bims-tremyl 2026-02-15 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2026–02–15
twenty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Prognostic impact of myelodysplasia-related gene mutations in FLT3-ITD-mutated acute myeloid leukemia.
A CRISPR-Based Humanized Model Reveals Cooperative Role of STAG2 Loss in Familial GATA2-Deficient MDS Progression.
Differential Prognosis and Transplant Strategies in CBF-AML With RUNX1::RUNX1T1 Versus CBFβ::MYH11 Fusions.
Tolerability and Outcomes With Serial Cycles of 28 Days of Venetoclax in Newly Diagnosed Patients With Acute Myeloid Leukemia.
A novel approach to defining progression in MDS and precursor myeloid conditions in The MDS Natural History Study.
FLT3 as a germ line driver in AML: expanding the landscape of leukemia predisposition.
Prognostic Model Combining Mutational and Cytogenetic Profiles in Acute Myeloid Leukemia Treated with Venetoclax and Hypomethylating Agents.
Clinico-genomic characterization of RAS-mutant acute myeloid leukemia.
Conventional Therapy vs HMA or LDAC ± Venetoclax in Older Adults With AML: Systematic Review and Meta-analysis.
Intrinsic and niche-dependent metabolic regulation of haematopoietic stem cells and implications for leukaemogenesis.
Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice.
Pivekimab Sunirine in Blastic Plasmacytoid Dendritic Cell Neoplasm.
Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis.
Intrinsic cellular resistance to BCR::ABL1 inhibitors.
Nucleoplasmic ZNF467 condensates boost hematopoietic stem cell engraftment via ICAM1-mediated mechanical reprogramming.
Heritable ER stress impairs mitochondrial metabolism and maintenance of hematopoietic stem cells after low-dose irradiation.
Intensive Chemotherapy With or Without Midostaurin in Adults ≥ 60 Years Old With FLT3-Mutated AML: A FILO-DATAML-PETHEMA Real-World Study.
Leptin Receptor + cells create a perisinusoidal niche for thrombopoiesis in the bone marrow by synthesizing CXCL14.
Single-cell atlas of AML reveals age-related gene regulatory networks in t(8;21) AML.
Prevention and management of febrile neutropenia in acute myeloid leukaemia and higher risk myelodysplastic syndrome: An international survey of current practice.
Dynamic feedback control of oncogenic tyrosine kinase signaling in acute leukemia.

Leukemia. 2026 Feb 09.

Prognostic impact of myelodysplasia-related gene mutations in FLT3-ITD-mutated acute myeloid leukemia.

Rabea Mecklenbrauck, Angela Villaverde Ramiro, Eric Sträng, Razif Gabdoulline, Javier Martinez Elicegui, Marta Sobas, Lisa Pleyer, Amin Turki, Maria Teresa Voso, Axel Benner, Alberto Hernández-Sánchez, Jesse M Tettero, Laura Tur Gimenez, Klaus H Metzeler, Guadalupe Oñate, Sören Lehmann, Brian Jp Huntly, Ian Thomas, Felicitas R Thol, Florian H Heidel, Peter Jm Valk, Konstanze Döhner, Torsten Haferlach, Kenneth I Mills, Hartmut Döhner, Gastone Castellani, Gert J Ossenkoppele, Jesus María Hernández-Rivas, Lars Bullinger, Michael Heuser.

The inclusion of nine myelodysplasia-related gene (MRG) mutations (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse risk factors in the ELN risk classification has reshaped classification in acute myeloid leukemia (AML). AML with FLT3-ITD mutations and co-occurring MRG alterations is now classified to the ELN adverse risk group although supporting evidence remains limited. Among 4,078 patients with AML with available molecular information included in the HARMONY platform, 862 harbored FLT3-ITD mutations and underwent intensive chemotherapy. Of these, 171 (20%) exhibited co-occurring MRG mutations at diagnosis. In this cohort, MRGs were not independently associated with relapse-free survival (RFS) or overall survival (OS). In the FLT3-ITD/NPM1 co-mutated subgroup, MRG mutations were rare (9%) and showed no prognostic impact. Conversely, in FLT3-ITD/NPM1 wildtype AML, MRG mutations were predictive of shorter RFS (HR 1.37, 95%CI 1.01 - 1.88, p = 0.046) and OS (HR 1.34, 95%CI 1.02-1.74, p = 0.032) in multivariable analysis with survival times comparable to the ELN adverse risk category. The allelic ratio of FLT3-ITD did not further stratify OS and RFS in this subgroup. These findings suggest that the prognostic relevance of MRG mutations in FLT3-ITD AML is modulated by NPM1 co-mutational status and mirror findings in AML lacking FLT3-ITD.

DOI: https://doi.org/10.1038/s41375-026-02874-w
bioRxiv. 2026 Feb 02. pii: 2026.01.30.702879. [Epub ahead of print]

A CRISPR-Based Humanized Model Reveals Cooperative Role of STAG2 Loss in Familial GATA2-Deficient MDS Progression.

Grace Freed, Miguel Quijada-Álamo, Linda Lee, Nikita Podar, Subrina Autar, Saul Carcamo, Persephone Fiore, Ke Wang, Isabella G Martinez, Mimi Zhang, Shayan Saniei, Clifford Chao, Levan Mekerishvili, Zayna Diaz, Sai Ma, Dan Hasson, Elvin Wagenblast.

