bims-tremyl 2026-10-25 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2026–10–25
34 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

A randomized phase 2 study combining midostaurin, low-dose cytarabine and venetoclax in newly diagnosed AML ≥60 years.
Prognostic implications of TET2 variant allele frequency in chronic myelomonocytic leukemia: a multicenter study.
Clinical characteristics of secondary myeloid neoplasms in patients with inflammatory bowel disease.
Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.
The immunophenotypic landscape of newly diagnosed acute myeloid leukemia: Associations with genotype and outcomes.
Modulation of the sensitivity to ruxolitinib-mediated JAK2 inhibition by mutationally activated SHP2 exhibits cell context dependency in pre-clinical models of myeloproliferative neoplasms.
Rusfertide for Polycythemia Vera: Incremental Benefit Assessment.
Hematopoietic Cell Transplantation Outcomes in the Era of Post-Transplant Cyclophosphamide: Comprehensive Donor Analysis.
Targeting the mitochondrial complex I subunit NDUFS2 potentiates FLT3 inhibition in acute myeloid leukaemia with FLT3 internal tandem duplication.
Pitavastatin counteracts venetoclax resistance mechanisms including TP53 mutation in acute myeloid leukemia.
Patient-derived neomorphic SEPTIN6 mutations induce hematopoietic stem cell senescence underlying congenital neutropenia and myelodysplasia.
TP53 mutations drive therapy resistance through post-mitochondrial caspase blockade.
Granulocyte-derived Resistin Inhibits Monocyte Maturation and Promotes an Immunosuppressive Phenotype in Chronic Myelomonocytic Leukemia Monocytes.
Polycomb factor PHF19 affects AML initiation, patient prognosis, and survival.
Venetoclax plus hypomethylating agent improves response rates but not survival in TP53-mutated myelodysplastic syndromes.
From ribosomal stress to clonal adaptation: Del(5q) MDS as a paradigmatic acquired ribosomopathy.
Predicting long-term survival in primary myelofibrosis.
Structural and Functional Analysis of GGPPS Inhibition as a Therapeutic Mechanism for Acute Myeloid Leukemia.
Firstline treatment with ruxolitinib versus best available therapy in patients with polycythemia vera: results from the randomized RuxoBEAT trial.
TET2-driven activation of AGO2 links epigenetic remodeling to myeloid commitment and leukemia.
A new reporter strategy reveals a subset of nonmigratory hematopoietic stem cells located in a dynamic bone marrow niche.
ALKBH8 promotes acute myeloid leukemia progression by coupling codon-dependent translation elongation to mRNA stability.
A comparison of overall survival and quality of life in patients with MDS treated with azacytidine vs decitabine.
A novel CD123xVδ2 bispecific T cell engager induces potent and tumor selective Vγ9Vδ2-T cell activity against CD123 expressing acute myeloid leukemia and myelodysplastic syndrome.
Subtype- and functional class-dependent prognostic impact of CSF3R mutations in acute myeloid leukaemia: A cohort study of 2500 patients.
How could calreticulin-targeting therapies change the myelofibrosis transplant paradigm?
Arid1a and Arid1b maintain B cell lineage fidelity and constrain myeloid transformation in mice.
Genetically Defined Acute Myeloid Leukemia Induced Pluripotent Stem Cell Clones Reveal Selective Impairment of Hematopoietic Development.
Cytoreductive therapy reduces JAK2V617F + blood velocity and adhesion to activated endothelium.
Patient-specific genomic measurable residual disease markers for monitoring acute myeloid leukaemia and myeloid malignancy.
Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome.
Phase separation of Rbpms sequesters translation elongation machinery to preserve hematopoietic stem cell function.
A European study on blood mutation monitoring in children with BRAFV600E-positive Langerhans Cell Histiocytosis.
High METTL16 expression is associated with inferior overall survival and transcriptional features of primitive cellular states in acute myeloid leukaemia.

Blood. 2026 Oct 19. pii: blood.2026035389. [Epub ahead of print]

A randomized phase 2 study combining midostaurin, low-dose cytarabine and venetoclax in newly diagnosed AML ≥60 years.

Chong Chyn Chua, Wei-Hsun Hsun Hsu, Anoop K Enjeti, Ashish Bajel, Paula Marlton, Shaun A Fleming, Devendra K Hiwase, Chun-Kei-Kris Kris Ma, Peter J Browett, Carolyn S Grove, ShuhYing Tan, Travis Perera, Jad Othman, Hannah Rose, Julian P Cooney, Edward S Morris, Derek McCulloch, Kate Mason, Rachel M Koldej, Amanda Johnston, Stephen B Ting, David Ritchie, Natasha S Anstee, John Reynolds, Andrew H Wei.

In randomized studies, addition of FLT3 inhibitors failed to improve survival in older patients with FLT3-ITD AML unfit for intensive chemotherapy. Although hypomethylating agents or low-dose cytarabine combined with venetoclax is standard, FLT3-ITD is an important mechanism of resistance and a barrier to improved survival. Recent studies show promise for the addition of gilteritinib or quizartinib to less intensive venetoclax-based therapy, however resulting marrow toxicity requires substantial reductions to administered treatment. The INTERVENE study (Investigating Novel Triplets to Extend Remission with VENetoclax in Elderly AML) (ACTRN12619001655134) examined the role of midostaurin (M) administered sequentially after low-dose cytarabine (L) combined with venetoclax (V) in patients with newly diagnosed AML ≥60 years with non-adverse karyotype. After a run-in phase (n=18) established that LDAC combined with venetoclax from days 1-28 and midostaurin from days 11-28 was tolerable, 120 patients were randomized 2:1 to receive either LVM or LV. For the primary endpoint, LVM did not improve composite complete remission (CRc), compared to LV (72% vs 68%). Combining midostaurin with LV enhanced CRc among the sub-group of patients (n=29) with FLT3-ITD (82% vs 57%, difference = 25%, 0.85 posterior probability true difference > 5%, 95% CrI: -10 to 59%) and improved FLT3-ITD clearance as measured by ultrasensitive NGS (65% vs 0%), resulting in longer OS (median 24.2 vs 8.8 months, HR=0.34, 95% CrI: 0.071 to 0.960), compared to LV. In conclusion, midostaurin combined with low-dose cytarabine and venetoclax is well-tolerated and may have a role in newly diagnosed FLT3-ITD AML unfit for intensive chemotherapy.

DOI: https://doi.org/10.1182/blood.2026035389
Blood Neoplasia. 2026 Nov;3(4): 100286

Prognostic implications of TET2 variant allele frequency in chronic myelomonocytic leukemia: a multicenter study.

Yu-Hung Wang, Dorothée Selimoglu-Buet, Carmelo Gurnari, Matthew T Villaume, Somedeb Ball, Nathalie Droin, Hussein Awada, Andres Jerez, Andrius Zucenka, Chi-Yuan Yao, Chien-Chin Lin, Hsin-An Hou, Wen-Chien Chou, Hwei-Fang Tien, Jaroslaw P Maciejewski, Michael R Savona, Eric Solary, Kiran Batta, Daniel H Wiseman.

Chronic myelomonocytic leukemia (CMML) is a heterogeneous myeloid neoplasm with highly variable prognosis. TET2 is mutated in ∼60% of patients, previously linked to favorable outcomes. However, no study has quantitatively characterized TET2 variant allele frequency (VAF) as a continuous, nonlinear prognostic variable, nor leveraged it to refine contemporary CMML risk stratification systems. We examined the prognostic role of TET2 VAF in 1206 patients across a UK discovery cohort (DC; TET2-mutated, 433/645 [67%]), an international validation cohort (validation cohort 1 [VC1]; TET2-mutated, 141/291 [48%]), and a French CD14+ monocyte-sequenced cohort (VC2; TET2-mutated, 176/270 [65%]). Segmented regression of TET2 VAF distributions reproducibly identified two inflection points (DC, 32%/55%; VC1, 33%/54%; VC2, 36%/56%), implying consistent subdivision of TET2 mutation burden across CMML of epidemiological (and potentially biological) relevance. Restricted cubic spline Cox regression revealed a nonlinear relationship between TET2 VAF and survival, with risk lowest near VAF 39% (the empirical first quartile), whereas patients with TET2 wild-type status had hazards comparable to patients with high VAF. Capitalizing on this continuous relationship, we constructed TET2-VAF-adjusted CMML-specific Prognostic Scoring System-Molecular, Groupe Francais des Myelodysplasies model, and Mayo Molecular Model scores by adding a per-integer VAF adjustment to each patient's original score. Across cohorts and prognostic tools, the adjusted scores improved discrimination (Harrell C-index gain in 16/18 comparisons; integrated discrimination improvement significant in all 18 comparisons; P < .01) and group-level stratification for overall survival and acute myeloid leukemia-free survival. These findings suggest that TET2 VAF represents a continuous prognostic variable in CMML and provide a robust, reproducible framework for refining standard risk stratification systems.

