International Working Group 2018 criteria at the end of the planned treatment period. CANFIRE was registered at ClinicalTrials.gov (NCT05237713; registered January 21, 2022). LUCAS was registered in the EU Clinical Trials Register (EudraCT 2020-003986-20; registered March 15, 2021) and at ClinicalTrials.gov (NCT05178342; registered November 2, 2021).
RESULTS: Here we show that of 11 patients enrolled in CANFIRE and 36 patients enrolled in LUCAS, no patients in either trial achieved the primary endpoint. Canakinumab treatment was well-tolerated, with no reported serious adverse events (SAEs) and no patients died in the CANFIRE trial. In the LUCAS trial, 15 patients reported SAEs, and four patients died. CANFIRE and LUCAS were terminated early due to inadequate patient recruitment and after a pre-planned interim futility analysis, respectively.
CONCLUSIONS: Inhibition of IL-1β or IRAK4 signaling with canakinumab or emavusertib did not result in hematologic improvement in patients with LR-MDS.

DOI: https://doi.org/10.1038/s43856-026-01885-z
Mod Pathol. 2026 Sep 17. pii: S0893-3952(26)00129-8. [Epub ahead of print] 101086

Acute Myeloid Leukemia With KMT2A Amplification: A TP53-Alteration-Enriched Subgroup Associated With Chromoanagenesis and Poor Prognosis.

Thura Win Htut, Wei-Ying Jen, Ghayas C Issa, Sanam Loghavi, Abhishek Maiti, Alexandre Bazinet, Jayastu Senapati, Eitan Kugler, Calos Bueso-Ramos, Qing Wei, Gokce A Toruner, Musa Yilmaz, Gautam Borthakur, Nicholas J Short, Tapan M Kadia, Farhad Ravandi, Naval G Daver, Courtney D DiNardo, Guilin Tang.

  KMT2A amplification (KMT2A-amp) is a rare but aggressive genomic abnormality in acute myeloid leukemia (AML), with limited characterization in prior studies. We retrospectively analyzed 96 patients with AML harboring KMT2A-amp, including 56 newly diagnosed (ND) and 40 relapsed/refractory (RR) cases, with a median age of 68 years. Approximately half of the cases had therapy-related or secondary AML. All cases demonstrated highly complex karyotypes, with frequent -5/del(5q), -7/del(7q), and -17/del(17p). TP53 alteration was present in 93% of patients, whereas other recurrent AML-associated mutations were uncommon, and no AML-defining gene fusions or mutations were identified. In cases evaluated by optical genome mapping, all showed chromoanagenesis involving chromosome 11q23 region. Clinical outcomes were poor, with a median overall survival of 5.5 months in ND and 2.3 months in RR patients. Intensive chemotherapy did not improve survival compared with lower-intensity therapy, whereas venetoclax-based regimens were associated with improved overall survival (7.1 vs 4.6 months; p = 0.04) and event-free survival (6.7 vs 0.17 months; p < 0.01). We conclude that KMT2A-amp AML represents an extremely high-risk subgroup occurring in the context of TP53-associated genomic instability and chromoanagenesis. Its refractoriness to conventional chemotherapy highlights the urgent need for more effective, targeted therapeutic strategies.

Keywords:  KMT2A amplification; TP53 mutation; acute myeloid leukemia; chromoanagenesis; complex karyotype; genomic instability; optical genomic mapping; venetoclax

DOI:  https://doi.org/10.1016/j.modpat.2026.101086
Cancer Discov. 2026 Sep 15.

Targeting BLVRB Overcomes Immunosuppression and Potentiates Immunotherapy in Monocytic Acute Myeloid Leukemia.

Zhuomao Mo, Jianyu Wang, Yin Zhao, Xinghua Liang, Lina Liu, Jun Liu, Kaiting Wang, Lulu Qin, Miaomiao Su, Hezhou Guo, Yuxuan Chen, Xiaoyang Sun, Ruiting Yan, Jie Sun, Yongxian Hu, He Huang, Shanshan Pei, Dongrui Wang.