Myelodysplastic syndrome (MDS) is a heterogeneous myeloid malignancy driven by hematopoietic stem cell dysfunction, leading to ineffective hematopoiesis and cytopenias. Familial GATA2 deficiency is the most common cause of Myelodysplastic syndrome in adolescents, with progression often accelerated by co-occurring mutations, notably STAG2 loss-of-function. Using CRISPR/Cas9-mediated genome engineering in primary human fetal liver-derived hematopoietic stem cells and xenotransplantation in mice, we modeled GATA2-deficient Myelodysplastic syndrome with acquired STAG2 loss to investigate disease initiation and progression. While GATA2 deficiency alone had minimal short-term impact in our model, combined GATA2 and STAG2 loss increased hematopoietic stem cell maintenance and self-renewal, induced a myeloid-lineage bias, and expanded primitive progenitors. Single-cell transcriptional profiling revealed upregulation of stemness genes and inflammatory pathways. This humanized model faithfully recapitulates high-risk GATA2-deficient Myelodysplastic syndrome, providing mechanistic insight into how cooperative mutations drive stem cell expansion, inflammatory signaling, and myeloid skewing.
Visual Abstract:
Key Points: Humanized model of familial GATA2-deficiency requires the loss of STAG2 for progression to an MDS disease phenotypeGATA2-ko+STAG2-ko increase HSC self-renewal, induce a myeloid-lineage bias, and trigger an inflammatory transcriptional program.

DOI: https://doi.org/10.64898/2026.01.30.702879
Am J Hematol. 2026 Feb 14.

Differential Prognosis and Transplant Strategies in CBF-AML With RUNX1::RUNX1T1 Versus CBFβ::MYH11 Fusions.

Jingtao Huang, Huihong Huang, Yunxiang Zhang, Yi Xia, Yuqing Tu, Hao Xu, Yeqian Zhao, Jiayu Huang, Han Yan, Zengkai Pan, Chuanhe Jiang, Luxiang Wang, Zilu Zhang, Xiangqin Weng, YongMei Zhu, Yanmin Zhao, Yang Cao, Jia Chen, Xiaodong Mo, Xiaoxia Hu.

  Core binding factor acute myeloid leukemia (CBF-AML) is defined by t(8;21) or inv. (16), which give rise to the RUNX1::RUNX1T1 and CBFβ::MYH11 fusion genes, respectively. CBF-AML is a favorable-risk AML subtype, yet differences in mutation profiles, measurable residual disease (MRD) response, and relapse risk may warrant tailored treatment approaches. We reviewed adult AML patients treated at five transplant centers across China and identified 825 de novo CBF-AML cases, of which 779 met our eligibility criteria: 536 harbored the RUNX1::RUNX1T1 fusion and 243 the CBFβ::MYH11 fusion. The 3-year overall survival (OS) was 80.6% for RUNX1::RUNX1T1 and 90.2% for CBFβ::MYH11 cases (p = 0.011). Among patients with RUNX1::RUNX1T1, those achieving MRD negativity after two consolidation cycles (PC2) had significantly better OS than nonresponders (86.3% vs. 76.5%, p = 0.008); no difference was observed for CBFβ::MYH11 patients. For RUNX1::RUNX1T1 nonresponders, allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1) reduced relapse (CR1-HCT vs. non-CR1-HCT, 8.3% vs. 18.9%; p = 0.024) and improved OS (CR1-HCT vs. non-CR1-HCT vs. chemotherapy, 85.8% vs. 71.4% vs. 64.9%; p < 0.001). In CBFβ::MYH11 patients, deferring allo-HCT until second complete remission (CR2) was associated with comparable outcomes. In RUNX1::RUNX1T1 patients, older age, elevated initial white blood cell count, lower hemoglobin, lower initial fusion transcript load, and the presence of FLT3-ITD or KIT D816/D822 mutations were associated with an increased likelihood of PC2 nonresponse. Based on these variables, we developed a weighted scoring system with good discrimination to identify RUNX1::RUNX1T1 patients at high risk of PC2 nonresponse.

Keywords:  allogeneic hematopoietic cell transplantation; core binding factor acute myeloid leukemia; measurable residual disease

DOI:  https://doi.org/10.1002/ajh.70237
Am J Hematol. 2026 Feb 13.

Tolerability and Outcomes With Serial Cycles of 28 Days of Venetoclax in Newly Diagnosed Patients With Acute Myeloid Leukemia.

Michael K Jones, Jesse Sanchez, Megan Connor, Katherine Julian, Rebecca Rezac, Kelsey Marciano, Jennifer Tobin, Grace Bosma, Diana Abbott, Katelyn Anttila, Connor Sohalski, Ayele Belachew, Christine McMahon, Andrew Kent, Maria Amaya, Mathew G Angelos, Marc Schwartz, Jonathan A Gutman, Daniel A Pollyea.

The standard of care for newly-diagnosed unfit patients with acute myeloid leukemia (AML) is venetoclax (VEN) with azacitidine (AZA). In the phase 3 trial, before remission, AZA was given with 28 days of VEN. This regimen is myelosuppressive; therefore, many decrease VEN duration before and/or after initial response assessment. We report our center's outcomes administering 28 days of VEN preremission, and in most cases, postremission, relying on other strategies to reduce cytopenias. All newly-diagnosed patients with AML treated outside of a clinical trial with VEN/AZA for > 7 days at our center from 2018 to 2024 were reviewed. 134 patients met inclusion criteria; median age was 70 years (interquartile range [IQR] 64-76), 57% male, and 63% had European LeukemiaNet adverse risk AML (85/134). Overall response rate (including complete remission and complete remission with incomplete hematologic recovery) was 87/134 (64.9%). Median cycles completed was 2 (IQR 1-3, range 0-26), with 117 (87%) completing ≥ 1 cycle with a response assessment. Median duration of cycles 1-5 was 42 days. Median overall survival was 381 days. Prior to response assessment, 113/117 (96.6%) received 28 days of VEN. Postresponse, 17/81 (21.0%) had a VEN reduction (in duration or dose). Grade ≥ 3 neutropenia or thrombocytopenia was higher in cycle 1 than in similar studies, without differences in transfusion needs or infectious complications. Hematologic toxicities improved with subsequent cycles. Serial cycles with 28 days of VEN can be administered pre- and postremission with higher early myelosuppression but similar transfusion and infection rates compared to studies of reduced VEN duration.

