bims-tremyl 2026-11-08 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2026–11–08
38 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Distinct clinical and molecular profiles of acute myeloid leukemia defined by mutations in IDH1, IDH2, and TET2.
Prognostic Impact of FLT3-ITD Microclones in AML: An EHA AML-Specialized Working Group Study.
Choline Kinase Alpha Inhibition is a Mutation Agnostic Therapeutic Vulnerability in Clonal Hematopoiesis.
Tyrosine kinase inhibitors are associated with reduced AML transformation in systemic mastocytosis with myeloid neoplasm.
Clonal haematopoiesis subtypes confer dose-dependent risk of serious bacterial infection.
Increase in fetal haemoglobin from baseline to day 10 is a biomarker for response to decitabine in AML: Results of the AML21 randomized phase III trial of the EORTC Leukemia Group, Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) and German MDS Study Group.
BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia.
Durable and reversible epigenetic programming of human hematopoietic stem cells as a platform for modulation of platelet function.
Mutant calreticulin-driven myeloproliferative neoplasms favour the emergence of TIGIT-positive NK cells.
Persistent Malignant Stem Cells Drive Relapse After Transplantation in the Myelodysplastic Neoplasms.
The JAK2 V617F revolution in myeloproliferative neoplasms.
Salvage-free, transplantation-free survival: a proposal for a new clinical endpoint in acute myeloid leukemia.
Multimodal omics identifies a lymphoid-biased multipotent progenitor population with limited age-associated remodeling.
Relcobatinib, a highly selective ATP-competitive ABL1 tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia.
DCAF7 regulates hematopoietic stem cell function and differentiation through polycomb repressive complex 1 modulation.
Improved multistate survival in younger AML patients over time.
Integrating functional marrow reserve and molecular risk improves prediction of post-transplant outcomes in HMA-treated myelodysplastic syndromes.
Salvage therapy for immune-mediated bone marrow failure.
Maternal Folate Nutrition Programs Adult Hematopoietic Stem Cell Function Through Mitochondrial Remodeling.
Shwachman-Diamond syndrome: A paradigm for ribosomopathies, somatic genetic rescue, and leukemia predisposition syndrome.
Maternal donor risk in haploidentical transplant with post-transplant cyclophosphamide: the role of recipient sex.
Bcl11a preserves hematopoietic stem cell function in culture by restraining Ncf1-dependent ROS.
JAK1/2 inhibition promotes aggressive cutaneous carcinogenesis through COT kinase-mediated alternative MAPK pathway activation.
5-Azacytidine incorporation into mRNAs disrupts translation and induces ribosome collisions.
Ascorbate and TET2 couple balanced hematopoiesis to disease tolerance.
Overall Survival in Adults With Acute Myeloid Leukemia Initiating Quizartinib vs Midostaurin With Chemotherapy.
More than the right ingredients: perfecting the recipe for human hematopoietic stem cell expansion.
Mechanistically distinct classes of BCR::ABL1 mutations confer resistance to asciminib.
A single-cell comprehensive atlas of leukemia and its microenvironment.
SF3B1 mutation significance in myeloid neoplasms without anaemia.
Clonal hematopoiesis and cytopenias following CAR19 therapy.
Myeloid leukemia cells utilize branched chain keto acids to acquire intrinsic resistance to methotrexate.
Establishing Absolute Neutrophil Count and White Blood Cell Count Reference Intervals for the Duffy Null Population.
Momelotinib for the treatment of myelofibrosis in patients with moderate-to-severe anemia: a drug safety evaluation.
Quantitative CD19 expression in pediatric NUP98-rearranged myeloid neoplasms: enrichment at relapse or progression and in the NUP98::NSD1 subtype.
Dasatinib in pediatric patients with chronic myeloid leukemia in chronic phase: long-term efficacy and endocrine analysis.
Pot1a maintains mesenchymal stem cell niche function to support hematopoietic stem cells.
RACK1 maintains mouse hematopoietic stem cells by directly binding to and stabilizing LDB1.

Haematologica. 2026 Nov 05.

Distinct clinical and molecular profiles of acute myeloid leukemia defined by mutations in IDH1, IDH2, and TET2.

Fanny Asbaghi, Erik Håkansson, Jakob Hofvander, Yuhong Ning, Yuan Xue, Tierney Philips, Vladimir Lazarevic, Christer Nilsson, Sören Lehmann, Samuel Levy, Gunnar Juliusson, Ravindra Majeti, Niklas Landberg.

Acute myeloid leukemia (AML) is a heterogeneous disease driven by recurring somatic mutations, frequently affecting genes involved in epigenetic regulation. Mutations in IDH1, IDH2, and TET2 are largely mutually exclusive and thought to converge on a shared pathway by impairing TET-mediated DNA demethylation, either directly through loss of TET2 activity or indirectly through the accumulation of the oncometabolite (R)-2-hydroxyglutarate (2-HG) in IDH1- and IDH2-mutant AML. Whether this biochemical convergence translates into similar disease biology remains unclear. Here, we analyzed AML defined by mutations in IDH1, IDH2, or TET2 using population-based data from the Swedish AML Registry, complemented by transcriptomic and 5-hydroxymethylcytosine (5hmC) profiling of purified blasts from a highly selected subset of primary AML samples. TET2-mutant AML occurred at an older age and was associated with a more pronounced thrombocytopenia, whereas IDH1- and IDH2-mutant AML showed deeper neutropenia and more favorable overall survival, including after adjustment for clinical covariates. Transcriptomic and 5hmC alterations showed only modest concordance, with 5hmC profiles providing clearer separation of the mutational subgroups. TET2-mutant samples showed significant enrichment of the oxidative phosphorylation pathway compared with IDH1- and IDH2-mutant AML. The mutational groups also showed distinct closest normal counterparts among healthy hematopoietic cell populations. Together, these findings demonstrate that IDH1, IDH2, and TET2 mutations define clinically and molecularly distinct subgroups of AML, highlighting the relevance of mutation-specific clinical stratification.

DOI: https://doi.org/10.3324/haematol.2026.301319
Am J Hematol. 2026 Nov 01.

Prognostic Impact of FLT3-ITD Microclones in AML: An EHA AML-Specialized Working Group Study.

Carmelo Gurnari, Tiziana Ottone, Alfonso Piciocchi, Daniela Späth, Annika Meid, Giovanni Marsili, Emiliano Fabiani, Francesca Romano, Maria Rosaria Pascale, Paola Ricci, Patrizia Chiusolo, Mauro Di Ianni, Marta Sobas, Lorenzo Brunetti, Guadalupe Oñate, Joana Brioso Infante, Jacopo Nanni, Calogero Vetro, Matilde Boada, Anna Candoni, Jorge Sierra, Nicola Potter, Amanda Gilkes, Sean James Johnson, Ian Thomas, Brian Huntly, Adriano Venditti, Nigel Russell, Richard Dillon, Hartmut Döhner, Konstanze Döhner, Maria Teresa Voso.

  The 2022 ELN recommendations reclassified fms-like tyrosine kinase-3 (FLT3)-ITD mutated acute myeloid leukemia (AML) as intermediate-risk, irrespective of allelic ratio (AR), and designated capillary electrophoresis (CE) as the preferred detection method. However, CE requires substantial expertise, particularly to identify FLT3-ITD microclones (FLT3-ITDm; AR < 0.05), whose clinical significance remains uncertain. Herein, we investigated diagnostic aspects and the prognostic impact of FLT3-ITDm. An initial methodological study performed on 48 FLT3-ITD+ samples, with AR 0.001-6.00, showed overall concordance between CE and next-generation sequencing (NGS) results (p < 0.001), with only three microclones (AR: 0.002, 0.001, and 0.008) identified by CE and not by NGS. We next analyzed 658 AML patients diagnosed with a FLT3-ITD+ AML (n = 446 with AR ≥ 0.05, and n = 212 with a microclone) between 2017 and 2022. Patients with FLT3-ITDm, as compared to patients with AR ≥ 0.05, were older, more often had secondary-type AML, and displayed a higher prevalence of myelodysplasia-related gene mutations, while NPM1-mutation frequency was similar in the two groups. Complete remission rates were lower in FLT3-ITDm (74%) than in patients with AR ≥ 0.05 (88%) treated with intensive chemotherapy without FLT3-inhibitors (FLT3i). In the intensively treated subgroup, multivariate analyses demonstrated that age, NPM1 mutation, and allogeneic stem cell transplantation, rather than FLT3-ITD AR, were independent predictors of disease-free survival. At relapse, 15 of 33 (45%) evaluable patients remained FLT3-ITD+, with 10 expanding the original microclone. In conclusion, FLT3-ITDm are associated with older age, secondary AML, and with expansion of the FLT3-ITD clone upon relapse, thereby providing a rationale for the evaluation of FLT3i in randomized clinical trials.

Keywords:  FLT3‐ITD microclones; acute myeloid leukemia; prognostic markers

DOI:  https://doi.org/10.1002/ajh.70546
bioRxiv. 2026 Oct 28. pii: 2026.10.26.760729. [Epub ahead of print]

Choline Kinase Alpha Inhibition is a Mutation Agnostic Therapeutic Vulnerability in Clonal Hematopoiesis.

Brandon J Gheller, Olivia Mitchell, Michael Quach, Jayakrishnan Gopakumar, Serine Avagyan, Song Yang, Thomas P Mathews, Chuck Haggerty, Alexander Meissner, Jacqueline S Garcia, Ralph J DeBerardinis, Siddhartha Jaiswal, Fernando Camargo, Leonard I Zon.