DOI: https://doi.org/10.1016/j.bneo.2026.100286
Br J Haematol. 2026 Oct 18.

Clinical characteristics of secondary myeloid neoplasms in patients with inflammatory bowel disease.

Tareq Abuasab, Shehab F Mohamed, Hyunsoo Hwang, Xuemei Wang, Koji Sasaki, Musa Yilmaz, Tapan Kadia, Courtney DiNardo, Naval Daver, Naveen Pemmaraju, Farhad Ravandi, Hagop Kantarjian, Guillermo Garcia-Manero, Koichi Takahashi.



Keywords:  Crohn disease; inflammatory bowel disease; myeloid neoplasm; ulcerative colitis

DOI:  https://doi.org/10.1111/bjh.70900
Leukemia. 2026 Oct 23.

Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.

Ilias Sinanidis, Panagiotis Tsakiroglou, Benjamin Dubner, Rebecca Foertsch, Julia Gondek, InYoung Choi, Bogdan Paun, Teodora Supeanu, Liang Zhao, Gabriel Ghiaur, W Brian Dalton.

Serine metabolism is of growing biologic and therapeutic interest in cancer. Upregulation of the serine synthesis pathway (SSP) can fuel tumor growth, and cancers with this phenotype are often sensitive to. SSP inhibitors. In parallel, dietary restriction of serine and glycine (SG) can suppress some cancers, but the determinants of sensitivity to. this approach are poorly understood. This is especially true in acute myeloid leukemia (AML), where serine metabolism has been less explored. We report that a subset of human AML cell lines and primary samples are completely dependent on external serine, known as serine auxotrophy. These leukemias consistently suppressed the SSP enzyme PSAT1, failed to. synthesize serine, responded to. SG restriction in vivo, and were rescued by restoring PSAT1. We also found that SG restriction synergized with venetoclax in serine auxotrophic AML, and that MECOM rearrangement was strongly associated with PSAT1 suppression and serine auxotrophy. These findings define a metabolically distinct AML subtype and nominate it for targeting by SG restriction.

DOI: https://doi.org/10.1038/s41375-026-03176-x
iScience. 2026 Nov 20. 29(11): 117762

The immunophenotypic landscape of newly diagnosed acute myeloid leukemia: Associations with genotype and outcomes.

Tim R Mocking, Tom Reuvekamp, Lukas H Haaksma, Eirini Papavasileiou, Angèle Kelder, Willemijn J Scholten, Dimitri A Breems, Thomas Fischer, Bjørn T Gjertsen, Laimonas Griškevičius, Gunnar Juliusson, Johan A Maertens, Markus G Manz, Thomas Pabst, Jakob R Passweg, Kimmo Porkka, Jeroen J W M Janssen, Patrycja Gradowska, Bob Löwenberg, Gert J Ossenkoppele, Arjan A van de Loosdrecht, David C de Leeuw, Jacqueline Cloos, Peter J M Valk, Costa Bachas.

  Despite widespread immunophenotyping in acute myeloid leukemia (AML), its immunophenotypic heterogeneity remains incompletely understood. Here, we applied state-of-the-art computational modeling to >50 million single cells from diagnostic bone marrow aspirates of 502 AML patients. Jointly modeling leukemic and non-malignant cells, we identified seven patient clusters with distinct immunophenotypic signatures. These clusters showed strong concordance with recurrent mutations, including NPM1, IDH1/IDH2, CEBPA, and t(8;21)(q22;q22); RUNX1-RUNX1T1 fusions, and enabled accurate prediction of genomic subgroups. Although these immunophenotypic signatures were not associated with therapy responses, loss of HLA-DR expression on leukemic blasts at diagnosis was independently associated with inferior outcomes in patients with chromatin-spliceosome mutations. In addition, we identified an immunophenotypic patient cluster comprising ∼11% of patients characterized by significant bone marrow lymphocyte enrichment where outcomes diverged depending on genetic risk. Together, these findings provide a comprehensive single-cell characterization of AML bone marrow and reveal clinically relevant genotype-phenotype relationships.

Keywords:  acute myeloid leukemia; flow cytometry; genomics; immunophenotyping; machine learning; patient stratification; unsupervised clustering

DOI:  https://doi.org/10.1016/j.isci.2026.117762
bioRxiv. 2026 Aug 20. pii: 2026.08.19.744423. [Epub ahead of print]

Modulation of the sensitivity to ruxolitinib-mediated JAK2 inhibition by mutationally activated SHP2 exhibits cell context dependency in pre-clinical models of myeloproliferative neoplasms.

Tegan M Rowsell, Garima Pandey, Lucia Mazzacurati, Narmin E Amin, Gary W Reuther.

Classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are hematopoietic stem cell cancers that result in aberrant trilineage myeloid cell proliferation, bone marrow fibrosis, and increased risk of acute myeloid leukemia. MPNs are driven by deregulated activity of the JAK2 kinase, induced by mutations in the JAK2, CALR, and MPL genes, but approved JAK2 inhibitors primarily offer palliative effects, not remission. Cell models that demonstrate MPN oncogene driven JAK2 activity requisite for cell proliferation are important research tools for the development of anti-JAK2 and anti-JAK2 signaling therapeutics for MPN. SET2 and UKE1 cells are two such cell lines, as they express JAK2-V617F, one of the major driving mutations of MPN, and require signaling by JAK2 for their growth and viability. These cell lines are AML cell lines that were derived from patients with a previous diagnosis of MPN before they developed AML. Our previous studies demonstrated that the SHP2 phosphatase may be a therapeutic target for MPNs, and here we report our identification and characterization of an activating point mutation of SHP2 (encoded by the PTPN11 gene), SHP2-F71L, in UKE1 cells. Given SHP2 functions downstream of JAK2 and mediates JAK2 activation of RAS, we set out to determine the effect of mutational activation of SHP2 on the sensitivity of MPN model cells to JAK2 inhibition. We used CRISPR-Cas9 to edit this mutation in UKE1 cells back to wildtype such that these cells only express wildtype SHP2. These cells exhibited enhanced sensitivity to SHP2 inhibition and, notably, enhanced sensitivity to the JAK2 inhibitor ruxolitinib. This altered sensitivity was reverted by exogenous expression of SHP2-F71L but not SHP2-WT, indicating expression of an activated SHP2 may alter sensitivity to JAK2 inhibition in MPN model cells. We further explored this by genetically editing SET2 cells to express SHP2-F71L but observed no change in SHP2 inhibitor or JAK2 inhibitor sensitivity in cells with a SHP2-F71L encoding allele of PTPN11. Using the cytokine dependent BaF3 cell line where deregulation of JAK2 signaling by expression of JAK2-V617F induces cytokine independent transformation that remains dependent on this JAK2 signaling, we observed no effect of the expression of an activated SHP2 mutant on the sensitivity of the growth and viability of these cells to ruxolitinib. Recent studies have demonstrated activation of RAS signaling can antagonize JAK2 inhibition in pre-clinical MPN models, and the presence of RAS pathway mutations associates with patients whose disease advances on ruxolitinib therapy. Such mutations include activating mutations in PTPN11, as SHP2 is an upstream activator of RAS signaling. Our results suggest that activating PTPN11 mutations have the potential to desensitize the effects of JAK2 inhibition therapy in patients undergoing therapy and may be dependent on unknown cell and molecular profile contexts.