Acute Myeloid Leukemia (AML) is characterized by significant immunosuppression, limiting the efficacy of immunotherapy. Monocytic AML presents unique immunosuppressive features and constitutes a challenging subtype necessitating focused investigation. Using single-cell multi-omics analyses of primary AML samples, we revealed the immunosuppression landscape of monocytic AML and identified BLVRB as a marker of immunosuppressive monocytic AML cells. BLVRB depletion downregulated immune-modulatory gene expression and sensitized AML cells to T cell cytotoxicity, resulting in improved therapeutic efficacy in cell line and patient-derived xenograft models. Mechanistically, BLVRB signals through the transcription factor MAFB to masterfully promote the expression of various immunosuppression-associated genes, resulting in inhibitory effect against anti-AML T cells. We further demonstrated that the small molecule Tamibarotene targets BLVRB, enhancing the efficacy of both CAR-T and anti-PD-1 antibody therapies in AML. These findings elucidate the critical mechanism regulating immunosuppression in monocytic AML and identify BLVRB as a therapeutic target for improving AML immunotherapy.

DOI: https://doi.org/10.1158/2159-8290.CD-26-0447
Nat Commun. 2026 Aug 07. pii: 9765. [Epub ahead of print]17(1):

Glycosylation orchestrates megakaryocytic fate of hematopoietic stem cells via Wnt-MUC13 signaling.

Alejandro Roisman, Leonardo Rivadeneyra, Lindsey Conroy, Natalia Weich, Agata Steenackers, Melissa M Lee-Sundlov, Simon Glabere, Shikan Zheng, Katelyn E Rosenbalm, Mark Zogg, George Steinhardt, Anthony J Veltri, Joseph T Y Lau, Monika Zielonka, Jacek Zielonka, Elisa Fadda, Tongjun Gu, Hartmut Weiler, Ramon C Sun, Karin M Hoffmeister.

Hematopoietic stem and progenitor cells (HSPCs) sustain blood production through tightly regulated fate decisions. Disruption of this control underlies disorders such as myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and inherited thrombocytopenias. While transcriptional and epigenetic regulation of HSPCs is well established, the contribution of glycosylation has remained largely unexplored. Here, we identify the glycosyltransferase B4GALT1 as a central regulator of hematopoiesis that integrates extrinsic niche cues with intrinsic transcriptional programs. B4GALT1 shapes the bone marrow microenvironment by generating complex glycan niches that support HSPC function. However, its deficiency produces oncogenic glycan signatures, disrupts HSPC niche integrity, and induces aberrant expression of Mucin 13 (MUC13). These changes expand stem and progenitor pools, enforce megakaryocyte lineage bias, and activate the Wnt-MUC13/β-catenin signaling axis, a pathway tightly linked to proliferation and malignant transformation. Consequently, B4GALT1 loss uncouples proliferation from self-renewal, altering key regulators of stem cell quiescence, lineage balance, and marrow homeostasis. Our findings define a previously unrecognized glycan-dependent regulatory axis that directs HSPC fate through coordinated transcriptional reprogramming, signaling modulation, and niche remodeling. This work establishes aberrant glycosylation as a driver of hematopoietic dysfunction and highlights B4GALT1 as a potential therapeutic target in stem cell-driven blood disorders.

DOI: https://doi.org/10.1038/s41467-026-76246-4
Leukemia. 2026 Sep 16.

Clinical evaluation of AI-assisted quantitative marrow fibrosis assessment using Continuous Indexing of Fibrosis (CIF).

Sharon Ruane, Rosalin A Cooper, Carlo Pescia, Neha Bhardwaj, Anna Green, Deborah Hay, Jana Ihlow, Fatima Zahra Jelloul, Rashmi Kanagal-Shamanna, Philip Macklin, Vidhya Manohar, Edoardo Olmeda, Mark Ong, Andres Quesada, Jens Rittscher, Hosuk Ryou, Saad Bashir, Sam Maxwell, Ka Ho Tam, Alan Aberdeen, Len Brandes, Korsuk Sirinukunwattana, Timothy Ebsworth, Daniel Royston.

Assessment of fibrosis is central to the evaluation of diagnostic bone marrow trephine (BMT) biopsies. However, manual fibrosis grading is subjective and only semi-quantitative. We evaluated the clinical utility of a previously developed AI-based quantitative fibrosis assessment tool, Continuous Indexing of Fibrosis (CIF), using ~1000 consecutive BMT biopsies without pre-selection. An international panel of 14 haematopathologists performed manual reads using whole-slide images (WSI) of reticulin-stained slides and two types of CIF-assisted reads (Sequential-assisted and Concurrent-assisted) across three study rounds. The AI-derived CIF scores correlated strongly with the manual consensus MF grade (Spearman ρ = 0.770) and demonstrated good discriminative performance across adjacent MF grade boundaries. The CIF-assisted protocols significantly improved intra-observer and inter-observer agreement compared to manual assessment, without increasing read times. Sequential-assisted reads yielded the largest gain in inter-observer agreement (12.6 percentage points; 95% CI 10.5-14.8) and improved agreement with the consensus reference (3.0 percentage points; 95% CI 0.4-5.7). Both assisted protocols reduced discordance across the clinically significant MF-1 / MF-2 boundary. These findings demonstrate that AI-assisted quantitative bone marrow fibrosis assessment using CIF is reproducible, efficient and well suited for future clinical deployment testing. This supports a future role in standardising routine diagnostic haematopathology and enhancing the sensitivity of fibrosis-based clinical trial endpoints.