Clonal hematopoiesis (CH) affects the aging population and is associated with increased risk of hematological malignancy, cardiovascular disease, and all-cause mortality. Therapeutic options for CH remain limited. Using hematopoietic stem and progenitor cell (HSPC) color barcoding and mosaic mutagenesis in zebrafish, we identified perturbed choline metabolism and increased phosphatidylcholine (PC) biosynthesis via choline kinase alpha (CHKA) in asxl1 -mutant HSPCs. Suppressing CHKA-dependent choline flux reduced ASXL1 -driven clonal expansion. This effect was conserved in a murine DNMT3A and human TET2 model. Mechanistically, CHKA-dependent choline flux controls phosphatidylcholine production that supports platelet activating factor (PAF) production. Exogenous PAF overcomes the suppressive effect of CHKA inhibition in ASXL1 and TET2 models. We isolated primary, human HSPCs from the peripheral blood of patients with endogenous ASXL1 mutations and demonstrated that perturbing PAF signaling reduces their competitive potential in an ex vivo clonal competition assay. This CHKA/PAF axis is conserved in TET2 -mutant HSPCs. Together, these findings identify a mutation agnostic metabolic dependency across the three most common CH genotypes and demonstrate that targeting the CHKA-dependent choline flux suppresses clonal expansion.

DOI: https://doi.org/10.64898/2026.10.26.760729
Blood. 2026 Nov 05. pii: blood.2026035465. [Epub ahead of print]

Tyrosine kinase inhibitors are associated with reduced AML transformation in systemic mastocytosis with myeloid neoplasm.

Olivier Hermine, Orianne Debeaupuis, Gandhi-Laurent Damaj, Johannes Lübke, Juliana Schwaab, Marc Heizmann, Frank Siebenhaar, Polina Pyatilova, Nicole Nojarov, Marek Niedoszytko, Aleksandra Górska, Mattias Mattsson, Khalid Shoumariyeh, Stephan de Bra, Friederike Wortmann, Nikolas von Bubnoff, Horia Bumbea, Delia Soare, Chiara Elena, Judit Varkonyi, Anna Belloni Fortina, Simge Erdem, Knut Brockow, Tobias Franz, Jens P Panse, Deborah Christen, Christine Breynaert, Akif Selim Yavuz, Luca Malcovati, Michael Doubek, Vito Sabato, Ilaria Tanasi, Massimiliano Bonifacio, Karin Hartmann, Axel Rüfer, Mariarita Sciumè, Valentina Bellani, Irena Angelova-Fischer, Alex Stefan, Massimo Triggiani, Roberta Parente, Saskia K Klein, Michael Makris, Sotirios G Papageorgiou, Paul van Daele, Ingunn Dybedal, Daniel Baffoe, Theo Gulen, Madlen Jentzsch, Olivier Lortholary, Maël Heiblig, Cristina Bulai Livideanu, Stéphane Barete, Clément Gourguechon, Sophie Dimicoli-Salazar, Olivier Tournilhac, Laurent Frenzel, Michel Arock, Andrzej Mital, Johannes N Woltsche, Hanneke C Kluin-Nelemans, Hanneke N G Oude Elberink, Jason Gotlib, Martina Sperr, Andreas Reiter, Peter Valent, Wolfgang R Sperr, Julien Rossignol.

In an international registry analysis of 201 patients with SM-AHN, KIT D816V-selective TKI exposure was associated with longer overall survival (37.9 vs 17.8 months; P <.001) and lower 36-month incidence of acute myeloid leukemia transformation (5.9% vs 27.1%; P <.001).

DOI: https://doi.org/10.1182/blood.2026035465
Nat Commun. 2026 Oct 07. pii: 11400. [Epub ahead of print]17(1):

Clonal haematopoiesis subtypes confer dose-dependent risk of serious bacterial infection.

Eleanor Fewings, Zhi Yu, Jacob C Gutierrez, Buu Truong, Petko P Fiziev, Jeremy McRae, Jeremy Schwartzentruber, Alexander G Bick, Pradeep Natarajan, Caleb A Lareau, Jacob C Ulirsch, Kyle Kai-How Farh.

Clonal haematopoiesis (CH) arises from somatic mutations in haematopoietic stem cells that drive clonal expansion and increase haematological malignancy risk. Here we show that CH confers mutation- and dose-dependent risk of serious bacterial infection (SBI). Using a multi-parameter somatic variant calling and filtering approach, we identified 19,822 mutations across 43 CH genes in 40,560 of 590,537 individuals from three population cohorts (6.87%), validated in a combined analysis of 889,215 individuals. CH was associated with SBI development (HR = 1.22, P = 4.66 × 10⁻²⁹) and 28-day post-infection mortality (RR = 1.84, P = 0.0012), independent of malignancy and robust to adjustment for inflammatory comorbidities and ancestry. Recurrent mutations in SRSF2, DNMT3A, SF3B1, IDH2, and NRAS (n = 2143) conferred substantial absolute risks: 22-25% of individuals with expanded SRSF2 P95 clones developed SBI within 10 years. These associations were consistent across diverse populations and largely independent of bacterial strain.

DOI: https://doi.org/10.1038/s41467-026-77934-x
Br J Haematol. 2026 Nov 03.

Increase in fetal haemoglobin from baseline to day 10 is a biomarker for response to decitabine in AML: Results of the AML21 randomized phase III trial of the EORTC Leukemia Group, Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) and German MDS Study Group.

Julia Stomper, Michal Kicinski, Tobias Ma, Thomas Meyer, Sylvain Chantepie, Richard Noppeney, Mario Luppi, Ernesta Audisio, Laimonas Griškevičius, Andreas Neubauer, Robin Foà, Walter J F M Van der Velden, Anna Candoni, Radovan Vrhovac, Gianluca Gaidano, Catharina Van Elssen, Mels Hoogendoorn, Maurizio Musso, Attilio Olivieri, Christian Junghanß, Emmanuel Bissé, Stephanie Antunes, Frédéric Baron, Adriano Venditti, Joop H Jansen, Pierre W Wijermans, Gerwin Huls, Michael Lübbert.

  Lack of response or delayed response to therapy are major challenges in the use of DNA-hypomethylating agents (HMA) in patients with acute myeloid leukaemia (AML). Fetal haemoglobin (HbF) is a potential biomarker for response to HMA treatment but has only been studied in small single-centre studies. We investigated the association between HbF and treatment outcome in the randomized phase 3 European Organisation for Research and Treatment of Cancer (EORTC)-1301 trial AML21, which included 606 fit, older AML patients who received 10-day decitabine or '3 + 7' chemotherapy as induction. HbF was measured twice in the decitabine arm (n = 135) and at baseline in the 3 + 7 arm (n = 97). In the decitabine arm, HbF increase from baseline to day 10 was associated with increased odds of reaching complete remission (CR) or CR with incomplete count recovery (CRi) (odds ratio [OR] 2.40, 95% confidence interval [CI] 1.15-5.02, p = 0.020). The hazard ratio (HR) for death comparing patients with HbF increase to those without was 0.83 (95% CI 0.55-1.28, p = 0.40). Baseline HbF in the decitabine arm was not associated with CR/CRi (OR 0.89, 95% CI 0.45-1.75, p = 0.73) or overall survival (HR 0.86, 95% CI 0.58-1.28, p = 0.47). In conclusion, this large prospective study adds to the body of evidence that HbF is an easy-to-measure early biomarker for response to HMA treatment.

Keywords:  HbF; adverse‐genetics AML; de‐escalation; hypomethylating agents

DOI:  https://doi.org/10.1111/bjh.70874
Sci Adv. 2026 Nov 06. 12(45): eaeg0571

BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia.

Laura López-Hernández, Stephanie J Crowley, Sara Cea-Sánchez, Ricardo de Arellano, Neetij Krishnan, Patrick Toolan-Kerr, Lynn White, Domenico Ignoti, Emily Soto-Hidalgo, Stefano Gustincich, Román González-Prieto, Luca Pandolfini, Isaia Barbieri, Patricia Altea-Manzano, Jeffrey A Magee, Francesca Ferraro, Samuel J Taylor, Jeffrey J Bednarski, Gonzalo Millán-Zambrano.

Acute myeloid leukemia (AML) is driven by genetic alterations and non-mutational mechanisms that disrupt normal hematopoiesis and support leukemic cell survival. While the mutational landscape of AML is well characterized, the non-genetic processes sustaining leukemic maintenance remain less understood. Using human AML cells and murine models, we identify BCL2-associated transcription factor 1 (BCLAF1) as a key regulator of leukemic progression through control of mRNA processing. BCLAF1 physically associates with core spliceosome components and regulates alternative splicing programs in leukemic cells. Mechanistically, BCLAF1 is required for productive splicing of activating transcription factor 4 (ATF4) mRNA, thereby sustaining ATF4 protein levels and downstream metabolic gene expression programs. Loss of BCLAF1 reduces ATF4 levels, leading to impaired de novo amino acid biosynthesis and increased sensitivity to venetoclax. Together, these findings uncover a previously unrecognized mechanism linking RNA splicing control to metabolic adaptation in AML, identifying BCLAF1 as a potential therapeutic vulnerability.

DOI: https://doi.org/10.1126/sciadv.aeg0571
Cell Stem Cell. 2026 Nov 05. pii: S1934-5909(26)00390-5. [Epub ahead of print]

Durable and reversible epigenetic programming of human hematopoietic stem cells as a platform for modulation of platelet function.