DOI: https://doi.org/10.64898/2026.08.19.744423
Am J Hematol. 2026 Oct 17.

Rusfertide for Polycythemia Vera: Incremental Benefit Assessment.

Ayalew Tefferi, Naseema Gangat, Paola Guglielmelli, Alessandro M Vannucchi, Tiziano Barbui.

Rusfertide mechanism of action and clinical trial results in polycythemia vera.

DOI: https://doi.org/10.1002/ajh.70528
Blood Adv. 2026 Oct 21. pii: bloodadvances.2026021883. [Epub ahead of print]

Hematopoietic Cell Transplantation Outcomes in the Era of Post-Transplant Cyclophosphamide: Comprehensive Donor Analysis.

Yosra M Aljawai, Masumi Ueda Oshima, Varuna Astha, Igor Litvinovich, Meilun He, Sarita A Layton, Caitrin Bupp, Kwang Woo Ahn, Javier Bolaños-Meade, Mahasweta Gooptu, Aleksandr Lazaryan, Monzr M Al Malki, Heather E Stefanski, Bronwen E Shaw, Stephen R Spellman, Jeffery J Auletta, Steven M Devine, Mark B Juckett, Hany Elmariah.

Donor types influence outcomes after allogeneic hematopoietic cell transplantation (HCT), but their relative impact in the post-transplant cyclophosphamide (PTCy) era is uncertain. We performed a multicenter retrospective cohort study using Center for International Blood and Marrow Transplant Research data for adults with acute leukemia or myelodysplastic syndromes undergoing first HCT from matched sibling donors (MSD), 8/8 matched unrelated donors (MUD), 7/8 mismatched unrelated donors (MMUD), or haploidentical donors between 2017 and 2023 with PTCy-based graft-versus-host disease (GVHD) prophylaxis. The primary cohort included 12,617 patients: 1,263 MSD, 4,117 MUD, 1,426 MMUD, and 5,811 haploidentical recipients. In multivariable models adjusted for donor age and clinical covariates, overall survival (OS) was lower with MUD (hazard ratio [HR], 1.16; 95% CI, 1.00-1.34, p=0.004), MMUD (HR, 1.32; 95% CI, 1.12-1.55, p<0.001), and haploidentical donors (HR, 1.43; 95% CI, 1.24-1.64, p<0.001) compared with MSD. GVHD-free, relapse-free survival (GRFS) was similar for MUD and MSD (reference) but lower with MMUD and haploidentical donors. Compared to MSD, all other donor groups had lower relapse risk but higher non-relapse mortality and acute GVHD, with similar chronic GVHD. In sensitivity analyses excluding donor-age adjustment, compared to MSD, OS was similar for MUD and MMUD, and GRFS was improved with MUD and similar for MMUD and haploidentical donors. These findings suggest that PTCy narrows outcome differences across donor types, shifting donor selection from rigid hierarchies and supporting timely HCT using the best available donor.

DOI: https://doi.org/10.1182/bloodadvances.2026021883
Leukemia. 2026 Oct 19.

Targeting the mitochondrial complex I subunit NDUFS2 potentiates FLT3 inhibition in acute myeloid leukaemia with FLT3 internal tandem duplication.

Xiqin Tong, Guopeng Chen, Yuzhe Pan, Yanling Chen, Yuxin Tan, Hongqiang Jiang, Qian Wang, Linlu Ma, Ruihang Li, Yuxing Liang, Xiaoyan Liu, Fuling Zhou.

Acute myeloid leukaemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) frequently relapses after FLT3 tyrosine kinase inhibitor (TKI) therapy, highlighting the need to define mechanisms of drug tolerance. Here, we identify the mitochondrial complex I core subunit NDUFS2 as a determinant of FLT3 TKI tolerance in FLT3-ITD AML. A metabolism-focused CRISPR-Cas9 sensitiser screen, integrated with transcriptomic profiling of gilteritinib-resistant cells and primary samples, identified NDUFS2 as upregulated in acquired resistance and preferentially expressed in FLT3-ITD AML. NDUFS2 knockdown impaired complex I activity, oxidative phosphorylation, mitochondrial membrane potential and ATP production, thereby promoting apoptosis and sensitising FLT3-ITD AML cells to gilteritinib. Pharmacologic complex I inhibition with IACS-010759 similarly enhanced gilteritinib activity in FLT3-ITD AML cell lines and primary FLT3-ITD samples, activated AMPK-PERK-ATF4-CHOP stress signalling, promoted apoptosis, and reduced leukaemia burden in a patient-derived xenograft model. Genetic NDUFS2 knockdown also prolonged survival in a xenograft model. A preliminary murine safety assessment showed no overt toxicity under the tested short-term dosing schedule. These findings identify NDUFS2-dependent complex I activity as an adaptive metabolic dependency supporting FLT3 inhibitor tolerance and provide mechanistic insight for further preclinical evaluation.

DOI: https://doi.org/10.1038/s41375-026-03170-3
Blood Neoplasia. 2026 Nov;3(4): 100296

Pitavastatin counteracts venetoclax resistance mechanisms including TP53 mutation in acute myeloid leukemia.

Roberta Buono, Dennis Juarez, Madhuri Paul, Sarah J Skuli, Ian B Wong, Ishita Tarnekar, Zhili Ying, Izabelle Marie F Le, Wen-Pin Chen, Min Zhang, Gerald Wertheim, A'ishah Bakayoko, Marisa Kruidenier, Dequina A Nicholas, Pankaj Gupta, Said M Sebti, Marina Konopleva, Angela G Fleischman, Cholsoon Jang, Martin Carroll, David A Fruman.

The B-cell lymphoma 2 inhibitor venetoclax has therapeutic activity in several hematological malignancies. In acute myeloid leukemia (AML), venetoclax combined with hypomethylating agents is the standard of care for patients unfit for intensive chemotherapy, but intrinsic and acquired resistance are common. Loss of p53 function is strongly associated with venetoclax resistance, and adding venetoclax to 5-azacitidine provides no overall survival benefit in TP53-mutant AML. Other frequent mechanisms of venetoclax resistance in AML include FLT3 mutations, myeloid cell leukemia 1 (MCL-1) upregulation, and altered mitochondrial metabolism. However, it has been challenging to develop agents that target these mechanisms directly and combinatorially. Here, we report that pitavastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, promotes apoptosis and overcomes several venetoclax resistance mechanisms in human AML cells. At clinically achievable concentrations, pitavastatin treatment has potent cytotoxic activity in cells with mutations in TP53 or FLT3, including primary cells resistant to venetoclax and 5-azacitidine. The apoptotic mechanism involves p53-independent PUMA upregulation and reduced MCL-1 expression. Pitavastatin also suppresses mitochondrial gene expression, oxidative metabolism, and MYC/E2F-driven transcription. These results provide a mechanistic rationale for clinical trials adding pitavastatin to AML regimens to prevent or overcome venetoclax resistance with TP53 mutations and other high-risk features.

DOI: https://doi.org/10.1016/j.bneo.2026.100296
JCI Insight. 2026 Oct 22. pii: e209595. [Epub ahead of print]11(20):

Patient-derived neomorphic SEPTIN6 mutations induce hematopoietic stem cell senescence underlying congenital neutropenia and myelodysplasia.

Safa F Mohamad, Meaghan McGuinness, Yu Zhou, Xin Jiang, Gabriele Casirati, Adele Mucci, Sara Canovas Nunes, Akiko Shimamura, Pietro Genovese, David A Williams.

  Septins are RAS-like GTP-binding proteins involved in cytoskeletal organization and cellular division. We previously described 2 pediatric patients harboring SEPT6 germline mutations (GM1: SEPT6 c.1282T>C and GM2: SEPT6 c.1282T>A) presenting with congenital neutropenia associated with the development of myelodysplastic syndrome. In one patient, an additional somatic mutation (SM: SEPT6 c.43C>T) was detected at a low allelic fraction in the BM. Here, we describe the consequences of these mutations for hematopoiesis. Transgenic expression or gene editing of GM1 or GM2 in human CD34+ cells led to enlarged, multinucleated cells associated with accelerated exhaustion and premature senescence of hematopoietic stem and progenitor cells (HSPCs). Senescence defects were associated with the upregulation of mTOR phosphorylation, and pharmacologic inhibition of the mTOR pathway resulted in rescue of senescence. In parallel, HSPCs exhibited marked mitochondrial abnormalities, including increased expression of OPA-1, a key regulator of mitochondrial fusion, and enhanced oxygen consumption during mitochondrial respiration. Introduction of the SM in cis with GM1 mitigated all observed defects. Collectively, our findings demonstrate a gain-of-function mechanism underlying marrow failure in patients carrying germline SEPT6 mutations and suggest that acquisition of a secondary somatic SEPT6 variant may confer a compensatory effect within hematopoietic cells.