DOI: https://doi.org/10.1038/s41375-026-03126-7
JCI Insight. 2026 Sep 15. pii: e205218. [Epub ahead of print]

Stabilization of the PP2A-B56α complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML.

Silvia Romero-Murillo, Irene Peris, Anna Maria Lucianò, Nerea Marcotegui, Carmen Vicente, Brian Tran, Kelsey Barrie, Caitlin M O'Connor, Andrea Torres-López, Maria C Mateos, Maria L Cayuela, Victoriano Mulero, Joaquín Fernández-Irigoyen, Enrique Santamaría, Maria D Odero, Goutham Narla.

  Cell metabolic rewiring is associated with resistance to venetoclax-azacitidine (Ven-Aza) combination therapy and relapse in acute myeloid leukemia (AML) patients. Drug-resistant cells exhibit an enhanced reliance on oxidative phosphorylation (OXPHOS) for energy production. Therefore, impairing mitochondrial metabolism represents an exciting strategy to face this unmet clinical need. We recently demonstrated that the specific activation of the phosphatase PP2A-B56α enhances the pro-apoptotic efficacy of venetoclax in AML. Here, through leveraging unbiased multi-omics-based approaches and using both genetic and pharmacological tools, we define key roles for the tumor suppressor PP2A-B56α complex in OXPHOS regulation and treatment response in disease-relevant AML models. From a translational perspective, the specific stabilization of PP2A-B56α heterocomplex with the novel PP2A molecular glue activator, RPT04402, reduces OXPHOS levels in treatment-resistant AML cells and improves treatment response in both Ven-Aza-sensitive and -resistant AML cell lines, primary cells, and in vivo models. Together, our work supports further research on targeted combination therapy approaches based on PP2A-B56α stabilization to counteract OXPHOS-related treatment resistance and improve AML responses in a patient population with historically poor outcomes.

Keywords:  Cell biology; Drug therapy; Hematology; Phosphoprotein phosphatases; Tumor suppressors

DOI:  https://doi.org/10.1172/jci.insight.205218
Leukemia. 2026 Sep 14.

Targeting CD38 with bispecific antibody XmAb 18968 in patients with relapsed/refractory acute myeloid leukemia and T-cell acute lymphoblastic leukemia.

Guru Subramanian Guru Murthy, Bijal Shah, Talha Badar, Jessica Leonard, Adam DuVall, Cecilia Arana Yi, Aniko Szabo, Arielle Baim, Alexandra Harrington, Lyndsey Runaas, Karen Carlson, Laura Michaelis, Sameem Abedin, Tyce Kearl, Ehab Atallah.

CD38 is a transmembrane glycoprotein highly expressed in acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL). XmAb18968 is a novel CD38-CD3 bi-specific T-cell engager with Fc domain modified to reduce non-selective activation of effector cells. In this phase 1 multicenter clinical trial, we evaluated the outcomes of XmAb18968 in adults with relapsed/refractory (RR) AML and T-ALL. Twenty-two patients with AML (n = 13) and T-ALL (n = 9) with a median age of 63 years (range 31-77) were enrolled. Prior lines of therapy (median 3, range 1-8) included venetoclax (77.3%), allogeneic HCT (22.7%), CD7 CAR-T cell therapy and daratumumab (11.1%). Grade ≥3 adverse events included anemia (14%), neutropenia (18%), and thrombocytopenia (14%). No grade ≥3 cytokine release syndrome or neurotoxicity was seen. Overall, 17 patients (AML = 11, ALL = 6) completed at least one cycle of therapy. Among 11 patients with RR-AML, one achieved partial remission (PR) and two achieved MRD negative complete remission (CR). In 6 patients with RR-T-ALL, 4 achieved meaningful improvement in disease burden with 1 clearance of MRD. Median OS was 8.5 months in AML and 8.7 months in T-ALL. XmAb18968 is safe and tolerable with encouraging preliminary efficacy, supporting further investigation of CD38 targeting therapies in this setting (NCT05038644).