Tianyi Ye, Wanying Xu, Maria N Barrachina, Peng Lyu, Mateusz Antoszewski, Lucrezia Della Volpe, Chun-Jie Guo, Andrew J Lee, Emily Villalpando, Isaac A Johnson, Madelaine S Theardy, Spencer D Shelton, Lara Wahlster, Alexis Caulier, Luana Messa, Michael Poeschla, Gaurav Agarwal, Ronodeep Mitra, Alec A Schmaier, Jonathan S Weissman, Kellie R Machlus, Vijay G Sankaran.

  Programmable epigenome editing offers control of gene expression without altering DNA sequence, but its capacity to program human hematopoietic stem cells (HSCs) and their differentiated progeny remains incompletely characterized. Here, we establish that DNA methylation-based epigenome editors delivered transiently as RNA induce heritable gene silencing in primary human HSCs. Targeting the platelet integrin β3 (ITGB3) produced silencing that persisted through long-term HSC self-renewal and megakaryocytic differentiation, impaired aggregation of in vitro-derived platelets, and was partially reversed through targeted demethylation at this locus. Silencing remained stable in human HSCs 4 months after transplantation into mice. Targeting additional platelet-associated genes demonstrated broad applicability with this approach. Together, these findings establish DNA methylation-based epigenome editing as a platform for durable and reversible programming of human HSCs and demonstrate its application to modulating platelet function.

Keywords:  DNA methylation; HSC engineering; epigenetics; epigenome editing; hematopoiesis; hematopoietic stem cell; platelet; thrombosis

DOI:  https://doi.org/10.1016/j.stem.2026.10.009
Leukemia. 2026 Nov 03.

Mutant calreticulin-driven myeloproliferative neoplasms favour the emergence of TIGIT-positive NK cells.

Agnieszka Witalisz-Siepracka, Theresa Harm, Thorsten Klampfl, Bernhard Zdársky, Brian Ringhofer, Elisabeth Gamper, Sophie Edtmayer, Uwe Graichen, Petra Pavić, Sabine Geiselhart, Johannes Foßelteder, Gregor Hoermann, Juan Li, Anthony R Green, Carl Crodel, Joachim Wolff, Florian H Heidel, Sascha Klee, Klaus Podar, Andreas Reinisch, Armin Zebisch, Karoline Kollmann, Dagmar Stoiber.

Myeloproliferative neoplasms (MPNs) are chronic diseases characterized by an excessive production of myeloid blood cells. Janus kinase (JAK2)V617F is the most common mutation in MPNs but a substantial proportion of patients harbour calreticulin (CALR) mutations-an attractive target for emerging immunotherapies. Natural killer (NK) cells have a central role in the elimination of malignant cells, but NK cells of MPN patients have reduced activity. Thus, reactivating their function might improve the disease outcome. Here, we demonstrate that NK cells from a CALR-mutant mouse model exhibit normal maturation but enhanced degranulation. Consistently, NK cells from CALR-mutant patients exhibit preserved degranulation ability, exceeding that observed in JAK2-mutant patients. Notably, NK cells from CALR-, but not JAK2-mutant patients express high levels of the immune checkpoint TIGIT possibly due to increased abundance of immunomodulatory proteins in the plasma. Moreover, CD34⁺ cells from MPN patients express elevated levels of the TIGIT ligand CD112. TIGIT blockade results in reduced platelet numbers in a transplant mouse model. These findings suggest that NK cells in CALR-mutant MPNs are activated but functionally constrained when encountering TIGIT ligand-expressing target cells, providing a strong rationale for exploring TIGIT blockade to restore NK-cell immunity in this disease subset.

DOI: https://doi.org/10.1038/s41375-026-03175-y
bioRxiv. 2026 Oct 29. pii: 2026.10.28.761431. [Epub ahead of print]

Persistent Malignant Stem Cells Drive Relapse After Transplantation in the Myelodysplastic Neoplasms.

Benjamin Kroger, Roni Tamari, Carmelo Gurnari, Yuanyuan Ji, Yazan Madanat, Yi Huang, Reiko Tachibana, Toby Thomas, Albert Son, Peter Carlsgaard, Clayton Jackson, Vivian Irizarry-Gatell, Alejandro Marinos, Zachary Brady, Prapti Patel, Valeria Visconte, Abishar Cherukuri, Madhuri Vusirikala, Asmita Mishra, Amy McLemore, Jerry Yuen, Bao Duy An Hoang, Russell Vittrup, Julio Alvarenga, Robert Collins, David A Sallman, Jaroslaw Maciejewski, Stephen S Chung.

The myelodysplastic neoplasms (MDS) are initiated in hematopoietic stem cells (HSCs). Allogeneic transplantation is the only curative treatment, but relapse remains common. To detect rare MDS HSCs, we developed an ultra-low-input DNA sequencing assay and applied it to a multicenter post-transplant cohort. HSC mutation detection preceded relapse by a mean of 98 days and strongly predicted relapse (95.7% vs. 30.3%; hazard ratio, 8.8; P=1.5e-7). Mutations detected only in unfractionated marrow did not predict relapse. We developed methods to measure donor-host HSC chimerism, improving relapse prediction sensitivity. Single-cell protein, DNA, and RNA analyses with mitochondrial lineage tracing confirmed MDS cell enrichment within immunophenotypically- and transcriptionally-defined HSCs, identifying shared ribosomal gene downregulation and candidate mechanisms of venetoclax sensitivity. Venetoclax/azacytidine depleted detectable MDS HSCs in longitudinally evaluated patients. These findings establish that HSC mutation detection predicts post-transplant relapse, provide a rationale for preemptive intervention, and define shared biological features of transplant-resistant MDS HSCs.

DOI: https://doi.org/10.64898/2026.10.28.761431
Haematologica. 2026 Nov 01. 111(11): 3547-3548

The JAK2 V617F revolution in myeloproliferative neoplasms.

Ayalew Tefferi.

DOI: https://doi.org/10.3324/haematol.2026.301902
Haematologica. 2026 Nov 05.

Salvage-free, transplantation-free survival: a proposal for a new clinical endpoint in acute myeloid leukemia.

Christian Récher, Emilie Bérard, Suzanne Tavitian, Thibaut Leguay, Anne Huynh, Edouard Forcade, Anne Banos, Alban Canali, Emilie Klein, Audrey Bidet, Laëtitia Largeaud, Véronique De Mas, Audrey Sarry, Madeline Mougenot, Anne-Charlotte De Grande, Karine Celli-Lebras, Cécile Pautas, Claude Gardin, Xavier Thomas, Thorsten Braun, Régis Peffault De Latour, Hervé Dombret, Stéphane De Botton, Arnaud Pigneux, Sarah Bertoli, Pierre-Yves Dumas.

Results from pivotal clinical trials evaluating the combination of intensive chemotherapy with targeted therapies in acute myeloid leukemia (AML) are expected soon. While overall survival (OS) or event-free survival (EFS) are the recommended endpoints, new criteria are needed for assessing the intrinsic effectiveness of new drugs. In this study, the salvage-free, transplantation-free survival (STFS) was measured from day 1 of induction chemotherapy to the date of induction failure or salvage therapy, allogeneic transplantation (allo-HSCT), relapse, or death from any cause, whichever occurs first and assessed in a cohort of 1966 AML patients from the DATAML registry treated with intensive chemotherapy and 100 acute promyelocytic leukemia (APL) patients treated with arsenic trioxide and all-trans retinoic acid. Validation cohorts from the ALFA group were used. At five years, STFS was estimated at 14.6% (95% confidence interval [CI], 13.0-16.2; median, 5.5 months) whereas OS, EFS and relapse-free survival estimations were 40.4% (95% CI, 38.2-42.6; median, 30.6 months), 31.4% (95% CI, 29.4-33.5; median, 15.3 months) and 37.6% (95% CI, 35.2-40.0; median, 21.9 months), respectively. Relapse was the most common first STFS event, followed by allo-HSCT. STFS varied depending on molecular subgroups and gene-gene mutation interactions. In the APL cohort, STFS (83.6% at five years) was similar to OS (85.6%) illustrating the impact of an effective and low-toxicity first-line treatment curing patients without salvage therapy or allo-HSCT. In the prospective randomized ALFA-0701 trial, gemtuzumab ozogamycin significantly improved STFS. STFS should complement other survival endpoints to accurately analyze the impact of new drugs in AML.

DOI: https://doi.org/10.3324/haematol.2026.301782
Blood. 2026 Nov 05. pii: blood.2026034629. [Epub ahead of print]

Multimodal omics identifies a lymphoid-biased multipotent progenitor population with limited age-associated remodeling.

Mari Carmen Romero-Mulero, Julian Wolter-Mess, Mirijam Lia Egg, Anna Konturek-Ciesla, Yu Wei Zhang, Ivan Berest, Jasmin Rettkowski, Helen Demollin, Alessandro Donada, Aishwarya Krishnan, Lucie S P Hustin, Karin Jäcklein, Beatriz Silva-Rego, Carolin Wadle, Francesco Cardamone, Isabella Maria Mayer, Dawn Lin, Andreas Trumpp, Nicola Iovino, Grant Challen, Pia Sommerkamp, Leila Perié, Judith B Zaugg, Katharina Schönberger, Dominic Grün, Timm Schroeder, Maria-Eleni Lalioti, Marta Derecka, Eirini Trompouki, Nina Cabezas-Wallscheid.