Keywords:  Hematology; Hematopoietic stem cells; Oncology

DOI:  https://doi.org/10.1172/jci.insight.209595
Cell Death Dis. 2026 Jul 28. pii: 902. [Epub ahead of print]17(1):

TP53 mutations drive therapy resistance through post-mitochondrial caspase blockade.

Ahmed M Mamdouh, Fizza Iftikhar, Elyse A Olesinski, Fang Qi Lim, Shaista Jasdanwala, Yuhan Wang, Yang Mi, Nicole Si En Lin, Daniel Tan En Liang, Md Al Nayem Chowdhury, Nishtha Chitkara, Leah Hogdal, Coleman R Lindsley, Anthony Letai, Koji Itahana, Shruti Bhatt.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a broad spectrum of molecular alterations that influence clinical outcomes. TP53 mutations define one of the most lethal subtypes of AML, driving resistance to nearly all available treatment modalities, including venetoclax plus azacitidine (VenAza). Yet, the molecular basis of this resistance, beyond affecting transactivation of BCL-2 family genes, has remained elusive. Here, we demonstrate that VenAza treatment leads to reduced transcriptional upregulation of the p53 signaling pathway in TP53 mutant/deficient AML compared to wild-type AML. Functionally, TP53 mutant/deficient AML exhibits selective failure in apoptosis induction rather than impaired G1 arrest or senescence. Despite inhibition of pro-apoptotic BAX and selective enrichment for MCL-1 in TP53 mutant isogenic AML cells, compensatory upregulation of BIM preserved functional mitochondrial outer membrane permeabilization (MOMP). TP53 mutant primary AML tumors at baseline also had retained capacity for MOMP. Instead, TP53 mutant AML exhibited disruption in caspase-3/7 activation to evade apoptosis after VenAza therapy - decoupling the mitochondrial and executioner phases of apoptosis. Importantly, this "post-MOMP brake" is not a bystander effect but itself a driver of VenAza and chemotherapy resistance in TP53 mutant/deficient AML. This previously unrecognized mechanistic insight shifts the focus from mitochondrial priming to terminal caspase blockade in TP53 mutant AML and opens the door for urgently needed therapeutic strategies that reignite apoptosis at its execution point.

DOI: https://doi.org/10.1038/s41419-026-09087-0
J Clin Invest. 2026 Oct 15. pii: e201335. [Epub ahead of print]

Granulocyte-derived Resistin Inhibits Monocyte Maturation and Promotes an Immunosuppressive Phenotype in Chronic Myelomonocytic Leukemia Monocytes.

Nathan J Hull, Rachel Cant, Laura A Guest, Yu-Hung Wang, Kristian Gurashi, Roberto Paredes, Carlos Rivera Rivera, Revekka Lefkati, Hector Huerga Encabo, Chien-Chin Lin, Hwei-Fang Tien, Robert Sellers, Sudhakar Sahoo, Dominique Bonnet, Eric Solary, Dorothee Selimoglu-Buet, Daniel H Wiseman, Kiran Batta.

  Chronic myelomonocytic leukemia (CMML) is a hematological neoplasm characterized by expansion of malignant monocytes. However, as a stem cell neoplasm, the disease clone comprises most blood lineages, including granulocytes. To investigate their pathogenic contribution, we performed extensive phenotypic, transcriptomic and functional characterization of CMML granulocytes. These cells exhibited reduced granularity and impaired maturation, the latter of which is associated with poor prognosis. Functionally, CMML granulocytes displayed reduced phagocytic capacity and impaired NETosis, together with aberrant gene expression programs. Notably, RETN, encoding the chemokine resistin, was uniquely upregulated in CMML granulocytes. Accordingly, resistin levels were 10-fold higher in CMML plasma, correlating with inferior survival. Ex vivo exposure to resistin directly blocked monocyte maturation and macrophage differentiation, partly via TLR4 interaction, recapitulating the classical monocytosis repartitioning phenotype that characterizes CMML. Resistin-treated monocytes upregulated gene signatures related to immune suppression and myeloid-derived suppressor cell phenotype. Consistent with these findings, CMML patients displayed higher Treg proportions and Th2/Th1 ratios. Furthermore, we demonstrated that resistin directly skews the Th2/Th1 ratio via binding to monocytes. Thus, CMML granulocytes produce high levels of resistin, which contributes to defective monocyte maturation and induction of myeloid-derived suppressor cell features in monocytes, thereby fostering an immune-suppressive state in this disease.

Keywords:  Cancer; Cell biology; Chemokines; Expression profiling; Hematology

DOI:  https://doi.org/10.1172/JCI201335
Sci Adv. 2026 Oct 23. 12(43): eaed6757

Polycomb factor PHF19 affects AML initiation, patient prognosis, and survival.

Gianni Paolo Gamarra Figueroa, Arantxa Gutierrez, Enrique Blanco, Pedro Vizán, Cecilia Ballaré, Aleksandra Sparavier, Marta Tosto, Saverio Minucci, Lars Velten, Luciano Di Croce.

Acute myeloid leukemia (AML) is marked by unchecked expansion of undifferentiated myeloid cells. Although oncogenic fusions such as MLL-AF9 can initiate disease, the early steps of leukemogenesis and the role of cell-intrinsic regulators remain unclear. We previously showed that the Polycomb-associated factor Phf19 is required for hematopoietic stem cell (HSC) maintenance and state control in mice and that its loss (Phf19KO) impairs HSC function. To define Phf19's role in transformation, we expressed MLL-AF9 in Phf19KO hematopoietic cells and performed integrated multiomic analyses. Phf19 deletion promoted acquisition of stemlike features and reduced responsiveness to differentiation-inducing AML therapies. Molecular and functional consequences of Phf19 loss paralleled those observed in the datasets of patients with AML. From these data, we derived a prognostic signature-PHFScore-which reveals previously unrecognized AML survival-correlating genes that robustly stratify patients across distinct cellular origins and leukemogenic stages, underscoring Phf19's key role in AML biology and prognosis.

DOI: https://doi.org/10.1126/sciadv.aed6757
Blood Neoplasia. 2026 Nov;3(4): 100316

Venetoclax plus hypomethylating agent improves response rates but not survival in TP53-mutated myelodysplastic syndromes.

Michael Canonico, Parth Patel, Najla H Al Ali, Ashwin Kishtagari, Kateryna Fedorov, Hayley Hawkins, Katherine Walsh, Kathryn Kennedy, Erica Mittlebeeler, Sarah Profitt, Callee M Brooks, Laura A Lee, Sanjay R Mohan, Emily F Mason, Rami S Komrokji, Michael R Savona, David A Sallman, Somedeb Ball.

DOI: https://doi.org/10.1016/j.bneo.2026.100316
Semin Hematol. 2026 Sep 30. pii: S0037-1963(26)00096-X. [Epub ahead of print]

From ribosomal stress to clonal adaptation: Del(5q) MDS as a paradigmatic acquired ribosomopathy.

Juliette E Pearce, Stephani Schmitz, Rebekka K Schneider.

  Ribosomopathies reveal how defects in ribosome biogenesis generate lineage-specific hematopoietic phenotypes and create selection pressure that shapes clonal evolution. Using the germline ribosomopathies Diamond-Blackfan anemia and Shwachman-Diamond syndrome to inform a conceptual framework, we examine del(5q) myelodysplastic neoplasm as a paradigmatic acquired ribosomopathy. We propose that disease trajectory is governed not only by the initiating ribosomal defect, but by adaptive responses to persistent ribosomal stress, including compensatory rescue mutations, p53 checkpoint bypass, and internalization of ribosomal stress. This framework links lineage-specific failure, inflammatory niche remodeling, and p53-driven progression to therapeutic vulnerabilities, offering a rationale for risk stratification and targeted treatment in ribosome-stressed myeloid neoplasms.