DOI: https://doi.org/10.1002/ajh.70231
Blood Adv. 2026 Feb 11. pii: bloodadvances.2025018770. [Epub ahead of print]

A novel approach to defining progression in MDS and precursor myeloid conditions in The MDS Natural History Study.

Amy E DeZern, Nancy Gillis, Michael Otterstatter, Gregory A Abel, Eric Padron, H Joachim Deeg, Tareq Al Baghdadi, Jane Jijun Liu, Zhuoer Xie, Ling Zhang, Lynn C Moscinski, Steven H Kroft, Alexandra M Harrington, James M Foran, Rami S Komrokji, Daniel T Starczynowski, Steven D Gore, Wael Saber, Rafael Bejar, R Coleman Lindsley, Seth Sherman, Cecilia Lee, Nancy L DiFronzo, Matthew J Walter, Mikkael A Sekeres.

Patients at risk for progression from myeloid precursor states (ICUS, CCUS) to MDS are not well defined. Epidemiologic risk factors, clonal changes for MDS development, and evolution from one MDS state to another (lower- (LR) or higher-risk (HR) disease or leukemia [AML]) are available in the MDS NHS, a prospective cohort enrolled at diverse US sites. Extensive clinical data and biospecimens are collected at baseline and follow-up. A total of 1,177(56%) individuals with MDS or MDS-related precursor conditions (ICUS/IDUS, CCUS, and MDS/MPN overlap) were enrolled and diagnosed in the MDS NHS. The median age was 74 years with 89% 60 years of age or older and a majority were male. Median follow-up time was 1.6 years and was similar among ICUS/IDUS, CCUS and MDS. During follow-up period, 68% of participants terminated the study, 35% died, and 38% had disease progression. Using a refined clinical definition of progression, the greatest proportion progression was observed among HR-MDS (116, 73%), followed by LR-MDS (170, 52%); fewer progression events were observed among CCUS (65, 22%) and ICUS/IDUS participants (46, 17%). Predictors of progression are delineated including female sex; higher quantity of mutations; the presence of TP53 mutation and poor/very poor cytogenetic score. Based on this prospective data, guidelines for clinical management including monitoring and surveillance are outlined. The MDS NHS provides real-world data to illustrate how clinical and genotypic differences inform the classification, disease course, and approach to therapy with informed monitoring guidelines for patients. NCT02775383.

DOI: https://doi.org/10.1182/bloodadvances.2025018770
Blood Neoplasia. 2026 Feb;3(1): 100197

FLT3 as a germ line driver in AML: expanding the landscape of leukemia predisposition.

Alok Swaroop, Natasha L Johnson, Michelle C Tophkhane, Courtnee Rodgers, Michelle Pogrebetskaya, Ashwin Koppayi, Salina Dominguez, Eric Padron, Jessica K Altman, Lucy A Godley.

DOI: https://doi.org/10.1016/j.bneo.2026.100197
Blood Cancer Discov. 2026 Feb 11.

Prognostic Model Combining Mutational and Cytogenetic Profiles in Acute Myeloid Leukemia Treated with Venetoclax and Hypomethylating Agents.

Dimitrios Drekolias, Fatima Tuz Zahra, Caroline Fileni, David A Sallman, Qianxing Mo, Onyee Chan, Ling Zhang, Nicole D Vincelette, Xiaoqing Yu, Rinzine Sammut, Jungwon Moon, Junyoung Park, Sura-Attha Umasangtongkul, Felyschia M Lledo, Tiffany N Razabdouski, Chia-Ho Cheng, Dahui Qin, Kathy Mai, Somedeb Ball, Rory M Shallis, Zhuoer Xie, Andrew T Kuykendall, Eric Padron, Kendra Sweet, Alison R Walker, Rami S Komrokji, Jeffrey E Lancet, Sandrine Niyongere, Thomas Cluzeau, Seongseok Yun.

Venetoclax (VEN) combined with hypomethylating agents (HMA) improves outcomes for patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy, yet overall survival (OS) remains variable. We analyzed 506 AML patients treated with front-line HMA/VEN at Moffitt Cancer Center to develop a genetics-based prognostic model. In multivariate analysis, mutations in TP53, KRAS, JAK2, U2AF1, CBL and cytogenetic lesions del(7q)/-7, del(17p)/-17/i(17q), del(20q), and MECOM rearrangements predicted inferior OS, whereas IDH1/2 mutations were favorable. A point-based system stratified patients into low-, intermediate-, and high-risk groups with median OS of 54.2, 22.3, and 7.5 months, respectively, (p<0.0001; C-index 0.648). External validation (n=126) retained prognostic separation (median OS 24.7, 17.4, and 4.3 months, p=0.0005; C-index 0.626). Compared to existing HMA/VEN-specific models, our model demonstrated superior low- vs. intermediate-risk discrimination (31.9-month separation, p=0.002; HR=0.45, p=0.003), with comparable C-index. Our model supports personalized risk stratification for HMA/VEN-treated AML, pending broader validation.

DOI: https://doi.org/10.1158/2643-3230.BCD-25-0193
Ann Hematol. 2026 Feb 09. 105(3): 99

Clinico-genomic characterization of RAS-mutant acute myeloid leukemia.