Hematopoietic aging is marked by declining regenerative capacity and a shift from lymphoid to myeloid output. Previous studies have focused primarily on hematopoietic stem cells (HSCs), yet whether aging uniformly remodels the hematopoietic stem and progenitor cell (HSPC) compartment, or selectively affects distinct populations, remains largely unknown. To address this, we profile HSCs and multipotent progenitors MPP1-6 from young and aged mice across transcriptomic, epigenomic, metabolomic and lipidomic layers, together with single-cell division and in vivo serial transplantation assays. We identify young MPP6 (negative for CD150, CD34, CD48 and CD135) as an HSC-like, lymphoid-biased population with long-term reconstitution capacity, positioned within the top-tier of the differentiation hierarchy and marked by low global chromatin accessibility and metabolic activity. Upon aging, MPP6 preserved long-term lymphoid reconstitution, underwent limited transcriptional and regulatory remodeling, and did not accumulate polyunsaturated phospholipids or show mitochondrial oxidation. By contrast, most HSPCs, and particularly HSCs, underwent pronounced age-associated changes, including myeloid-biased expansion, metabolic rewiring, extensive distal regulatory alteration and accumulation of long-chain polyunsaturated phospholipids linked to increased oxidative stress. Pseudotime analysis further resolved the aged MPP6 compartment into two subsets, including a dormant, lymphoid-biased Dlk1-expressing population characterized by reduced mitochondrial activity, which was distinctly affected by inflammatory challenge in vivo. Together, these findings establish MPP6 as a comparatively resilient population within the aged HSPC compartment and suggest that it may represent a potential target for restoring hematopoietic balance.

DOI: https://doi.org/10.1182/blood.2026034629
Leukemia. 2026 Nov 03.

Relcobatinib, a highly selective ATP-competitive ABL1 tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia.

Stefan D Gross, Christopher A Eide, Michael R Burkard, Anna Reister Schultz, Alex Chao, Kevin T DuPrez, Frank Han, Amanda J Broad, Donald Reuther, Yiheng Zhang, Joseph E Aslan, Owen J T McCarty, Monette A Aujay, Samuel Kintz, Brian J Druker, Joseph P Lyssikatos.

Relcobatinib (ELVN-001) is a next-generation, investigational, BCR::ABL1 active-site tyrosine kinase inhibitor (TKI) with a unique P-loop folded-in binding mode designed to deliver best-in-class efficacy with an improved tolerability profile over that of other TKIs for the treatment of chronic myeloid leukemia (CML). We demonstrate that relcobatinib has marked selectivity for BCR::ABL1, without inhibition of off-target kinases implicated in toxicities related to other TKIs. Relcobatinib exhibited greater selectivity than other active-site TKIs and demonstrated robust activity in vitro against native BCR::ABL1 and a broad range of clinically relevant TKI-resistant mutants. A BCR::ABL1 mouse xenograft model of human CML showed marked anti-tumor activity with relcobatinib as monotherapy, and, in combination with asciminib, showed further durable tumor regression, supporting the complementary mechanism of action between an active-site TKI and an allosteric inhibitor. Collectively, the preclinical profile of relcobatinib, marked by selective BCR::ABL1 targeting, supports its potential to improve efficacy and tolerability in the treatment of CML and other BCR::ABL1-driven malignancies, as monotherapy and in combination with an allosteric inhibitor.

DOI: https://doi.org/10.1038/s41375-026-03184-x
Nat Commun. 2026 10 03. pii: 11316. [Epub ahead of print]17(1):

DCAF7 regulates hematopoietic stem cell function and differentiation through polycomb repressive complex 1 modulation.

Johanna Melo-Cardenas, Lavanya Bezavada, Te Ling, Trent Hall, Amber Broadhurst, Anitria Cotton, Jeremy Chase Crawford, Amanda Nourse, Vishwajeeth Pagala, Kiran Kodali, Mollie S Hutton, Shondra M Pruett-Miller, Qiong Zhang, Wojciech Rosikiewicz, Hongjian Jin, Dirk Loeffler, John D Crispino.

DCAF7 is one of the few DCAFs expressed in hematopoietic stem cells (HSCs). Using a conditional knockout mouse model, we discovered that the absence of DCAF7 leads to accumulation of differentiating progenitors in the bone marrow, and impairs self-renewal capacity of HSCs upon transplantation. Furthermore, loss of Dcaf7 accelerates the differentiation of HSCs into the myeloid lineage. At the molecular level, DCAF7 interacts with components of the polycomb repressive complex 1 (PRC1) and promotes their assembly into large macromolecular complexes. Chromatin profiling revealed that loss of DCAF7 leads to increased localization of RING1B at transcriptionally active genomic loci. This increased binding was observed at genes involved in myeloid differentiation and was associated with increased mRNA expression. Lastly, inhibition of KDM2/7 proteins rescues the defective growth of Dcaf7 null HSCs in vitro. Together, these data reveal that DCAF7 is a novel regulator of the PRC1 complex and epigenetic enzymes that control HSC differentiation.

DOI: https://doi.org/10.1038/s41467-026-78299-x
Hemasphere. 2026 Nov;10(11): e70503

Improved multistate survival in younger AML patients over time.

Sjoerd J F Hermans, Jurjen Versluis, Gert J Ossenkoppele, Edo Vellenga, Thomas Pabst, Leo F Verdonck, Johan Maertens, Dimitri Breems, Markus G Manz, Bart Biemond, Jürgen Kuball, Marinus van Marwijk Kooy, Mojca Jongen-Lavrencic, Peter C Huijgens, Jakob Passweg, Bjørn T Gjertsen, Soren Lehmann, Patrycja Gradowska, Berna Beverloo, Peter Valk, Gerwin Huls, Liesbeth C de Wreede, Bob Löwenberg, Jan J Cornelissen.

Over the last three decades, HOVON-SAKK has performed six randomized controlled trials (RCTs) in newly diagnosed younger adults with acute myeloid leukemia (AML). While overall survival (OS) improved over time, no OS benefit was apparent in individual RCTs. We investigated whether complete remission (CR) rates, postremission treatment (PRT), and/or a reduction of early mortality might have accounted for improved OS. Two multistate models, from the start of induction treatment until the date of death or last contact, were developed. These models included (1) CR ≤ 2 cycles and (2) CR followed by type of PRT as intermediate states and overall mortality as an end state. Patients were categorized by decade of diagnosis. Transition probabilities were adjusted for age and European LeukemiaNet (ELN) 2017 risk classification. Multistate survival (MS) was defined by the probability of obtaining CR with the intention or actual receipt of PRT and surviving thereafter. A total of 924, 1896, and 2253 patients were enrolled between 1987-1996, 1997-2006, and 2007-2017, respectively. OS at 5 years increased from 33 ± 2% to 47 ± 1% in the most recent cohort. CR rates increased from 77.5% to 83.9%. Sixty-day mortality decreased from 9.9% to 7.8%. The proportion of alloHSCT as PRT increased from 16.6% to 48.3%. MS at 5 years increased from 28.8% to 47.4% and from 11.3% to 26.1% for ELN17 intermediate and adverse risk patients, which was largely due to improved OS in CR patients proceeding to alloHSCT. Increased CR rates and an increased application of alloHSCT mainly accounted for improved MS and OS. MS, as a novel endpoint, effectively captures favorable treatment outcome, while allowing quantification of the survival gain of pivotal, subsequent intermediate states.

DOI: https://doi.org/10.1002/hem3.70503
Blood Neoplasia. 2026 Nov;3(4): 100275

Integrating functional marrow reserve and molecular risk improves prediction of post-transplant outcomes in HMA-treated myelodysplastic syndromes.

Luis E Aguirre, Haesook T Kim, Hany Elmariah, Stacey M Frumm, Amar H Kelkar, Vincent Ho, Mahasweta Gooptu, John Koreth, Roman M Shapiro, Rizwan Romee, Sarah Nikiforow, Joseph H Antin, Robert J Soiffer, Shai Shimony, Marlise R Luskin, Jacqueline S Garcia, Evan C Chen, Martha Wadleigh, Eric S Winer, Richard M Stone, Daniel J DeAngelo, Najla Al Ali, David Sallman, Andrew Kuykendall, Kendra Sweet, Jeffrey E Lancet, Eric Padron, Onyee Chan, Zhuoer Xie, Corey S Cutler, Maximilian Stahl, Rami S Komrokji.

In patients with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMA) and proceeding to allogeneic hematopoietic stem-cell transplantation (alloHSCT), pretransplant risk assessment remains dominated by morphologic remission-based frameworks despite uncertain prognostic value in the transplant setting. We retrospectively analyzed 280 HMA-treated patients with MDS undergoing alloHSCT at DFCI and Moffitt between 2013-2021 to evaluate the predictive performance of IWG 2023 response criteria and to develop an alternative framework integrating functional marrow reserve (FMR) with baseline molecular risk. Progression-free survival (PFS) was the primary outcome. Median overall survival (OS) was 52 months, with 5-year PFS and OS of 43% and 48%, respectively. IWG 2023 response categories showed substantial overlap in outcomes, and assessment by composite complete remission status did not discriminate PFS (5-year PFS 46% vs 40%; P = .16). In contrast, preconditioning hemoglobin and platelet counts were strongly associated with outcomes, whereas marrow blasts and absolute neutrophil count were not. Recursive partitioning identified clinically relevant platelet and hemoglobin thresholds, enabling construction of FMR strata with markedly distinct 5-year PFS (70%, 40%, and 24% for favorable, intermediate and poor risk strata, respectively; P < .0001). Baseline IPSS-M independently predicted outcomes (5-year PFS 58%, 45%, and 29%; P = .003) and further refined prognostication when integrated with FMR. In multivariable analysis, the integrated IPSS-M/FMR model remained independently associated with PFS (hazard ration 3.00-8.31 across risk tiers; P < .004) and showed superior discrimination compared with IWG 2023 and classical transplant variables (PFS concordance index 0.676). These findings support an integrated framework that outperforms remission-based criteria for post-alloHSCT risk prediction in HMA-treated MDS.