Keywords:  Acute myeloid leukemia; Clonal hematopoiesis; Del(5q) Myelodysplastic neoplasms; Erythroid Differentiation; Ribosomal stress; Ribosomopathy

DOI:  https://doi.org/10.1053/j.seminhematol.2026.09.006
Leukemia. 2026 Oct 19.

Predicting long-term survival in primary myelofibrosis.

Giovanni Barosi, Vittorio Rosti, Annalisa De Silvestri, Robert Peter Gale.

We interrogated data from 217 subjects with primary myelofibrosis (PMF) diagnosed before 2001 to identify covariates at diagnosis associated with long-term survival. Forty-one survived more than 25 years. Long-term survivors were more often female, younger than 50 years and less likely to have anemia, splenomegaly, increased blood CD34-positive cells, a JAK2V617F variant, and more likely to have grade-0 bone marrow fibrosis and increased platelets. In multivariable logistic regression analyses, age <50 years, platelet count >450 × 10⁹/L, and grade-0 bone marrow fibrosis independently predicted long-term survival. These co-variate associations were confirmed in Cox regression with landmark analyses. Long-term survivors had a lower cumulative incidence of anemia and thrombocytopenia during follow-up. Identifying long-term survivors at diagnosis provides clinically meaningful prognostic information in PMF and may influence therapy decisions.

DOI: https://doi.org/10.1038/s41375-026-03177-w
J Med Chem. 2026 Oct 08. 69(19): 21862-21878

Structural and Functional Analysis of GGPPS Inhibition as a Therapeutic Mechanism for Acute Myeloid Leukemia.

Fraser G Ferens, Daniel D Waller, Rebecca Boutin, Hiu-Fung Lee, Mathieu Tremblay, Marc K Saba-El-Leil, Tian Lai Guan, Kathryn Skorey, Eric Grignano, Michael Sebag, Arun P Wiita, M Joanne Lemieux, Youla S Tsantrizos.

  Acute myeloid leukemia (AML) is a hematological malignancy with poor treatment options and high mortality rates. AML progression is influenced by signaling events facilitated by small GTPases anchored to cellular membranes via post-translational modification with geranylgeranyl pyrophosphate (GGPP). Herein, we show that CML-07-119, a selective inhibitor of GGPP synthase (GGPPS), exhibits nanomolar potency in blocking the viability of AML cell lines, including cells with TP53 wild-type and TP53 mutations, and has antitumor efficacy in vivo. Bone marrow and splenocytes harvested from mice treated with CML-07-119 displayed significantly higher concentrations of unprenylated RAP1A as compared to the controls, confirming the expected biochemical outcome of in vivo GGPPS inhibition. X-ray crystallography and cryo-EM were used to determine the binding mode of this compound and to identify conformational changes to the GGPPS quaternary structure upon binding of CML-07-119. These studies strongly support GGPPS inhibition as a novel mechanism for the treatment of AML.

Keywords:  AML; GGPPS; TP53; binding; treatment

DOI:  https://doi.org/10.1021/acs.jmedchem.6c00808
Blood Cancer J. 2026 Oct 22. pii: 189. [Epub ahead of print]16(1):

Firstline treatment with ruxolitinib versus best available therapy in patients with polycythemia vera: results from the randomized RuxoBEAT trial.

German Study Group for Myeloproliferative Neoplasms (GSG-MPN)

Ruxolitinib (RUX) is approved as second-line treatment for HU-intolerant/-resistant patients with polycythemia vera (PV). Here, we assessed RUX vs. best available therapy (BAT) as first-line treatment in PV in the randomized multicenter RuxoBEAT clinical trial (NCT02577926). Crossover from BAT to RUX was possible after 6 months. Baseline characteristics in the RUX (n = 44) and BAT (n = 34) arms were comparable. The primary endpoint, the clinico-hematologic complete response (CR) rate at month 6, was not met (2.3% vs. 2.9%, p = 1.000). Analyses of secondary and exploratory endpoints showed that RUX was significantly more effective than BAT in improving hematocrit, splenomegaly, and patient-reported pruritus and fatigue, but less effective in reducing platelet counts. Compared to baseline, JAK2V617F variant allele frequency decreased significantly in both RUX and BAT groups at 6 months. The time on treatment (p < 0.001) and duration of treatment (p = 0.022) were significantly superior for RUX vs. BAT during the 24-month study period. There were no new safety signals. These findings demonstrate that RUX did not lead to higher CR rates than BAT and suggest that RUX may induce clinically meaningful additional disease improvements in first-line therapy of PV patients.

DOI: https://doi.org/10.1038/s41408-026-01644-2
Sci Adv. 2026 Oct 23. 12(43): eaee5701

TET2-driven activation of AGO2 links epigenetic remodeling to myeloid commitment and leukemia.

Aleksey Lazarenkov, Gemma Valcárcel, Alba Martinez, Clara Berenguer, Anna V López-Rubio, Mireia Obiols, Claudia Fontanet, Ana Barba, Juan José Rodríguez-Sevilla, Gregoire Stik, Irmela Jeremias, Pablo Menendez, José Luis Sardina.

DNA methylation dynamics shape hematopoietic differentiation and leukemogenesis, yet how the dioxygenase TET2-frequently mutated in myeloid malignancies-directs lineage-specific regulatory programs remains unclear. Here, we integrated DNA methylation, chromatin accessibility, three-dimensional (3D) genome architecture, transcriptional profiling, and TET2 chromatin occupancy to define TET2-dependent control of human myeloid commitment. We found that TET2-bound regulatory regions gain short- and long-range chromatin interactions and that a distinct subset of distal, enhancer-enriched sites undergoes TET2-driven demethylation and activation. Among these, we identified and functionally validated an AGO2 myeloid-specific intragenic enhancer that is frequently hypermethylated in patients with TET2-mutant acute myeloid leukemia. AGO2 expression stratifies patient survival, and AGO2 depletion abrogates leukemic engraftment in vivo. These findings uncover a TET2-AGO2 regulatory axis that integrates epigenetic remodeling, 3D genome reorganization, and leukemic fitness, and they highlight AGO2 as a potential biomarker and therapeutic target in myeloid leukemia.

DOI: https://doi.org/10.1126/sciadv.aee5701
Blood. 2026 Oct 19. pii: blood.2025031114. [Epub ahead of print]

A new reporter strategy reveals a subset of nonmigratory hematopoietic stem cells located in a dynamic bone marrow niche.

Marine A Secchi, Cera Mai, Qi Liu, Aya M F E Elmeligy, Sara Gonzalez Anton, Aisha Jibril, Thorsten Richter, Jiarui Xu, Dónal O'Carroll, Nicola K Wilson, Konstantinos Kokkaliaris, Kamil R Kranc, Berthold Gottgens, Cristina Lo Celso, Tiago C Luis.

Interactions of hematopoietic stem cells (HSCs) with the bone marrow microenvironment are critical to regulate stem cell function in homeostasis, emergency hematopoiesis and ageing. The dynamic behavior of endogenous HSCs in their niches has been challenging to study due to the complexity of markers required to define pure HSCs. Multiple recently developed reporter strategies advanced our capacity to identify HSCs in situ. Yet, they provide different levels of HSC enrichment and are frequently not stable in situations of perturbed hematopoiesis, leading to contradictory observations of HSC localization and migratory behavior. Here we employed a new double reporter strategy by combining the Hoxb5-mKO2 and Vwf-GFP reporters, that are stably expressed in homeostasis, stress and ageing. Hoxb5+Vwf+ cells represent a subset of highly pure and potent long-term HSCs with a platelet-biased pattern of differentiation, that are included in the populations identified by other reporter strategies. Intravital microscopy revealed Hoxb5+Vwf+ cells to be non-migratory in homeostasis, ageing, or following acute thrombocytopenia when these cells are actively proliferating, indicating that this non-migratory behavior is independent of cell cycle status. We found Hoxb5+Vwf+ HSCs in perivascular niches with a higher coverage by LepR+ mesenchymal cells but not preferentially located closer to megakaryocytes, when compared to Hoxb5+Vwf- cells. Nevertheless, stress-induced megakaryopoiesis following acute thrombocytopenia bring megakaryocytes into closer proximity of Hoxb5+Vwf+ HSCs, revealing previously unrecognized niche dynamics in HSC regulation during regeneration.