Robert Yuan, Yiyu Xie, Patricia M Miron, Anne W Higgins, Lloyd Hutchinson, Jan Cerny, Shyam A Patel.

  Somatic mutations within NRAS or KRAS are recurrent in acute myeloid leukemia (AML) and often arise as obligatory late events regarding AML ontogeny. RAS mutations have implications in solid cancers and in AML; however, their prognostic significance and codon-level characteristics are poorly understood, especially regarding response to intensive chemotherapy. There is an unmet need for targeting the RAS pathway. Herein, we performed clinico-genomic profiling of 89 patients with RAS-mutant AML, alongside 99 patients with RAS-wild-type AML. Median overall survival (OS) for RAS-mutant AML was shorter compared to RAS-wild-type AML (19.2 vs. 63.3 months, p = 0.05). For patients receiving cytarabine-based front-line chemotherapy, those with RAS mutations had shorter median OS compared to RAS-wild-type AML (27.1 vs. 122.2 months, p < 0.001). Within the RAS-mutant AML group, cytarabine-based front-line therapy resulted in longer median OS compared to front-line hypomethylating agents (27.1 vs. 13.2 months, p = 0.04). Hematopoietic cell transplantation (HCT) for RAS-mutant AML conferred longer median OS compared to no HCT (45.1 vs. 13.2 months, p = 0.004). There was no difference in survival among heterogeneous RAS-mutant subgroups (NRAS vs. KRAS vs. double-mutant) or among hotspot codons. Analysis of variant allele frequencies suggested that NRAS/KRAS mutations were subclonal. Although 80 (66.1%) of 121 total RAS mutations were found in codons G12 or G13, most substitutions were G12D or G13D, which are not targetable by commercial RASG12C inhibitors. This study sheds light on prognostic implications of RAS mutations and may inform extension of the therapeutic reach of RAS inhibitors to AML.

Keywords:  Acute myeloid leukemia; Genomics; KRAS; Myeloid malignancies; NRAS

DOI:  https://doi.org/10.1007/s00277-026-06843-2
Blood Adv. 2026 Feb 11. pii: bloodadvances.2025016877. [Epub ahead of print]

Conventional Therapy vs HMA or LDAC ± Venetoclax in Older Adults With AML: Systematic Review and Meta-analysis.

Sara Ibrahim, Barbara Burgos-Mansilla, Yetiani Roldan, Maria-Jose Oliveros, Gurleen Bhogal, Gonzalo Bravo-Soto, Mobina Bagherianlemraski, Hamed Movahed, Ruvistay Gutierrez-Arias, Francesca Mulazzani, Tanin Khorrami Taj, Seyed Kaveh Hadeiy, Manahil Qureshi, Saifur R Chowdhury, Rachel Couban, Andrew S Artz, Luke Fletcher, Linda Gilberto, Ryan J Mattison, Mikkael A Sekeres, Romina Brignardello-Petersen.

This systematic review summarizes the evidence informing two recommendations from the updated American Society of Hematology (ASH) guidelines for the treatment of newly diagnosed acute myeloid leukemia (AML) in older adults, comparing conventional induction and post-remission therapy versus hypomethylating agents (HMA)- or low-dose cytarabine (LDAC)-based strategies, with or without venetoclax. We searched MEDLINE, Embase, and Cochrane CENTRAL through February 2024, and monitored these databases for new studies throughout November 2024. We included randomized controlled trials (RCTs) and non-randomized studies (NRS). Reviewers screened studies, extracted data, assessed risk of bias, conducted random-effects meta-analyses, and rated certainty of evidence using GRADE. We included 21 studies (3 RCTs, 18 NRS). Compared with HMA- or LDAC-based monotherapy, conventional 7+3-type remission induction therapy may reduce mortality at longest follow-up (RR 0.94; 95% CI, 0.85-1.04; low certainty), increase complete remission rates (OR 1.75; 95% CI, 1.25-2.38; high certainty), and may reduce recurrence at longest follow-up (RR 0.81; 95% CI, 0.64-1.04; low certainty). Conventional therapies probably increase most severe toxicities (moderate certainty). Compared with HMA or LDAC combined with venetoclax, very low certainty evidence suggests that conventional therapy may reduce 1-year mortality (RR 0.72; 95% CI, 0.60-0.87), increase allogeneic transplant rates (RR 2.28; 95% CI, 1.70-3.06), result in no important differences in complete remission or recurrence, and have variable effects on severe toxicities. Conventional therapy may have benefits over HMA or LDAC alone; however, compared to HMA or LDAC plus venetoclax, the evidence remains of very low certainty.

DOI: https://doi.org/10.1182/bloodadvances.2025016877
Nat Cell Biol. 2026 Feb 11.

Intrinsic and niche-dependent metabolic regulation of haematopoietic stem cells and implications for leukaemogenesis.

Ayşegül Erdem, Claudia Morganti, Haruhito Totani, Nick van Gastel, Keisuke Ito.

Haematopoietic stem cells (HSCs) rely on precisely coordinated metabolic programs to preserve their functionality, adapt to environmental cues, and sustain lifelong haematopoiesis. Here we analyse recent advances in understanding the metabolic landscape of HSCs, emphasizing how their intrinsic bioenergetic programs facilitate quiescence, self-renewal and differentiation. We also summarize the dynamic metabolic interactions with the bone marrow microenvironment, including stromal cells, osteoblasts, endosteal cells and adipose tissue, highlighting how they support proper HSC fate. In addition, we discuss how alterations in metabolic homeostasis in healthy and aged HSCs are linked to haematological disorders, particularly leukaemogenesis. We discuss metabolic dysregulation in leukaemic cells that maintains malignant persistence by mimicking certain intrinsic-extrinsic key HSC metabolic features, while simultaneously activating distinct metabolic pathways to support their growth and survival. Understanding the complex role of metabolism in HSC biology will be essential to advance regenerative medicine and blood cancer prevention strategies.