DOI: https://doi.org/10.1016/j.bneo.2026.100275
Leukemia. 2026 Nov 03.

Salvage therapy for immune-mediated bone marrow failure.

Serhan Unlu, Aashray Mandala, Mark D Orland, Carlos Bravo-Perez, Valeria Visconte, Akriti G Jain, Alan Lichtin, Hetty E Carraway, Carmelo Gurnari, Jaroslaw P Maciejewski.

Most acquired idiopathic bone marrow failure syndromes (BMFS) are thought to be cytotoxic T cell-mediated and are responsive to immunosuppressive therapies (IST) targeting T cells. However, in addition to frequent relapses, a proportion of cases remain refractory to first- and second-line agents due to a lack of clinical trials in the refractory and relapsed disease setting. Recently, the landscape of IST has expanded significantly, harnessing multiple molecular pathways that could be theoretically useful in the BMFS setting. In this manuscript, we retrospectively analyzed clinical responses to selected salvage IST, including sirolimus, tofacitinib, and subcutaneously administered abatacept and alemtuzumab, in a cohort of 151 patients with aplastic anemia, pure red cell aplasia, large granular lymphocytic leukemia, and other rare hypoproliferative BMFS. Our results indicate significant salvage rates with these agents and differential efficacy in specific clinical scenarios, showing differences in responses in affected lineages and in different disease states. We report that different modalities of IST may have lineage-restricted and overall responses in relapsed or refractory BMFS states, and durable response can be achieved in clinically difficult cases. These findings underscore the need for clinical trials to establish the safety and efficacy of alternative agents as substitute lines of therapy in BMFS.

DOI: https://doi.org/10.1038/s41375-026-03180-1
bioRxiv. 2026 Oct 28. pii: 2026.10.26.761955. [Epub ahead of print]

Maternal Folate Nutrition Programs Adult Hematopoietic Stem Cell Function Through Mitochondrial Remodeling.

Brian P Krum, Ava Niazi, Victoria Chiou, Brittany M Curtiss, Noah Huerta, Fanny Zhou, Luisa F Castillo, Sweta B Patel, Alana M Franceski, Sajesan Aryal, Anton Classen, Travis Nemkov, Angelo D'Alessandro, Martha S Field, Rui Lu, Robert A J Signer, Robert S Welner, Anna E Beaudin.

Folic acid fortification for the prevention of neural tube defects has been a cornerstone of public health policy for nearly three decades, but its broader consequences for other developing organ systems, particularly the hematopoietic system, are poorly studied. Hematopoietic stem cell (HSC) emergence overlaps developmentally with neural tube closure, and folate-dependent one-carbon metabolism is critical for nucleotide synthesis, cellular methylation, and redox balance, positioning folate as a candidate regulator of HSC programming. Using dietary models of maternal folate deficiency or supplementation in mice, we demonstrate that maternal folate acts as a dose-dependent developmental tuner of hematopoiesis, programming adult offspring HSC function through divergent mitochondrial and chromatin states. Maternal folate deficiency impaired adult HSC self-renewal, associated with mitochondrial defects, disrupted cristae, elevated proteotoxic stress and a stress-adapted chromatin landscape. In contrast, maternal folate supplementation enhanced HSC self-renewal accompanied by improved mitochondrial quality control and CDC42-associated organelle remodeling, and established chromatin states permissive for stem cell maintenance. Fetal HSC metabolomics identified shifts in one-carbon intermediates, pyruvate and lipid pools, suggesting that divergent fetal metabolic states provide substrate-level inputs that drive persistent and opposing chromatin programs in offspring HSCs. Our findings establish maternal folate availability as an unappreciated regulator of lifelong hematopoietic output demonstrating that a single maternal micronutrient, folate, is sufficient to program adult HSC function and regenerative capacity through persistent metabolic and mitochondrial programming.

DOI: https://doi.org/10.64898/2026.10.26.761955
Semin Hematol. 2026 Oct 05. pii: S0037-1963(26)00098-3. [Epub ahead of print]

Shwachman-Diamond syndrome: A paradigm for ribosomopathies, somatic genetic rescue, and leukemia predisposition syndrome.

Neha Prasad, Noah M Saito, Seth J Corey.

  Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, skeletal abnormalities, and an increased risk of developing myelodysplastic syndromes/acute myeloid leukemia (MDS/AML). The estimated incidence is approximately 1 in 75,000 to 125,000 live births. Its prevalence may be greater because of milder phenotypes or underdiagnosis, with some individuals diagnosed in adulthood with MDS/AML. Cloning of the SBDS gene, named after the 3 physicians who reported its early clinical characterization, led to its identification as a ribosomal assembly factor. The gene is evolutionarily conserved from archaea through yeast to humans. Almost all affected individuals harbor biallelic mutations in SBDS. Others have been identified to have biallelic mutations in EFL1 or DNAJC21; the former is a physical and functional partner of SBDS in the pre-60S large ribosomal subunit, and the latter is a chaperone for the small ribosomal subunit. SBDS interacts with EFL1 to displace eIF6, which permits the assembly of the 80S monosome from the 60S and 40S ribosomal subunits. The pathophysiology of SDS remains poorly understood. TP53-dependent pathways are activated and can contribute to bone marrow failure. Other studies that demonstrate the failure of TP53 to rescue animal models and the absence of TP53 in sdo1 mutant yeast that display slower growth indicate that additional stress pathways are involved. Selection pressure promotes outgrowth of TP53 or EIF6 mutant cells, that is, somatic genetic rescue. Greater understanding of the stress and rescue pathways may lead to therapies to improve quality of life and survival.

Keywords:  Bone marrow failure; Myeloid malignancy; Ribosome assembly; Shwachman–Diamond syndrome

DOI:  https://doi.org/10.1053/j.seminhematol.2026.09.010
Leukemia. 2026 Nov 05.

Maternal donor risk in haploidentical transplant with post-transplant cyclophosphamide: the role of recipient sex.

Rachel E Granberg, Feng Gao, Melissa Mavers, Shalini Shenoy, Jeffrey J Bednarski, Akshay Sharma, Thomas Pfeiffer.

DOI: https://doi.org/10.1038/s41375-026-03179-8
J Exp Med. 2027 Jan 04. pii: e20261384. [Epub ahead of print]224(1):

Bcl11a preserves hematopoietic stem cell function in culture by restraining Ncf1-dependent ROS.

Xiang Xu, Linlin Zhang, Yandong An, Jing Wang, Xiaoyan Ding, Jing Xie, Yong Yu.

Ex vivo expansion of hematopoietic stem cells (HSCs) is limited by culture-induced oxidative stress, yet the upstream transcriptional drivers remain poorly defined. Here, we show that the transcription factor Bcl11a is rapidly and persistently downregulated during HSC culture and that this decline drives functional deterioration. Bcl11a was both required and sufficient to maintain quiescence, clonogenic activity, and serially transplantable HSC function. Mechanistically, Bcl11a directly represses a Nox2 NADPH oxidase gene module, including Ncf1, encoding the p47phox organizer subunit; Ncf1 deletion reduced ROS and partially rescued the defects of Bcl11a-deficient HSCs. Rapamycin-but not the ROS scavenger N-acetylcysteine-restored Bcl11a expression, suppressed Ncf1 and ROS, and improved HSC function, identifying Bcl11a as a candidate effector linking mechanistic target of rapamycin complex 1 inhibition to redox control. This axis was conserved in human hematopoietic stem and progenitor cells, revealing a druggable transcriptional vulnerability of cultured HSCs and a framework for improving ex vivo-expanded grafts.

DOI: https://doi.org/10.1084/jem.20261384
J Clin Invest. 2026 Nov 02. pii: e199141. [Epub ahead of print]136(21):

JAK1/2 inhibition promotes aggressive cutaneous carcinogenesis through COT kinase-mediated alternative MAPK pathway activation.

Hélène Pasquer, Antoine Forget, Maxime Battistella, Raphael Marie, Léa Provent, Barouyr Baroudjian, Emmanuelle Latour, Cécile Culeux, Blandine Roux, Khansa Saadallah, Amandine Gouverneur, Maxime Demourgues, Fanélie Jouenne, Jérôme Lambert, Bérangère Lombard, Damarys Loew, Sophie Tartare-Deckert, Lionel Adès, Emmanuel Raffoux, Bruno Cassinat, Juliette Soret-Dulphy, Pernelle Noize, Samia Mourah, Camille Lobry, Jean-Jacques Kiladjian, Alexandre Puissant, Céleste Lebbé, Lina Benajiba.

  Secondary malignancies are the most feared adverse effects of cancer therapies. In this study, we explored the cutaneous oncogenic effects of the JAK inhibitor ruxolitinib. First, we demonstrated an epidemiological association between ruxolitinib exposure and development of aggressive cutaneous squamous cell carcinoma (cSCC) by analyzing international pharmacovigilance data and conducting a large cohort study. We next demonstrated the causal link between ruxolitinib treatment and cSCC development using in vitro and in vivo models. Mechanistically, we revealed that ruxolitinib induces transformation of premalignant keratinocytes by activating the MAPK pathway. This effect is mostly driven by JAK2 inhibition, suggesting a pharmacological class effect. To unravel the mechanistic underpinnings of ruxolitinib-induced MAPK activation, we then applied a phosphoproteomic approach. Alternative MAPK signaling downstream of the kinase COT was pinpointed as the main activator of the pathway in this context. The central role of COT was functionally validated using chemical inhibition, genetic impairment, and inactivated COT mutant expression. Indeed, impairment of COT rescued the pro-oncogenic effect of ruxolitinib. Finally, we determined using a combination of epidemiological, in vitro, and in vivo studies that ruxolitinib-mediated oncogenic effects also result in an increased risk of melanoma, suggesting that the uncovered cellular signaling mechanism might be extrapolated to other cancers with a high dependency on the MAPK pathway.