DOI: https://doi.org/10.1038/s41375-026-03130-x
Nature. 2026 Sep 16.

Targeted genomic integration and rearrangement using prime assembly.

Sébastien Levesque, Nozomu Kawashima, Gue-Ho Hwang, Jing Zeng, Vasil Toskov, Timothy Barry, William Mannherz, Luke Homfeldt, Basheer Becerra, Vivien A C Schoonenberg, Luca Pinello, Suneet Agarwal, Daniel E Bauer.

Although therapeutic genome editing holds great potential to remedy diverse inherited and acquired disorders, targeted installation of medium-to-large genomic modifications in therapeutically relevant cells remains challenging1. Here we develop prime assembly, an approach that permits DNA sequence assembly and integration in human cells leveraging CRISPR-targeted dual flap synthesis. This method enables RNA-programmable site-specific integration of single or double-stranded DNA fragments. Unlike homology-directed repair, prime assembly is similarly active in dividing and non-dividing cells. We applied prime assembly to perform targeted exon recoding, transgene integration and megabase-scale rearrangements, including at therapeutically relevant loci in primary human cells. Prime assembly expands the capabilities of genome engineering by enabling the targeted integration of medium to large-sized DNA sequences without relying on double-stranded DNA donors, nuclease-driven double-strand breaks or cell cycle progression.

DOI: https://doi.org/10.1038/s41586-026-11024-2
Ann Hematol. 2026 Aug 04. pii: 415. [Epub ahead of print]105(10):

Optimizing venetoclax duration with hypomethylating agents for newly diagnosed acute myeloid leukemia: impact on response and survival.

Anush A Ginosyan, Karam Ashouri, Justin Cheng, Lauren Ford, Mihir Baya, Lucas Humayun, Danielle Hong, Elaine Huang, Grace Kim, Brandon Tang, Brian Hom, Robert Ireland, Imran Siddiqi, Amir Ali, Karrune Woan, Eric Leon Tam, George Yaghmour.

  The addition of venetoclax to hypomethylating agents (HMAs) is standard for older adults with newly diagnosed acute myeloid leukemia (AML). However, prolonged venetoclax (VEN) exposure can cause cytopenias and infections, raising questions about optimal duration. We conducted a single‑center retrospective study of 102 patients treated between 2018 and 2025 with azacitidine or decitabine plus VEN administered for 14 (n = 22), 21 (n = 48), or 28 (n = 32) days per 28‑day cycle. Baseline cytogenetic and molecular profiling, responses by 2022/2024 ELN criteria, measurable residual disease (MRD), cumulative incidence of relapse (CIR), disease‑free survival (DFS), and overall survival (OS) were analyzed using competing‑risks regression and Cox models. Median age was 68 years and patients received a median of 4 cycles. Composite remission (CR/CRi/CRh/MLFS) was 66.7%, with MRD negativity in 75.0% of responders. Remission and MRD negativity rates did not differ significantly across VEN‑duration cohorts. Median OS and DFS were 17.3 and 12.3 months, respectively, with no significant differences in OS, DFS, and CIR between 14‑, 21‑, and 28‑day cohorts. Grade ≥ 3 cytopenias and transfusion independence rates also did not differ significantly. In this cohort, shortening VEN exposure to 14 or 21 days did not show a significant difference in response, survival, relapse risk, and toxicity profiles relative to a 28‑day schedule in our cohort. These findings support further prospective evaluation of reduced VEN durations in this population.

Keywords:  AML; Elderly; Hypomethylating agents; Survival outcomes; Treatment duration; Venetoclax

DOI:  https://doi.org/10.1007/s00277-026-07219-2
Tzu Chi Med J. 2026 Oct-Dec;38(4):38(4): 434-445

Targeting lipid metabolic vulnerabilities with small-molecule inhibitors in acute myeloid leukemia: Emerging insights and therapeutic opportunities.

Jui-Hung Yen, Trung Q Phan, Je-Wen Liou, Pei-Yi Chen.