DOI: https://doi.org/10.1038/s41556-026-01872-5
Nat Commun. 2026 Feb 12. 17(1): 1645

Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice.

Veronica Bergo, Pavlos Bousounis, Giang To Vu, Mélodie Douté, Aikaterini Polyzou, Maria-Eleni Lalioti, Bogdan B Grigorash, Lyudmila Tsurkan, Nicholas Morchel, Ward Deboutte, Frédéric Brau, Thomas Manke, Sagar, Hind Medyouf, Dmitry V Bulavin, Nina Cabezas-Wallscheid, Marta Derecka, Eirini Trompouki.

"Inflammaging", the chronic increase in inflammatory signaling with age, remains poorly understood in hematopoietic aging. Here, we identify the innate immune RNA sensor melanoma differentiation-associated protein 5 (MDA5) as an important factor of hematopoietic stem cell (HSC) aging. Aged Mda5-/- mice exhibit reduced HSC accumulation and myeloid bias. Importantly, aged Mda5-/- HSCs retain greater quiescence and superior repopulation capacity in noncompetitive transplants compared to wild-type counterparts. Multiomic analyses- including chromatin accessibility, transcriptomics, and metabolomics-reveal decreased inflammatory signaling, a youthful metabolic profile, and improved proteostasis in Mda5-/- HSCs, through regulation of HSF1 and phospho-EIF2A, key proteostasis regulators. Activation of HSF1 in aged wild-type HSCs partially restores youthful features, supporting a causal role for proteostasis maintenance. Collectively, our findings demonstrate that attenuating MDA5-dependent inflammation preserves HSC function during aging by maintaining metabolic fitness and proteostasis and provide insight into potential therapeutic strategies for mitigating hematopoietic aging.

DOI: https://doi.org/10.1038/s41467-026-69424-x
J Clin Oncol. 2026 Feb 11. JCO2502083

Pivekimab Sunirine in Blastic Plasmacytoid Dendritic Cell Neoplasm.

Naveen Pemmaraju, Giovanni Marconi, Pau Montesinos, Andrew A Lane, Luca Mazzarella, David A Sallman, Matthew L Ulrickson, Gary J Schiller, Harry P Erba, Eunice S Wang, Roland B Walter, Eric Deconinck, Ahmed Aribi, Ollivier Legrand, Delphine Lebon, Valerio Maisano, Giovanni Martinelli, Daniel J DeAngelo, Enrico Derenzini, Yining Du, Sribalaji Lakshmikanthan, Jalaja Potluri, Hagop M Kantarjian, Naval G Daver.

PURPOSE: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a unique myeloid malignancy with CD123 interleukin-3 receptor-α overexpression and poor prognosis.
METHODS: This phase I/II, open-label, multicenter study evaluated pivekimab sunirine (PVEK), a novel CD123 antibody-drug conjugate, 0.045 mg/kg once every 3 weeks, in adults with frontline (no previous systemic therapy and de novo BPDCN or coexisting hematologic malignancy) or relapsed/refractory BPDCN (ClinicalTrials.gov identifier: NCT03386513) The primary end point in the primary analysis population (PAP; frontline de novo) was composite complete response (CCR; CR+ clinical CR) rate.
RESULTS: Of 84 patients, 33 had frontline BPDCN (22 de novo [20 in PAP]; 11 with previous or concomitant malignancy) and 51 had relapsed/refractory disease. The median (range) age was 72 (63-76) years. In the PAP (n = 20), the CCR rate was 75% (95% CI, 51 to 91; n = 15; median duration: 10.6 [95% CI, 3.8 to not reached] months) and the median overall survival (OS) was 16.6 (95% CI, 7.2 to not reached) months. Eight of these 15 (53%) patients proceeded to stem-cell transplant (SCT). The corresponding rate for relapsed/refractory disease was 14% (95% CI, 6 to 26; n = 7; median duration: 9.2 [95% CI, 2.4 to not reached] months), and the median OS was 5.8 (95% CI, 3.9 to 8.4) months. Adverse events (AEs) included peripheral edema (54%), fatigue (26%), and infusion-related reactions (26%). Grade ≥3 events included neutropenia (16%), thrombocytopenia (14%), and peripheral edema (12%). Serious AEs included pneumonia (6%) and febrile neutropenia (5%). Two on-treatment cases of reversible veno-occlusive disease (VOD) occurred. Of the total 19 patients who proceeded to SCT, VOD was reported in five patients (four with relapsed/refractory BPDCN).
CONCLUSION: PVEK, with convenient dosing, led to high, durable responses, especially in frontline BPDCN, and a manageable safety profile.

DOI: https://doi.org/10.1200/JCO-25-02083
Cell Chem Biol. 2026 Feb 10. pii: S2451-9456(26)00026-7. [Epub ahead of print]

Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis.

Peter Geon Kim, Christopher B Hergott, Aidan P Miller, Amy Deik, Meaghan Boileau, Kevin Bullock, Kerry A Pierce, Angelina H Choy, Wesley Shin, Marie McConkey, Justin Loke, Birgitta A Ryback, Michael N Trinh, Justine C Rutter, Hong Yue, Hojong Yoon, Paul Park, Shourya S Roy Burman, Matthew G Vander Heiden, Eric S Fischer, Scott A Armstrong, Clary Clish, Benjamin L Ebert.