Keywords:  Clinical practice; Dermatology; Drug therapy; Hematology; Oncology; Skin cancer

DOI:  https://doi.org/10.1172/JCI199141
Cell Rep. 2026 Nov 04. pii: S2211-1247(26)01326-4. [Epub ahead of print]45(11): 118247

5-Azacytidine incorporation into mRNAs disrupts translation and induces ribosome collisions.

Alexis B Roberson, James Marks, Ruby Pitts, Bavavarshini Tamilselvam, Grace D Britt, Brian Grieb, William P Tansey, Sezen Meydan.

  5-Azacytidine (5-AzaC) is a cytidine analog chemotherapeutic widely used to treat myeloid malignancies. Although its activity is primarily attributed to DNA hypomethylation, the majority of 5-AzaC is incorporated into RNA, where its functional consequences are less understood. Here, we show that 5-AzaC treatment of cells leads to inhibition of protein synthesis. Ribo-seq, Disome-seq, and RNA-seq in treated cells exhibit a time-dependent C-to-G conversion in mRNAs. These conversion events are enriched within footprint positions corresponding to the A-site of monosomes or stalled leading ribosomes in a disome complex. Footprints are accumulated at sites with C-rich codons in the A-site, with particular emphasis on the second codon position. Consistent with disome-mediated signaling, 5-AzaC activates ZAK- and GCN2-dependent stress responses. Furthermore, loss of the ribosome-associated quality control factor, ZNF598, sensitizes cells to 5-AzaC. These findings suggest that translation disruption represents an additional layer of 5-AzaC's mechanism of action, alongside its known DNA-mediated effects.

Keywords:  CP: molecular biology; RNA damage; azacytidine; chemotherapy; integrated stress response; ribosome collisions; ribosome-associated quality control; ribotoxic stress response

DOI:  https://doi.org/10.1016/j.celrep.2026.118247
bioRxiv. 2026 Nov 01. pii: 2026.10.27.762224. [Epub ahead of print]

Ascorbate and TET2 couple balanced hematopoiesis to disease tolerance.

Tobias Wijshake, Joseph Rose, Ji Hyung Jun, Jacob Zielke, Li Li, Joseph S Takahashi, Filipa Rijo-Ferreira, Michalis Agathocleous.

Infections stimulate myelopoiesis but this comes at the cost of reduced production of other lineages. It is unclear if this imbalance is protective or damaging, and if factors that promote balanced hematopoiesis can impact infection pathology. Here we show that the ascorbate-TET axis limits excessive myelopoiesis, promotes balanced hematopoiesis, and is essential for surviving malaria. Hematopoietic-specific ascorbate depletion promoted myelopoiesis. The effects of ascorbate were mediated by TET2/TET3 activity in myeloid progenitors. Combined ascorbate and TET2 depletion markedly skewed hematopoiesis to the myeloid lineage and impaired erythropoiesis. Ascorbate is commonly depleted in infections, but the functional significance of this remains unclear. In the absence of ascorbate and TET2, mice infected with Plasmodium parasites could clear the pathogen, but had exacerbated myeloid and impaired erythroid response, anemia, and tissue damage and they succumbed to infection, indicating compromised disease tolerance. Therefore ascorbate and TET2 promote balanced hematopoiesis to impart tolerance to malaria.

DOI: https://doi.org/10.64898/2026.10.27.762224
JAMA Netw Open. 2026 Nov 02. 9(11): e2642122

Overall Survival in Adults With Acute Myeloid Leukemia Initiating Quizartinib vs Midostaurin With Chemotherapy.

Michelle Hyunju Lee, Angela C Tramontano, Chenyu Lin, Ellen Madarang, Joanna M Cwykiel, Wyatt McCall, Stephanie Begley, Nayan Hemant Mainkar, Sarah Chen, Kyle Dykstra, Vincent Lok, Sarvarinder Gill, Jared Vega, Jeffrey Baron, Abdur Rahman Jabir, Katie Moffitt, Alifya Lokhandwala, Joshua Zeidner, Madelyn Burkart, Eunice Wang, James McCloskey, David Swoboda, Vanessa E Kennedy, Brittany Ragon, Andrew H Matthews, Alexander E Perl, Yasmin Abaza, Justin M Watts, Harry P Erba, Andrew M Brunner, Amir T Fathi.

Importance: Midostaurin and quizartinib are approved with intensive chemotherapy (IC) in patients with newly diagnosed FLT3 internal tandem duplication (ITD)-positive acute myeloid leukemia (AML), but no randomized clinical trials have directly compared them.
Objective: To compare 1-year overall survival (OS) among patients with FLT3-ITD variant AML initiating IC with midostaurin or quizartinib.
Design, Setting, and Participants: This multicenter, retrospective cohort study included patients with newly diagnosed FLT3-ITD variant AML treated at 12 US referral centers between January 1, 2018, and May 31, 2025. Data analysis was performed from January 2026 to August 2026.
Exposures: Induction therapy with IC plus midostaurin or quizartinib.
Main Outcomes and Measures: The primary outcome was 1-year overall survival (OS). Secondary outcomes included 1-year event-free survival (EFS), induction response, and hematopoietic cell transplant (HCT) rates at first remission; FLT3 clearance after induction was exploratory. Safety outcomes included rates of febrile neutropenia, infections, intensive care unit use, total parenteral nutrition and granulocyte colony-stimulating factor use, discharge to a rehabilitation facility after index hospitalization, and early mortality. Cox proportional hazards regression models were adjusted for baseline covariates and HCT as time dependent.
Results: Among 215 patients (median [IQR] age, 56.0 [45.0-65.0] years; 119 [55.3%] female), 127 (59.1%) received midostaurin and 88 (40.9%) received quizartinib. Median (IQR) follow-up was 667.0 (289.0-1368.0) days for midostaurin and 324.0 (168.0-546.5) days for quizartinib, reflecting the latter's more recent approval. One-year OS was 78.0% for midostaurin and 93.0% for quizartinib (hazard ratio [HR], 0.22; 95% CI, 0.08-0.58; P = .002). The 1-year EFS was 56.0% for midostaurin and 77.0% for quizartinib (HR, 0.43; 95% CI, 0.25-0.74; P = .003). Patients receiving quizartinib had higher rates of composite complete remission (75 [85.2%] vs 93 [73.2%]; P = .03), whereas rates of FLT3 clearance after induction (20 [38.5%] for quizartinib vs 27 [40.3%] for midostaurin; P = .84) and HCT in first remission (47 [53.4%] for quizartinib vs 83 [65.4%] for midostaurin; P = .08) were comparable. Midostaurin was associated with higher intensive care unit use (19 [15.0%] vs 4 [4.5%]; P = .02), discharge to a rehabilitation facility (9 [7.1%] vs 1 [1.1%]; P = .04), and treatment interruptions (32 [25.2%] vs 10 [11.4%]; P = .01). A sensitivity analysis limited to patients treated in 2023 or later (more balanced follow-up) showed directionally consistent but nonsignificant OS and EFS differences.
Conclusions and Relevance: In this cohort study of adults with FLT3-ITD variant AML, IC plus quizartinib was associated with improved 1-year survival, induction response, and safety compared with IC plus midostaurin.

DOI: https://doi.org/10.1001/jamanetworkopen.2026.42122
Exp Hematol. 2026 Nov 05. pii: S0301-472X(26)00596-5. [Epub ahead of print] 105963

More than the right ingredients: perfecting the recipe for human hematopoietic stem cell expansion.

Lucrezia Della Volpe, Vijay G Sankaran.

Ex vivo expansion of human hematopoietic stem cells (HSCs) has long been a major objective in regenerative medicine, with the potential to improve hematopoietic stem cell transplantation, enable more effective gene therapies, and broaden patient access to curative treatments. Despite decades of investigation, preserving long-term HSC self-renewal while achieving clinically meaningful expansion has proven challenging because HSC fate is tightly regulated by intrinsic molecular programs and the specialized bone marrow microenvironment. Over the past decade, however, substantial progress has transformed the field. The discovery of small molecules that modulate key regulatory pathways, advances in chemically defined culture systems, and a growing understanding of the cellular, biochemical, and biophysical cues provided by the bone marrow niche have led to significant improvements in ex vivo HSC maintenance and expansion. In parallel, the clinical translation of several expansion platforms has demonstrated the therapeutic potential of these approaches, particularly for umbilical cord blood transplantation and genome-edited HSC therapies. This Review discusses the biological principles underlying HSC expansion, summarizes current culture strategies, and highlights recent clinical advances. We also examine the remaining challenges associated with genomic stability, manufacturing scalability, and quality control, as well as emerging in vivo gene therapy approaches. Altogether, these advances are redefining HSC engineering and provide a foundation for the next generation of regenerative and gene-based therapies.

DOI: https://doi.org/10.1016/j.exphem.2026.105963
Blood. 2026 Nov 05. pii: blood.2026036032. [Epub ahead of print]

Mechanistically distinct classes of BCR::ABL1 mutations confer resistance to asciminib.

Inga B Leske, Pietro Vidossich, Wieland Steinchen, Gert Bange, Marco De Vivo, Oliver Hantschel.