DOI: https://doi.org/10.1182/blood.2025031114
Cell Rep. 2026 Oct 22. pii: S2211-1247(26)01272-6. [Epub ahead of print]45(11): 118193

ALKBH8 promotes acute myeloid leukemia progression by coupling codon-dependent translation elongation to mRNA stability.

Songyu Li, Yunguang Hong, Songze Deng, Xiang Wu, Zhirong Jia, Yan Liu, Ya Liu, Guocai Wu, Yinhui Chen, Aibing Wu, Xiangwei Gao, Zhanghui Chen.

  Dysregulated mRNA translation is a critical driver of acute myeloid leukemia (AML) progression. While translation initiation is extensively studied, mechanisms governing translation elongation in AML remain unclear. Here, we show that the RNA methyltransferase ALKBH8 is overexpressed in patients with AML and correlates with poor prognosis. ALKBH8 is required for the proliferation and leukemogenic capacity of human and murine AML cells in vitro and in vivo. Mechanistically, ALKBH8 promotes translation-coupled mRNA stabilization via its methyltransferase domain. Loss of ALKBH8 induces ribosome pausing and preferentially destabilizes transcripts enriched in adenine-ending codons. Specifically, ALKBH8 regulates the expression of the DNA repair gene BRCA1 in a codon-dependent manner, supporting homologous recombination and cell survival. Moreover, ALKBH8 depletion sensitizes AML cells to the PARP inhibitor olaparib. Collectively, our study reveals a codon-specific mechanism of ALKBH8-mediated translation, highlighting the ALKBH8-BRCA1 axis as a potential target for therapeutic intervention.

Keywords:  ALKBH8; AML; BRCA1; CP: cancer; CP: molecular biology; tRNA modification; translation elongation

DOI:  https://doi.org/10.1016/j.celrep.2026.118193
Blood Neoplasia. 2026 Nov;3(4): 100293

A comparison of overall survival and quality of life in patients with MDS treated with azacytidine vs decitabine.

James T England, Liying Zhang, Karen Yee, Michelle Geddes, Nancy Zhu, April Shamy, Heather Leitch, Mitchell Sabloff, Grace Christou, Brett L Houston, Ivan Landego, Brian Leber, Dina Khalaf, Alejandro Garcia-Horton, Eve St-Hilaire, Nicholas Finn, Thomas Nevill, Amy Trottier, John Storring, Mohamed Elemary, Robert Delage, Laura Habib, Lisa Chodirker, Signy Chow, Matthew Cheung, Lee Mozessohn, James A Kennedy, Rena Buckstein.

Patients with high-risk myelodysplastic neoplasms or syndromes (MDS) are considered for therapy with hypomethylating agents (HMA) to help restore hematopoiesis, delay progression to acute myeloid leukemia, and improve overall survival (OS). Azacytidine (AZA) and decitabine (DEC) have commonly been used without direct clinical trial comparison between the 2 agents. Prior studies have demonstrated no difference in OS; however, these analyses are limited by the lack of patient-level and disease-risk factors that may influence efficacy and tolerability. This study retrospectively evaluated differences in clinical outcomes for patients treated with AZA or DEC, adjusting for disease-risk category and patient-specific factors, using data from the Canadian MDS registry (NCT02537990). The primary outcome for the study was OS, which was compared using the log-rank test, evaluated for the whole cohort, and then stratified by the Revised International Prognostic Scoring System (IPSS-R) disease-risk. Secondary outcomes included leukemia-free survival (LFS), change in transfusion dependence or independence status, and differences in quality-of-life (QoL) measurements. In total, 424 patients were treated with AZA (median of 10 cycles) and 85 patients were treated with DEC (median of 5 cycles). In unadjusted analysis, median OS was longer in the patients treated with DEC (37.0 vs 21.4 months; P = .001), which remained significant for patients with high-risk defined by an IPSS-R score >3.5 (34.4 vs 19.6 months; P = .01). However, in a propensity score-matched analysis, there was no difference in OS or LFS between HMA therapies. There was no significant difference in global, physical, or social QoL scores between patients treated with either HMA.

DOI: https://doi.org/10.1016/j.bneo.2026.100293
Clin Immunol. 2026 Oct 23. pii: S1521-6616(26)00124-5. [Epub ahead of print] 110786

A novel CD123xVδ2 bispecific T cell engager induces potent and tumor selective Vγ9Vδ2-T cell activity against CD123 expressing acute myeloid leukemia and myelodysplastic syndrome.

Jurjen M Ruben, Charlotte M Mousset, Dorien van de Berg, Kim Hofman, Milon de Jong, Patricia Brouwer, Sanne Graeve, Victoria Iglesias-Guimarais, Pauline M van Helden, Anton E P Adang, Rob C Roovers, Hans J van der Vliet.

  Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) have poor outcomes. We developed a humanized, half-life-extended CD123 × Vδ2 bispecific T-cell engager (bsTCE) to redirect Vγ9Vδ2 T cells to CD123-expressing malignancies. The engager bound selectively to Vγ9Vδ2 T cells and CD123-positive AML cells, with no detectable off-target interactions in specificity and tissue cross-reactivity assays. In vitro, it induced potent lysis of tumor cell lines and patient-derived AML and MDS cells, including at low effector-to-target cell ratios, supportive of serial killing. Compared with a CD123 × CD3 bsTCE, it induced lower levels of cytokines associated with cytokine release syndrome. Vγ9Vδ2-T cells preferentially lysed tumor cells over CD123-positive non-malignant cells, including plasmacytoid dendritic cells, and were detectable in patients' peripheral blood and bone marrow. The engager reduced tumor growth in an AML xenograft model and showed antibody-like pharmacokinetics in nonhuman primates. A phase 1 clinical trial was initiated (ACTRN12624001214527).

Keywords:  Acute myeloid leukemia (AML); Bispecific T cell engager; CD123; Cancer immunotherapy; Myelodysplastic syndrome (MDS); Tumor-selective cytotoxicity; Vγ9Vδ2 T cells; γδ T cells

DOI:  https://doi.org/10.1016/j.clim.2026.110786
Br J Haematol. 2026 Oct 18.

Subtype- and functional class-dependent prognostic impact of CSF3R mutations in acute myeloid leukaemia: A cohort study of 2500 patients.

Jingyao An, Yan Hui, Yan Li, Ying Wang, Benfa Gong, Yuntao Liu, Shouyun Li, Dong Lin, Kaiqi Liu, Guangji Zhang, Chunlin Zhou, Xiaoyuan Gong, Shaowei Qiu, Bingcheng Liu, Yingchang Mi, Qiuyun Fang, Jianxiang Wang, Hui Wei.

  Colony-stimulating factor 3 receptor (CSF3R) mutations occur in acute myeloid leukaemia (AML), but their prognostic significance remains unclear. We analysed 2500 patients with newly diagnosed de novo non-acute promyelocytic leukaemia (APL) AML treated with intensive induction therapy. CSF3Rmut were identified in 3.5% and frequently co-occurred with CCAAT/enhancer-binding protein alpha bZIP domain (CEBPA-bZip) mutations and RUNX family transcription factor 1::RUNX1 partner transcriptional co-repressor 1 (RUNX1::RUNX1T1) fusions. In the entire cohort, CSF3Rmut were associated with inferior relapse-free survival (RFS), but not overall survival (OS) or event-free survival (EFS). The prognostic impact was context-dependent. The adverse association was most consistent in CEBPA-bZip AML, with inferior OS, EFS (hazard ratio [HR], 2.76; p = 0.001) and RFS (HR, 2.66; p = 0.002) and persisted after multivariable adjustment and time-dependent modelling of transplantation. Membrane-proximal activating mutations (MPM) were associated primarily with inferior RFS (HR, 2.27; p = 0.001) in the overall cohort, whereas cytoplasmic-tail truncating mutations (CTTM) showed no consistent adverse effect. In CEBPA-bZip AML, both MPM and CTTM showed adverse EFS and RFS associations, although the CTTM subgroup was small. The prognostic impact of CSF3Rmut in AML depends on molecular context and functional mutation class, with the strongest adverse associations observed in CEBPA-bZip AML.