  Somatic mutations in TET2 drive hyper-inflammation in clonal hematopoiesis of indeterminate potential (CHIP), but the molecular link between TET2 inactivation and myeloid immune activation remains unclear. We used in vivo genome-wide genetic perturbations enabled by ultra-diverse barcoding in primary wild-type (WT) or Tet2 knockout (KO) Cas9+ hematopoietic stem-progenitor cells (HSPCs) to elucidate the basis of Tet2 KO inflammation. We uncover a metabolic circuit by which Tet2 restrains O-linked N-acetylglucosamine (O-GlcNAc) glycosyltransferase (Ogt), a Tet2 binding partner and metabolic sensor. Tet2 loss disrupts this inhibitory Tet2-Ogt interaction, and dysregulated Ogt facilitates widespread H3K4 trimethylation including lipid-related gene loci and inflammatory lipid droplet formation. We identified that ATP citrate lyase (Acly) is decorated with O-GlcNAc and is a critical node for lipid accumulation and inflammation in Tet2 KO. These findings reveal that Tet2 suppresses inflammation by gating nutrient-responsive chromatin remodeling and nominate metabolic interventions to restrain inflammatory disease in TET2-mutant clonal hematopoiesis.

Keywords:  Tet2-mutant inflammation; clonal hematopoiesis; hematopoietic stem-progenitor screens; lipid droplets

DOI:  https://doi.org/10.1016/j.chembiol.2026.01.006
Haematologica. 2026 Feb 12.

Intrinsic cellular resistance to BCR::ABL1 inhibitors.

Nataly Cruz-Rodriguez, Yulieth Torres-Llanos, Michael W Deininger.

The clinical implementation of BCR::ABL1 tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) represents one of the big successes of mechanism-based cancer therapy. In 2025, survival of patients who start TKI therapy while in the chronic phase is approaching that of age-matched controls. Despite this paradigm shift, significant challenges remain. Some patients still develop overt TKI resistance and progress to bast phase, and the majority continue to harbor residual leukemia and require life-long TKI therapy. Growth and survival signals arising from the microenvironment or from within the leukemia cells confer various degrees of resistance to support a spectrum of leukemic activity ranging from overt acute leukemia in blast phase to persistence of minimal residual disease in patients with a deep molecular response. Here we review cell-intrinsic resistance, covering both reactivation of BCR::ABL1 kinase activity and the less welldefined mechanisms underlying BCR::ABL1-independent TKI resistance. We propose that the pathways used by CML to escape TKI effects reflect the potential and the constraints of BCR::ABL1- driven reprogramming of hematopoietic stem and progenitor cells and that the role of BCR::ABL1 functions other than kinase activity may be underappreciated, providing a rationale for the clinical development of BCR::ABL1 degraders.

DOI: https://doi.org/10.3324/haematol.2025.287814
Blood. 2026 Feb 11. pii: blood.2025031247. [Epub ahead of print]

Nucleoplasmic ZNF467 condensates boost hematopoietic stem cell engraftment via ICAM1-mediated mechanical reprogramming.

Yandan Chen, Jinghao Shen, Zaisheng Lin, Qingwei Ding, Xiashiyao Zhang, Meng Zhang, Haoxiang Yang, Han Yao, Sheng Liu, Jun Wan, Shize Liu, Xiaopeng Jia, Xiaodong Wang, Uet Yu, Siguo Hao, Muqing Cao, Hongyuan Jiang, Bin Guo.

Hematopoietic stem cell (HSC) transplantation is a life-saving therapy for immune deficiencies and hematologic malignancies, but its efficacy is limited by poor engraftment. Therapeutic enhancement of HSC grafts requires deeper insight into the intrinsic determinants of their regenerative capacity. Here, we identify mechanical robustness as a critical feature distinguishing human HSCs from multipotent progenitors (MPPs). Through integrative biomechanical and transcriptomic profiling, we show that ZNF467 is a key regulator of HSC mechanical integrity. Loss of ZNF467 disrupts HSC mechanical fitness and abolishes long-term engraftment. Conversely, an engineered phase-separating ZNF467 variant enhanced mechanical strength and engraftment by activating a mechanoresponsive transcriptional program, including upregulation of ICAM1. ICAM1+ HSPCs exhibit superior biomechanical properties and improved engraftment efficiency. Furthermore, phase separation activity of nucleoplasmic ZNF467 (npZNF467) is crucial for its mechanical reprogramming function, and ectopic npZNF467 expression enhances the engraftment capacity of MPPs. Our findings establish biomechanical regulation as an important determinant of stem cell identity and reveal new strategies for engineering stem cells with enhanced regenerative capacity.

DOI: https://doi.org/10.1182/blood.2025031247
iScience. 2026 Feb 20. 29(2): 114738

Heritable ER stress impairs mitochondrial metabolism and maintenance of hematopoietic stem cells after low-dose irradiation.

Stephanie G Moreno, Federica Ferri, Daniel Lewandowski, Vilma Barroca, Saiyiramii Devanand, Nathalie Dechamps, Paul-Henri Romeo, Nathalie Gault.