The first-in-class allosteric BCR::ABL1 inhibitor asciminib has expanded the therapeutic landscape of chronic myeloid leukemia (CML). However, the molecular mechanisms underlying secondary resistance remain incompletely understood. We investigated clinically observed asciminib resistance mutations by integrating structural modeling, hydrogen-deuterium exchange mass spectrometry (HDX-MS), quantitative biochemical assays and molecular dynamics simulations. Resistance mutations were grouped into two mechanistically distinct classes: Mutations within the BCR::ABL1 myristate pocket (class I) and mutations located up to 40 Å from the asciminib binding site in the kinase N-lobe, SH2-kinase domain (KD) linker and SH3 domain (class II). HDX-MS demonstrated that asciminib induces conformational stabilization across the KD extending beyond the myristate pocket, establishing a long-range allosteric network. We show that class I mutations reduced asciminib affinity up to 90-fold, consistent with steric interference at the binding site. In contrast, class II mutations retained wildtype binding affinity despite conferring clinical resistance. Instead, the class II mutations F359I and M244V increased intrinsic kinase activity and enhanced BCR::ABL1 autophosphorylation, indicating overactivation. Molecular dynamics simulations revealed allosteric communication linking the myristate and ATP-binding pockets, which is disrupted by class II mutations. Together, these findings establish that asciminib resistance arises through two distinct mechanisms: direct impairment of drug binding or disruption of the asciminib binding-induced autoinhibited conformation. Our study provides a mechanistic framework for understanding resistance to allosteric BCR::ABL1 inhibitors and has important implications for resistance monitoring, combination therapies and therapeutic sequencing.

DOI: https://doi.org/10.1182/blood.2026036032
Cell Rep. 2026 Nov 02. pii: S2211-1247(26)01253-2. [Epub ahead of print]45(11): 118174

A single-cell comprehensive atlas of leukemia and its microenvironment.

Bofei Wang, Yu-An Kuo, Enes Dasdemir, Wei Xiao, Elisabeth Rebboah, Guilin Tang, Wei Wang, Hussein A Abbas.

  Acute myeloid leukemia (AML) remains highly lethal, with treatment failure and relapse driven by dynamic cellular states and evolving interactions within the leukemic ecosystem. In this study, we built a comprehensive atlas of leukemia and its microenvironment (CALM) by integrating single-cell profiling from 73 AML samples and 9 healthy donors, bulk RNA sequencing (RNA-seq) from 87 newly diagnosed patients, and 4 paired bone marrow and peripheral blood single-cell data. All datasets were linked to clinical, cytogenetic, molecular, and treatment-response annotations. Immune analysis revealed diverse T cell distribution across disease status, where patients with persistent disease exhibited greater clonal expansion. Machine learning modeling on conventional T cells identified a T-cell signature pertinent to AML and outcomes, which were validated in two cohorts. CALM is a publicly accessible and interactive portal (calm.mdanderson.org) for exploring cellular compartments, cell-cell interactions, and longitudinal transcriptional and clonal dynamics to enable hypothesis generation, biomarker discovery, and target validation.

Keywords:  CP: cancer; CP: immunology; T cell phenotype; clonotype; immune microenvironment; leukemia atlas; machine learning

DOI:  https://doi.org/10.1016/j.celrep.2026.118174
Br J Haematol. 2026 Nov 05.

SF3B1 mutation significance in myeloid neoplasms without anaemia.

Sergi Camarillas, Xavier Calvo, Esther Alonso, Alba Mesa, Lurdes Zamora, Eugenia Rivero, Evelin Casanova, Leonor Arenillas, Bárbara Tazón-Vega, Marta Garrote, María Rozman, Juan Restrepo, Núria Brey, Irene Rocío Media-Rangel, Marina Serra, Laura Gallur, María Gabarrós-Subirà, Francisco Beas, Adoración Blanco, Margarita Ortega, Gloria Hidalgo-Gómez, María Julia Montoro, Andrés Jerez, Pamela Acha, David Valcárcel, Sílvia Saumell.



Keywords:   MDS ; MDS/MPN‐SF3B1‐T ; MDS‐SF3B1 ; MPN ; SF3B1

DOI:  https://doi.org/10.1111/bjh.70942
Nat Genet. 2026 Nov 02.

Clonal hematopoiesis and cytopenias following CAR19 therapy.

Mark P Hamilton, Nick Phillips, Troy Noordenbos, Jan Boegeholz, Takeshi Sugio, Brian J Sworder, Stefan K Alig, Zinaida Good, Joseph G Schroers-Martin, John Tamaresis, Mohammad S Esfahani, Ying Lu, Mari Olsen, Chih Long Liu, Zach Ehlinger, Moksha Desai, Lori Muffly, Robert S Negrin, Sally Arai, Laura Johnston, Robert Lowsky, Everett Meyer, Andrew Rezvani, Judith Shizuru, Wen-Kai Weng, Parveen Shiraz, Surbhi Sidana, Sushma Bharadwaj, Melody Smith, Saurabh Dahiya, Bita Sahaf, Matthew J Frank, Crystal L Mackall, Maximilian Diehn, David M Kurtz, David B Miklos, Ash A Alizadeh.

CD19-directed chimeric antigen receptor T cell therapy (CAR19) improves survival in relapsed/refractory large B cell lymphoma compared with immunochemotherapy with intent for autologous hematopoietic cell transplantation (autoHCT). However, major toxicities include prolonged cytopenias, infection and secondary hematologic malignancies. Here, to investigate these complications, we studied patients with lymphoma receiving CAR19 and compared clinical outcomes to propensity-matched autoHCT-treated controls. CAR19-treated patients exhibited impaired immune reconstitution and increased infection. Bone marrow analysis showed that prolonged post-CAR cytopenias are associated with clonal cytopenias of undetermined significance and interferon-mediated inflammation. Clonal hematopoiesis (CH) commonly expanded following CAR19 infusion and was associated with impaired immune reconstitution and treatment-related myeloid malignancy (tMN). Post-CAR tMN was molecularly and clinically comparable to post-autoHCT tMN. Single-cell DNA analysis revealed mostly independent CH clones, while CAR integration into CH-mutant T cells occurred frequently and may drive expansion and persistence. Together, these findings implicate CH expansion and marrow inflammation in key CAR19-associated toxicities.

DOI: https://doi.org/10.1038/s41588-026-02795-5
J Biochem. 2026 Nov 04. pii: mvag082. [Epub ahead of print]

Myeloid leukemia cells utilize branched chain keto acids to acquire intrinsic resistance to methotrexate.

Naoki Tamura, Ayuna Hattori, Kenkyo Matsuura, Takashi Sakamoto, Hiroshi Arima, Akifumi Takaori-Kondo, Takahiro Ito.

Cancer reprograms cellular metabolism to support and accelerate malignant properties, which is known as cancer metabolism. The cancer metabolism has specific roles in acquiring drug resistance mechanisms in multiple types of cancer tissues. Myeloid leukemia cells deregulate branched chain amino acid (BCAA) metabolism to maintain their proliferation and undifferentiated status, but the contribution of this rewired pathway to drug resistance remains poorly understood. Here, we demonstrate that supplementation with branched chain keto acids (BCKAs), the transamination products of BCAAs, specifically attenuates methotrexate (MTX) toxicity in myeloid leukemia cells, whereas direct BCAA supplementation fails to provide a similar protective effect. Conversely, BCKA supplementation inhibits lymphoid leukemia cells, an effect potentially mediated by the activation of hypoxia-inducible factor 1α (HIF-1α). Gene expression analysis further suggests the involvement of activating transcription factor 5 (ATF5) in the BCKA-mediated rescue from MTX toxicity. Clinically, MTX serves as a standard-of-care treatment for lymphoid malignancies, whereas it typically exhibits limited efficacy against myeloid leukemia. Our results highlight a divergent, lineage-specific response to BCKAs, which may underlie metabolic basis for the intrinsic resistance of myeloid leukemia to MTX.

DOI: https://doi.org/10.1093/jb/mvag082
Blood Adv. 2026 Nov 05. pii: bloodadvances.2026020900. [Epub ahead of print]

Establishing Absolute Neutrophil Count and White Blood Cell Count Reference Intervals for the Duffy Null Population.

Lauren E Merz, Aliza Fink, Hyojeong Han, Cyril Jacquot, Abraham Haimed, Stella T Chou, Alexis A Thompson, Vivian Y Chang, Zhen Wei Mei, J Mark Sloan, Eric J Burks, Gary Rose, Corinna L Schultz, Charlotte M Story, Elizabeth Patricia Crowe, Ivo Mb Francischetti, Emmanuel Fadeyi, Amy Soni, Gilles Attipoe, Christina M Barriteau, Michael Blechner, Cecelia Calhoun, Sally Campbell-Lee, Adam Cuker, Warren B Fingrut, Victoria E Forbes, Vijayakrishna K Gadi, Richard C Godby, Lucy A Godley, George Goshua, Richard L Haspel, Chibuzo Ilonze, Peng Ji, Jennifer Jones, Justin E Juskewitch, Matthew S Karafin, Nicole Kucine, Priyadarshini Kumar, Margarita Kushnir, David Levitz, Michael R Lewis, Geling Li, Johnson M Liu, Patrick T McGann, Christian P Nixon, Sabrina E Racine-Brzostek, Karishma Vijay Rupani, Linda Song, Alexa J Siddon, Christine Sillings, Don A Stevens, James Szymanski, Clifford Takemoto, Taylor A Van Denakker, Kelly Walkovich, Rahma Warsame, Angela C Weyand, Samuel R Wilson, Nibal Zaghloul, Yadashe Belay, Patricia Frustace, Jamie Tyson, Nathalie Van Havre, Maureen Okam Achebe.