  Metabolic reprogramming has recently been recognized as a hallmark of cancer. In acute myeloid leukemia (AML), clinically relevant metabolism-targeted therapies have primarily focused on inhibiting mitochondrial energy production; however, their clinical progress has been limited by substantial and nonspecific toxicity. Emerging evidence indicates that reprogramming of lipid metabolism represents a defining feature of leukemic transformation. Lipids not only serve as fundamental structural components of cellular membranes but also function as key signaling molecules and energy sources. In AML cells, lipid uptake, storage, and de novo synthesis are markedly increased, thereby supporting rapid proliferation, survival, and leukemic progression. Consequently, dysregulated lipid metabolism has attracted growing attention as a promising therapeutic vulnerability in AML. This review summarizes the conceptual framework underlying AML cell dependence on cholesterol, fatty acids (FAs), sphingolipids, and broader lipid metabolic pathways. We highlight recent advances in understanding aberrant lipid metabolic programs in AML, including alterations in cholesterol biosynthesis, FA uptake and lipogenesis, FA oxidation, and sphingolipid metabolism. Particular emphasis is placed on the regulatory mechanisms that maintain lipid metabolic homeostasis and how their disruption contributes to leukemogenesis and therapy resistance. Furthermore, we discuss emerging therapeutic strategies aimed at targeting lipid metabolic pathways, with a focus on small-molecule inhibitors that selectively interfere with lipid metabolism-associated enzymes and signaling networks. By delineating key molecular targets and their pharmacological inhibitors, this review highlights the potential of lipid metabolism-based interventions as innovative and effective treatment strategies for AML.

Keywords:  Acute myeloid leukemia; Fatty acid oxidation; Lipid metabolism; Metabolic reprogramming; Small-molecule inhibitors

DOI:  https://doi.org/10.4103/tcmj.TCMJ-D-26-00039
Stem Cell Res. 2026 Sep 11. pii: S1873-5061(26)00196-0. [Epub ahead of print]96 104100

Generation of TWO iPSC lines (CRICKi025-A and CRICKi026-A) from healthy donor bone marrow mesenchymal stromal cells.

Liani Devito, Khadidja Habel, Ruta Meleckyte-Martinez, Lyn Healy, Syed A Mian, Dominique Bonnet.

Mesenchymal stromal cells (MSCs) are key components of the bone marrow (BM), providing structural support and paracrine signals that regulate haematopoietic stem cell maintenance, self-renewal and differentiation. However, primary BM MSCs are rare, heterogeneous, and subject to donor variability and have limited ex-vivo expansion capacity, restricting their utility. Here, we describe two human induced pluripotent stem cells lines, CRICKi0025-A and CRICKi0026-A, reprogrammed from adult BM-derived MSCs using non-integrating Sendai virus vectors. Both lines showcase grade-A morphology, are genomically stable, upregulate essential pluripotent markers and can differentiate into the three germ layers. These lines are a well-characterised resource for generating MSCs.

DOI: https://doi.org/10.1016/j.scr.2026.104100
Mol Cell. 2026 Sep 15. pii: S1097-2765(26)00587-3. [Epub ahead of print]

5-Azacytosine induces cytotoxicity via 5-methylcytosine depletion on chromatin-associated RNA in leukemia.

Boyang Gao, Ying Li, Xinyuan Ma, Long Zhao, Zhongyu Zou, Juyeong Hong, Junhong Xiang, Xiaoyang Dou, Feng-Chun Yang, Mingjiang Xu, Chuan He.

  5-Azacytidine (5-azaC) is a DNA hypomethylating agent clinically used in myeloid malignancies. As a ribonucleoside analogue, 5-azaC incorporates more readily into nascent RNA than DNA. Here, we demonstrate that RNA 5-methylcytosine (m5C) depletion by 5-azaC treatment, particularly at early time points, is sufficient to induce leukemia cell death. In contrast to its DNA demethylation function, the RNA-dependent effects of 5-azaC lead to transcriptional repression, disrupting genes involved in cell-cycle regulation and DNA repair. Mechanistically, depletion of m5C by 5-azaC in chromatin-associated RNA (caRNA) disrupts the MBD6-mediated H2AK119ub deubiquitination. This also impairs SRSF2 recruitment and the downstream H3K27ac deposition by p300. Consistently, loss of the caRNA methyltransferase NSUN2 caused prolonged cell cycle, defective DNA repair, and shifted hematopoietic lineage commitment toward erythropoiesis, mirroring the effects of 5-azaC treatment. Our findings highlight the transcriptional repression by 5-azaC through depleting caRNA m5C, providing additional insights into the mechanism of action for 5-azaC.

Keywords:  5-azaC; RNA epitranscriptomics; histone modifications; leukemia; m(5)C

DOI:  https://doi.org/10.1016/j.molcel.2026.08.018