  How hematopoietic stem cells (HSCs) respond to low doses of radiation currently used in medicine is largely unknown. Here, we show that HSC exposed to a single 20 mGy dose of irradiation (20 mGy-HSC) exhibit, when proliferating, oxidative stress and altered metabolism associated with increased mitochondrial reactive oxygen species and mitochondrial Ca2+ overload. These mitochondrial defects arise from immediate and sustained endoplasmic reticulum (ER) stress, induced by proliferative 20 mGy-HSC through the activation of the eIF2α-ATF4 branch of the unfolded protein response (UPR). The ER stress is heritable and leads, in long-term quiescent 20 mGy-HSC, to the activation of the IRE1α-Xbp1 branch of UPR, which fails to restore ER homeostasis, resulting in a decreased long-term HSC pool. Finally, we show that this heritable ER stress leads to global DNA hypomethylation, partially reversed by the early inhibition of ER stress. Our studies illuminate how adaptive ER stress responses can lead to mitochondrial defects and HSC dysfunctions.

Keywords:  Cell biology

DOI:  https://doi.org/10.1016/j.isci.2026.114738
Am J Hematol. 2026 Feb 11.

Intensive Chemotherapy With or Without Midostaurin in Adults ≥ 60 Years Old With FLT3-Mutated AML: A FILO-DATAML-PETHEMA Real-World Study.

Gaspar Aspas Requena, Pau Montesinos, Emilie Bérard, Sarah Bertoli, Rebeca Rodríguez-Veiga, Celestine Simand, Laura Torres, Pierre Peterlin, Mar Tormo, Rudy Birsen, Juan Miguel Bergua-Burgues, Emmanuelle Tavernier, Teresa Bernal Del Castillo, Martin Carré, Cristina Gil, Adrien Contejean, Eduardo Rodríguez-Arbolí, Corentin Orvain, Carlos Rodríguez-Medina, Lauren Veronese, Maria Jose Sayas Lloris, Eric Delabesse, Josefina Serrano, Ariane Mineur, María García-Fortes, Romain Guieze, Maria Luz Amigo, Arnaud Pigneux, Lorenzo Algarra Algarra, Christian Recher, Pierre-Yves Dumas, David Martínez-Cuadrón.

  The addition of midostaurin (MIDO) to intensive chemotherapy (IC) improves survival in younger adults with FLT3-mutated acute myeloid leukemia (AML); however, real-world data in elderly patients (≥ 60 years) are limited. This large, retrospective, multicenter study from three European registries (PETHEMA, FILO, DATAML) evaluated MIDO+IC (n = 194) versus IC alone (n = 371) in 565 patients with FLT3-mutated AML aged ≥ 60 years (median age 67.5 years; 35.6% ≥ 70 years). MIDO+IC was associated with lower day-60 early death (8.2% vs. 21.4%, p < 0.0001) and higher composite complete remission (CRc) rates (78.9% vs. 63.1%, p < 0.0001). After a median follow-up of 46.0 months, median overall survival (OS) was 24.2 months for MIDO+IC versus 8.7 months for IC (p < 0.0001), with 5-year OS rates of 40.6% vs. 12.9%, respectively. Event-free survival (EFS; median 13.5 vs. 4.6 months; 5-year EFS: 36.0% vs. 10.1%) and relapse-free survival (RFS; median 20.2 vs. 8.0 months; 5-year RFS: 45.4% vs. 15.7%) were also significantly improved (both p < 0.0001). The 5-year cumulative incidence of relapse was lower with MIDO+IC (47.8% vs. 67.1%, p < 0.001). In multivariate analyses, midostaurin was an independent favorable prognostic factor for CRc (aOR 1.97 [95% CI: 1.29-2.98]), OS (aHR 0.46 [95% CI: 0.36-0.58]), EFS (aHR 0.49 [95% CI: 0.39-0.60]), and RFS (aHR 0.47 [CI: 0.36-0.62]) (all p ≤ 0.002). These benefits were confirmed by propensity score matching. This large real-world study demonstrates that combining midostaurin with IC significantly improves remission rates and survival outcomes in elderly patients with FLT3-mutated AML, supporting its consideration in this population.

Keywords:  FLT3‐mutated AML; elderly patients; intensive chemotherapy; midostaurin; real‐world data

DOI:  https://doi.org/10.1002/ajh.70233
bioRxiv. 2026 Jan 28. pii: 2026.01.27.702029. [Epub ahead of print]

Leptin Receptor + cells create a perisinusoidal niche for thrombopoiesis in the bone marrow by synthesizing CXCL14.

Yuanyuan Xue, Salma Merchant, Amanda Reyes, Maowu Luo, Ruixuan Zhang, Trevor Tippetts, Gerik Grabowski, Tai Ngo, Yanan Zhang, Zhiguo Shang, Nisi Jiang, Elise Jeffery, Yafeng Li, Tao Wei, Wen Gu, Liming Du, Ralph J DeBerardinis, Kevin M Dean, Thomas P Mathews, Daniel Lucas, Zhiyu Zhao, Sean J Morrison.

Leptin Receptor-expressing (LepR + ) stromal cells in the bone marrow are a critical source of growth factors for the maintenance of hematopoietic stem cells (HSCs) and most restricted hematopoietic progenitors. An important unresolved question is whether they also regulate terminal differentiation in some hematopoietic cells. We found that LepR + cells promote thrombopoiesis by synthesizing the chemokine CXCL14, which is expressed in the bone marrow by a subset of LepR + cells. Cxcl14 -expressing LepR + cells extend fine processes that wrap around perisinusoidal megakaryocytes. Deletion of Cxcl14 from LepR + cells did not significantly alter HSC function or most aspects of bone marrow hematopoiesis, including megakaryocyte generation; however, it significantly reduced the numbers of proplatelet-forming megakaryocytes in the bone marrow and platelets in the blood. CXCL14 promoted platelet formation by remodeling lipid metabolism in megakaryocytes, increasing fatty acid transporter expression and enabling megakaryocytes to use more polyunsaturated fatty acids from the circulation. A high fat diet rescued the formation of proplatelet-forming megakaryocyte and platelets in Lepr-cre; Cxcl14 fl/fl mice. CXCL14 protein was sufficient to promote platelet formation by megakaryocytes in vitro and in vivo. LepR + cells thus create a perisinusoidal niche for thrombopoiesis by producing CXCL14, which regulates lipid metabolism and terminal differentiation in megakaryocytes.
Key points: Leptin Receptor + stromal cells regulate terminal differentiation in megakaryocytes in addition to maintaining stem and progenitor cells CXCL14 from Leptin Receptor + cells promotes the formation of platelets by remodeling lipid metabolism in megakaryocytes in the bone marrow.