Most reference intervals (RI) for absolute neutrophil count (ANC) and white blood cell count (WBC) in the United States (US) are not representative of people with the Duffy null phenotype (10% of the US population), which leads to misdiagnoses and inequity in care. We aimed to verify the adult Duffy null ANC RI and develop WBC and ANC RIs for pediatrics. 1,412 healthy Duffy null participants from 23 sites were included. All sites agreed on eligibility criteria. Otherwise, this was a pragmatic design with site-specific variation in collection approach. ANC and WBC were stratified into 5 age categories: 6 months-2 years, 3-6 years, 7-12 years, 13-17 years, and 18+ years. RI were calculated by Clinical and Laboratory Standards Institute guidelines. Duffy null-specific ANC RI were 0.53-4.50×109/L (6 months-2 years, n=184), 0.78-4.67×109/L (3-6 years, n=160), 0.87-5.34×109/L (7-12 years, n=190), 0.90-4.89×109/L (13-17 years, n=216), and 1.03-7.30×109/L (18+ years, n=662). 25% of adults had ANC <2.00×109/L and 24-53% of children had ANC <1.50×109/L. Sensitivity analyses did not show any significant differences in ANC RI when accounting for blood draw type, setting, collection site, hematology analyzer, or hemoglobin and platelet counts. This study provides the first report of Duffy null-specific pediatric ANC and WBC RI, as well as a large-scale verification of adult Duffy null-specific ANC and WBC RI. Adoption of Duffy null-specific RIs is necessary for the accurate interpretation of laboratory values that will support appropriate and equitable medical decision-making.

DOI: https://doi.org/10.1182/bloodadvances.2026020900
Expert Opin Drug Saf. 2026 Nov 04. 1-6

Momelotinib for the treatment of myelofibrosis in patients with moderate-to-severe anemia: a drug safety evaluation.

Andrea Duminuco, Patrick Harrington.

   INTRODUCTION: Momelotinib is an oral inhibitor of Janus kinase 1 and 2 (JAK1/JAK2) and of activin A receptor type 1 (ACVR1). Its key distinguishing feature is the suppression of hepcidin through ACVR1 inhibition, which mitigates the iron-restricted anemia observed in myelofibrosis (MF) due to the hyperinflammatory state. It is the first agent approved for intermediate- or high-risk MF with potential to treat anemia and reduce transfusion dependence.
AREAS COVERED: We review the pharmacology, efficacy, and principally, the safety profile of momelotinib in MF patients with moderate-to-severe anemia. We integrate the controlled safety data of SIMPLIFY-1, SIMPLIFY-2 and MOMENTUM with the rapidly expanding post-marketing real-world evidence (>700 patients across five independent cohorts) and place the profile in the context of the alternative second-line JAK inhibitors fedratinib and pacritinib.
EXPERT OPINION: Momelotinib reshapes the therapeutic algorithm for the anemic myelofibrosis patient, an unmet need that other JAK inhibitors aggravate rather than relieve. The trial-derived haematological profile is favorable, but real-world monitoring has surfaced two signals - treatment-emergent nephropathy and peripheral neuropathy - that were not fully detected in the registration program and now warrant active monitoring. Outstanding questions concern long-term renal and neurological safety, optimal sequencing, and survival benefit.

Keywords:  ACVR1; JAK inhibitor; Myelofibrosis; anaemia; drug safety; hepcidin; momelotinib

DOI:  https://doi.org/10.1080/14740338.2026.2756129
Haematologica. 2026 Nov 05.

Quantitative CD19 expression in pediatric NUP98-rearranged myeloid neoplasms: enrichment at relapse or progression and in the NUP98::NSD1 subtype.

Mahsa Khanlari, Wei Wang, Beenu Thakral, Patrick R Blackburn, Laura Key, Stacie Woolard, Branko Cuglievan, Jeffery M Klco.

DOI: https://doi.org/10.3324/haematol.2026.301817
Blood Adv. 2026 Nov 05. pii: bloodadvances.2026021359. [Epub ahead of print]

Dasatinib in pediatric patients with chronic myeloid leukemia in chronic phase: long-term efficacy and endocrine analysis.

Jill Samis, Briana C Patterson, Lia Gore, C Michel Zwaan, Patricia Martín-Regueira, Yu Tian, Nobuko Hijiya.

Chronic myeloid leukemia (CML) accounts for 2-3% of childhood leukemias. CA180 226 is a prospective phase 2 trial evaluating dasatinib in pediatric patients with newly diagnosed (ND) or imatinib resistant/intolerant (IM R/I) chronic phase CML (CML CP). Analyses showed rapid molecular responses, but long term efficacy, deep molecular responses (DMR), and endocrine effects of tyrosine kinase inhibitors (TKIs) in children have not been reported. This study reports long term outcomes in the largest pediatric cohort to date with endocrine assessment during TKI therapy. ND patients received dasatinib tablets (Cohort 3A) or oral suspension (Cohort 3B), while IM R/I patients were enrolled in Cohort 1. Cohorts 3A and 1 received 60 mg/m² daily; Cohort 3B received 72 mg/m² daily. Median follow-up was 94.8 months for Cohort 3 and 92.4 months for Cohort 1. Height z scores declined over the first few years of therapy particularly in prepubertal children, whereas BMI and bone density changes were mild. Thyroid and gonadal abnormalities were infrequent. Major molecular responses (MMR) occurred within the first 2 years, with 96 month MMR rates of 83.3% in Cohort 3 and 69.0% in Cohort 1. DMR accumulated, with MR4 and MR4.5 rates of 54.8% and 41.7% in Cohort 3 and 37.9% and 27.6% in Cohort 1 at 96 months, respectively. Median progression free and disease free survival were not reached. These long-term data demonstrate durable dasatinib efficacy to induce DMR alongside initial height z-score decline and modest additional endocrine effects, providing important insight into TKI therapy in pediatric CML-CP. NCT00777036.

DOI: https://doi.org/10.1182/bloodadvances.2026021359
Cell Rep. 2026 Oct 30. pii: S2211-1247(26)01319-7. [Epub ahead of print]45(11): 118240

Pot1a maintains mesenchymal stem cell niche function to support hematopoietic stem cells.

Yuki Esaki, Kentaro Hosokawa, Hisayuki Yao, Shunichi Adachi, Yoshihiro Baba, Fumio Arai.

  Hematopoietic stem cells (HSCs) maintain their function through interactions with niche cells in the bone marrow. We previously demonstrated that protection of telomeres 1a (Pot1a), a shelterin component, maintains HSCs and neuron-glial antigen 2-expressing (NG2+) mesenchymal stem cells (MSCs) by suppressing DNA damage response (DDR) and reactive oxygen species (ROS) production. However, the role of Pot1a in leptin receptor-expressing (LepR+) MSCs, a primary HSC niche component, remains unclear. LepR-specific Pot1a knockout mice showed decreased LepR+ MSC numbers, increased DDR and ROS production, reduced HSC quiescence, and impaired long-term hematopoietic reconstitution. In contrast, cell-permeable Pot1a enhanced the hematopoietic-supporting function of LepR+ MSCs. Pot1a deficiency reduced pleiotrophin (Ptn) expression, whereas Pot1a overexpression increased its expression. These findings suggest that Pot1a preserves LepR+ MSC function by limiting stress-associated changes, maintaining MSC numbers, and regulating hematopoietic-supportive factor expression, including PTN.

Keywords:  CP: stem cell research; DNA damage response; LepR(+) stromal cells; Pot1a; bone marrow niche; hematopoietic stem cells; mesenchymal stem cells; pleiotrophin; reactive oxygen species

DOI:  https://doi.org/10.1016/j.celrep.2026.118240
Cell Death Dis. 2026 Aug 09. pii: 943. [Epub ahead of print]17(1):

RACK1 maintains mouse hematopoietic stem cells by directly binding to and stabilizing LDB1.

Lijiao Deng, Junjie Du, Zhe Xu, Lu Guo, Qingyang Wang, Anbiao Wu, Guang Yang, Yu-Chen Lu, Tingting Guo, Chunxiao Niu, Junxia Cao, Yu Lan, Bingshui Xiu, Jiannan Feng, Jiyan Zhang.

A core complex with transcription factors (TFs) TAL1/TCF3/GATA2 and adaptors LMO2/LDB1 lies at the top of the hematopoietic transcriptional hierarchy. The mechanism(s) underlying the expression of these components remain elusive. Adaptor RACK1 interacts with multiple TFs and modulates their activation and/or stability. However, a role of RACK1 in the transcriptional control of hematopoietic stem cell (HSC) fates hasn't been disclosed. Here, we report that RACK1 is expressed across various hematopoietic cell types. Adulthood Rack1 deletion in type I interferon- (IFN-I)-responsive cells leads to rapid and profound hematopoietic failure and HSC loss. HSC exhaustion upon adulthood Rack1 deletion results from cell-intrinsic defects with massive apoptosis. Single-cell RNA sequencing indicates that adulthood Rack1 deletion in IFN-I-responsive cells leads to aberrant lineage-geneset-scores of transcriptional HSCs and the emergence of stressed HSCs. Furthermore, prenatal deletion of Rack1 in hematopoietic cells results in reduced and defective HSCs in the fetal liver. Mechanistically, RACK1 prevents HSC loss through maintaining the protein level of LDB1. The direct interaction between RACK1 and LDB1 suppressing its ubiquitination and subsequent degradation, thereby stabilizes LDB1. Therefore, RACK1 maintains adult and fetal mouse HSCs through, at least partially, directly binding to and stabilizing LDB1.

DOI: https://doi.org/10.1038/s41419-026-09177-z