Keywords:   CEBPA‐bZip ; CSF3R mutations; acute myeloid leukaemia; cytoplasmic‐tail truncating mutations; membrane‐proximal mutations; prognosis

DOI:  https://doi.org/10.1111/bjh.70909
Bone Marrow Transplant. 2026 Oct 23.

How could calreticulin-targeting therapies change the myelofibrosis transplant paradigm?

Amy MacDonald, Isaac Gannon, Elena Torre, Trung Ngo, Jonathan Lambert, Claire Roddie, Donal P McLornan, Alexandros Rampotas.

Myelofibrosis (MF), the most severe Philadelphia chromosome-negative myeloproliferative neoplasm, is driven by mutations in JAK2, CALR, or MPL, with CALR mutations accounting for 30-35% of cases. Mutant CALR forms an aberrant complex with the thrombopoietin receptor, resulting in constitutive JAK-STAT signalling and is expressed on the malignant cell surface as a tumour-specific neoantigen absent from normal tissues, making it an attractive therapeutic target. Allogeneic haematopoietic cell transplantation (allo-HCT) remains the only curative treatment but is limited to selected patients with adequate fitness and a suitable donor. This review summarises the rapidly evolving landscape of CALR-directed therapies, including peptide vaccines, the Fc-silenced monoclonal antibody INCA033989, bispecific T-cell engagers, antibody-drug conjugates, and the CAR T-cell therapy RPG4, and explores their potential impact on transplant decision-making. INCA033989 has generated the most mature clinical data, demonstrating improvements in splenomegaly, constitutional symptoms, anaemia and early markers of disease modification, whereas cytotoxic approaches such as CAR T-cell therapy offer the prospect of deeper clonal eradication. Collectively, these therapies have the potential to redefine the role and timing of allo-HCT and expand treatment opportunities in the peri-transplant setting, including the targeted eradication of measurable residual disease following transplantation.

DOI: https://doi.org/10.1038/s41409-026-03060-3
Exp Hematol. 2026 Oct 23. pii: S0301-472X(26)00589-8. [Epub ahead of print] 105956

Arid1a and Arid1b maintain B cell lineage fidelity and constrain myeloid transformation in mice.

Phyo Nay Lin, Sarah M Zimmerman, Joohyung Park, Yoon-A Kang, George P Souroullas.

  Chromatin remodeling by mammalian SWI/SNF complexes is essential for hematopoietic lineage specification and differentiation. Although the canonical BAF subunits ARID1A and ARID1B are recurrently altered in B-cell malignancies, their overlapping and stage-specific functions during B-cell development remain incompletely understood. Here, we used CD19-Cre-mediated deletion of Arid1a and Arid1b to define their roles in B-cell development and hematopoietic transformation in vivo. Loss of either Arid1a or Arid1b impaired B-cell differentiation, reduced immature and recirculating B-cell output, and compromised germinal center responses following antigen challenge, with more pronounced defects following combined deletion. Unexpectedly, combined Arid1a/Arid1b loss resulted in a lethal, transplantable myeloid leukemia rather than a B-cell malignancy. CD19-Cre lineage tracing and allele-recombination analysis identified a subset of multipotent progenitors carrying CD19-Cre activity, while combined deletion was associated with selective MPP3 expansion and impaired myelo-erythroid colony-forming capacity. Transcriptional profiling of Arid1a/Arid1b-deficient MPP2/3 cells revealed loss of HSPC- and lymphoid-associated programs together with aberrant activation of erythroid and megakaryocyte-erythroid transcriptional states, without acquisition of a conventional mature myeloid program. These findings reveal overlapping functions of ARID1A and ARID1B in B-cell development and support a broader role for canonical BAF complexes in maintaining hematopoietic lineage fidelity and constraining malignant transformation.

Keywords:  ARID1A; ARID1B; B cell development; BAF; MPPs; Myeloid leukemia; SWI/SNF; lineage fidelity; multipotent progenitors

DOI:  https://doi.org/10.1016/j.exphem.2026.105956
Stem Cells Dev. 2026 Oct 19. 15473287261495853

Genetically Defined Acute Myeloid Leukemia Induced Pluripotent Stem Cell Clones Reveal Selective Impairment of Hematopoietic Development.

Deanna P Porras, Amy Qiao, Meaghan Doyle, Hailey Kadonoff, Kinga Vojnits, Diana Golubeva, Cameron G Hollands, Allison Boyd, Mickie Bhatia.

  Patient-derived induced pluripotent stem cells (iPSCs) provide a renewable model for studying acute myeloid leukemia (AML), but whether AML-iPSCs faithfully preserve the functional heterogeneity of genetically distinct AML clones remains unclear. Here, we functionally characterized a genetically defined AML-iPSC resource comprising 34 AML-iPSC lines from 11 AML patients, with complementary assays performed across partially overlapping subsets of lines. AML-iPSC lines were classified as aberration-positive (Ab+) or aberration-negative (Ab-) based on retention of the clinically defining patient-specific leukemia-associated genetic abnormalities. Representative Ab+ and Ab- AML-iPSC lines derived from donor hematopoietic cells exhibited comparable differentiation capacity across nonhematopoietic lineages, whereas Ab+ AML-iPSC lines demonstrated reduced hematopoietic differentiation, as determined by phenotypic analysis and functional colony-forming assays. Across overlapping subsets of AML-iPSC lines, these clone-specific hematopoietic phenotypes were conserved across four independent differentiation platforms, supporting that they reflect stable clone-specific properties rather than methodological artifacts. Residual hematopoietic progenitors derived from Ab+ AML-iPSC lines retained leukemic features, including persistence of leukemia-associated genetic abnormalities, immature blast-like morphology, and enhanced serial replating capacity indicative of self-renewal-associated properties. In a representative paired patient model, these progenitors also demonstrated persistent myeloid-skewed hematopoietic output following xenotransplantation. Together, these findings establish a renewable platform for mechanistic studies investigating how clonal heterogeneity contributes to disease evolution and therapeutic resistance in AML following pluripotent reprogramming.

Keywords:  AML-induced pluripotent stem cells (AML-iPSCs); acute myeloid leukemia (AML); cell fate; colony-forming unit (CFU) assay; functional disease modeling; hematopoietic differentiation; induced pluripotent stem cells (iPSCs); leukemic progenitor cells (LPCs); patient-derived disease modeling; reprogramming

DOI:  https://doi.org/10.1177/15473287261495853
Br J Haematol. 2026 Oct 20.

Cytoreductive therapy reduces JAK2V617F + blood velocity and adhesion to activated endothelium.

Angelica DaSilva, Taimur Ul Islam, Swati Menon, Julia Nguyen, Paul Krenik, Conglin Ruan, Xianghua Luo, David K Wood, Joan D Beckman.



Keywords:  MPN; cytoreduction; endothelium; vascular biology

DOI:  https://doi.org/10.1111/bjh.70906
Br J Haematol. 2026 Oct 20.

Patient-specific genomic measurable residual disease markers for monitoring acute myeloid leukaemia and myeloid malignancy.

Libby Huang, Louise Doculara, Luis Enriquez, Jodie Giles, Umma Habiba, Anita Y Bahar, Tammy Law, Weronika Lesnowolska, Hannah McCalmont, Erika Ong, Laura Piras, Benjamin Schreiber, Nicola Venn, Wiebke Wessels, Yianni Bletas, Minjina Kang, Sam Yuen, Patrick Strong, Paulette Barahona, Ann-Kristin Altekoester, Kimberly Dias, Dianne Sylvester, Marie Erasmus Wong, Renee Eslick, Luciano Dalla Pozza, Bhavna Padhye, Ashanka Beligaswatte, Chow Yee Lai, Michelle Ng, Chris Fraser, David Hughes, Seong Lin Khaw, Karen McCleary, Sophie Jessop, Manika Pal, Lucie Winkowska, Jan Zuna, Patrizia Larghero, Rolf Marschalek, Claus Meyer, Rishi S Kotecha, Andrew S Moore, Mark J Cowley, Rosemary Sutton, Michelle J Henderson, Toby N Trahair.

  Measurable residual disease (MRD) has improved acute lymphoblastic leukaemia (ALL) outcomes. Applying acute myeloid leukaemia (AML) MRD has been limited due to complexity identifying leukaemia-specific targets. Current AML MRD relies on flow cytometry or ribonucleic acid (RNA)-based quantitative polymerase chain reaction (PCR) but cannot be applied to all patients. With next-generation or whole genome sequencing (NGS/WGS), myeloid MRD targets can be identified, suggesting that DNA-based PCR-MRD could be used. Genomic data including RNA-seq, targeted NGS or WGS were used to develop patient-specific PCR-MRD assays, which were reported using EuroMRD guidelines. We developed PCR-MRD assays in 97.6% patients and conducted prospective PCR-MRD monitoring in 40 myeloid malignancy patients. Myeloid MRD reports had a similar turnaround time to ALL MRD. Myeloid MRD markers were highly sensitive with a higher proportion of myeloid malignancy patients (50%) having an MRD marker with a quantitative range of ≤5 × 10-5 compared to ALL patients (29%). In patients with two MRD markers, there was excellent inter-assay concordance. Serial MRD correlated with disease outcome. Two patients with isolated CNS relapse had low-level BM involvement at extra-medullary relapse. Myeloid malignancy PCR-MRD should be studied prospectively in clinical trials across experienced MRD laboratories using the standardised EuroMRD guidelines.

Keywords:  acute myeloid leukaemia; measurable residual disease; myelodysplasia

DOI:  https://doi.org/10.1111/bjh.70880
Cancer Cell. 2026 Oct 19. pii: S1535-6108(26)00474-5. [Epub ahead of print]

Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome.

Maurice Labuhn, Kelly Perkins, Sören Matzk, Leila Varghese, Catherine Garnett, Elli Papaemmanuil, Marlen Metzner, Alison Kennedy, Vyacheslav Amstislavskiy, Thomas Risch, Raj Bhayadia, David Samulowski, David Cruz Hernandez, Bilyana Stoilova, Valentina Iotchkova, Udo Oppermann, Carina Scheer, Kenichi Yoshida, Adrian Schwarzer, Jeffrey W Taub, John D Crispino, Mitchell J Weiss, Yasuhide Hayashi, Takashi Taga, Etsuro Ito, Seishi Ogawa, Dirk Reinhardt, Marie-Laure Yaspo, Peter J Campbell, Irene Roberts, Stefan N Constantinescu, Paresh Vyas, Dirk Heckl, Jan-Henning Klusmann.

DOI: https://doi.org/10.1016/j.ccell.2026.10.008
Cell Stem Cell. 2026 Oct 21. pii: S1934-5909(26)00355-3. [Epub ahead of print]

Phase separation of Rbpms sequesters translation elongation machinery to preserve hematopoietic stem cell function.

Le Chang, Mengyao Sun, Lingyan Zhao, Jiahuan He, Sijia Bai, Zhongyang Chen, Siqi Liu, Xinyan Shen, Fanqi Zhou, Yu Rong, Chenxi Han, Yanmin Si, Hualu Zhao, Fang Wang, Yanni Ma, Jia Yu.

  The mechanisms by which hematopoietic stem cells (HSCs) maintain long-term (LT) hematopoietic capacity and transition from quiescence remain incompletely understood, limiting their in vitro expansion and applications. Accumulating evidence underscores the importance of maintaining a low protein synthesis rate for HSC function, yet the underlying mechanisms remain elusive. Here, we identified ribosome-associated proteins specifically enriched in HSCs and multipotent progenitors (MPPs) and found that RNA-binding protein gene with multiple splicing (Rbpms) is required for sustaining low protein synthesis rates in HSCs. Rbpms forms biomolecular condensates that sequester translation elongation factors and protein-folding chaperones from ribosomes, slowing translation elongation and ensuring proper protein folding in HSCs. Rbpms deletion led to accelerated protein synthesis, accumulation of misfolded proteins in HSCs, impaired LT hematopoietic reconstitution capacity, accompanied by aberrant exit from quiescence. Our findings unveil a unique mechanism of translation elongation regulation in HSCs and highlight significance of spatial compartmentalization and translational control in HSCs.

Keywords:  Rbpms; biomolecular condensates; hematopoietic stem cells; translation elongation

DOI:  https://doi.org/10.1016/j.stem.2026.09.013
Blood Adv. 2026 Oct 23. pii: bloodadvances.2026021834. [Epub ahead of print]

A European study on blood mutation monitoring in children with BRAFV600E-positive Langerhans Cell Histiocytosis.

Paul Milne, Linda Beneforti, Aurora Chinnici, Maria Luisa Coniglio, Francesco Pegoraro, Irene Trambusti, Zofia Hélias-Rodzewicz, Raphaela Schwentner, Philipp Ben Soussia-Weiss, Natasja Shireen Roozeboom, Jamie Liam Macdonald, Sarah Pagan, Venetia Bigley, Olga Slater, Vasanta Nanduri, Paola Consuelo Corti, Alessandra Todesco, Michele Tanturli, Jean-François Emile, Cor van den Bos, Jean Donadieu, Milen Minkov, Sebastien Heritier, Caroline Hutter, Astrid G S van Halteren, Matthew Collin, Elena Sieni.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm driven by somatic variants in MAPK-encoding genes, most commonly BRAFV600E. The prognostic value of BRAFV600E in the peripheral blood of children with LCH has never been investigated in an international setting characterized by different approaches. To this aim, five centers from the European Consortium for Histiocytosis (ECHO) analyzed the peripheral blood of 226 children enrolled in, or managed according to, the LCH-IV protocol. We quantified BRAFV600E burden in different DNA sources at diagnosis and after 6 weeks of vinblastine/prednisone and evaluated its association with 2-year event-free survival (EFS). At diagnosis, BRAFV600E positivity could be equally determined through circulating cell-free (ccf) or peripheral blood mononuclear cell (PBMC)-DNA in patients with multi-system (MS) LCH. In single-system (SS) LCH, analyzing both substrates improved diagnostic sensitivity. For each clinical subgroup at diagnosis, we identified BRAFV600E levels associated with inferior 2-year EFS: ≥LOQ (0.1% for ccf-DNA, 0.01% for PBMC-DNA) in SS and MS risk-organ negative (RO-) groups; ≥1% (both ccf- and PBMC-DNA) in MS risk-organ positive (RO+) group. Notably, BRAFV600E burden was independently associated with inferior EFS in multivariable analysis (HR 2.05, 95%CI: 1.11-3.78 for BRAFV600E ≥LOQ, p=0.022; HR 4.53, 95%CI: 2.34-8.79 for BRAFV600E≥1%, p<0.001). After 6 weeks of vinblastine/prednisone, decreasing BRAFV600E burden (<0.1% in ccf-DNA or <0.01% in PBMC-DNA) was significantly associated with higher 2-year EFS (p<0.001 and p=0.009). These findings provide a framework for refining risk-stratification in pediatric LCH through the incorporation of peripheral blood BRAFV600E testing into international prospective clinical trials.

DOI: https://doi.org/10.1182/bloodadvances.2026021834
Br J Haematol. 2026 Oct 21.

High METTL16 expression is associated with inferior overall survival and transcriptional features of primitive cellular states in acute myeloid leukaemia.

Marcio T Reis-Silva, Vitoria J Silva-Xavier, Isabelle C Santos, Maria L Salustiano-Bandeira, Amanda Moreira-Aguiar, Lidiane P Santos, Aleide S Lima, Elisa A Azevedo, Clarice N Morais, Marcos A Bezerra, Pedro L Franca-Neto, Diego A Pereira-Martins, Juan L Coelho-Silva, Antonio R Lucena-Araujo.



Keywords:  RNA; leukaemic stem cells; metabolic reprogramming; methylation

DOI:  https://doi.org/10.1111/bjh.70878