DOI: https://doi.org/10.64898/2026.01.27.702029
Elife. 2026 Feb 11. pii: RP104978. [Epub ahead of print]14

Single-cell atlas of AML reveals age-related gene regulatory networks in t(8;21) AML.

Jessica Whittle, Stefan Meyer, Georges Lacaud, Syed Murtuza-Baker, Mudassar Iqbal.

  Acute myeloid leukemia (AML) is characterized by cellular and genetic heterogeneity, which correlates with clinical course. Although single-cell RNA sequencing (scRNA-seq) reflects this diversity to some extent, the low sample numbers in individual studies limit the analytic potential when comparing specific patient groups. We performed large-scale integration of published scRNA-seq datasets to create a unique single-cell transcriptomic atlas for AML (AML scAtlas), totaling 748,679 cells, from 159 AML patients and 51 healthy donors from 20 different studies. This is the largest single-cell data resource for human AML to our knowledge, publicly available at https://cellxgene.cziscience.com/collections/071b706a-7ea7-47a4-bddf-6457725839fc. This AML scAtlas allowed investigations into 20 patients with t(8;21) AML, where we explored the clinical importance of age, given the in-utero origin of pediatric disease. We uncovered age-associated gene regulatory network (GRN) signatures, which we validated using bulk RNA sequencing data to delineate distinct groups with divergent biological characteristics. Furthermore, using an additional multiomic dataset (scRNA-seq and scATAC-seq), we validated our initial findings and created a de-noised enhancer-driven GRN reflecting the previously defined age-related signatures. Applying integrated data analysis of the AML scAtlas, we reveal age-dependent gene regulation in t(8;21) AML, potentially reflecting immature/fetal HSC origin in prenatal origin disease vs postnatal origin. Our analysis revealed that BCLAF1, which is particularly enriched in pediatric AML with t(8;21) of inferred in-utero origin, is a promising prognostic indicator. The AML scAtlas provides a powerful resource to investigate molecular mechanisms underlying different AML subtypes.

Keywords:  AML; AML-ETO; Atlas; age-related disease; cancer biology; computational biology; gene regulatory network; human; single cell; systems biology

DOI:  https://doi.org/10.7554/eLife.104978
Br J Haematol. 2026 Feb 12.

Prevention and management of febrile neutropenia in acute myeloid leukaemia and higher risk myelodysplastic syndrome: An international survey of current practice.

Australasian Leukaemia and Lymphoma Group Supportive Care Working Group and UK AML/Supportive Care Working Parties

  Febrile neutropenia causes substantial morbidity in acute myeloid leukaemia and higher risk myelodysplastic syndrome. We aimed to describe current practice and priorities for clinical trials in the prevention and management of febrile neutropenia across Australia/New Zealand (ANZ), the United Kingdom (UK), Canada and Europe. We performed an international survey of haematologists recruited via professional networks. Eighty-five unique hospitals were represented (ANZ = 20; Canada = 14; UK = 30; Europe = 21). Antibacterial prophylaxis was more commonly prescribed in Canada (79%) and the UK (83%) than in ANZ (30%) and Europe (48%, p < 0.001), and was prescribed more frequently to outpatients than inpatients. The most common empiric treatment was piperacillin-tazobactam monotherapy (66/84, 79%), with nurse-initiated antibiotic orders used in 35/84 (42%). Screening for multidrug-resistant organisms varied and was not usually used to direct antibiotic treatment. Antibiotic de-escalation was attempted in most institutions; for uncomplicated short-lived fever of unknown source, 39/85 (46%) reported ceasing antibiotics at 72 h and 68/85 (80%) within 7 days. For patients with bacteraemia, de-escalation strategies included narrowing spectrum, oral switch and cessation after defined duration. Most respondents (79/85, 93%) reported interest in recruiting for clinical trials. Clinical trials addressing practice variability in febrile neutropenia are needed, and are supported by haematologists.

Keywords:  antibiotics; febrile neutropenia; infection; prophylaxis; survey of practice

DOI:  https://doi.org/10.1111/bjh.70358
Sci Signal. 2026 Feb 10. 19(924): eadw5054

Dynamic feedback control of oncogenic tyrosine kinase signaling in acute leukemia.

Jaewoong Lee, Ruifeng Sun, Kohei Kume, Mark E Robinson, Zhangliang Cheng, Kadriye Nehir Cosgun, Ning Ma, Christian Hurtz, Huimin Geng, Selina M Luger, Mark R Litzow, Elisabeth Paietta, Jianjun Chen, Nagarajan Vaidehi, Markus Müschen.

CD25 is a subunit of the interleukin-2 (IL-2) receptor on T cells and natural killer (NK) cells. Acute leukemias with oncogenic tyrosine kinases often include CD25+ leukemia subpopulations, which portend poor clinical outcomes for patients; however, acute leukemia cells do not respond to IL-2. Here, we identified CD25 and its phosphorylation by protein kinase Cδ (PKCδ) as central elements of a feedback loop that stabilized fluctuations in oncogenic tyrosine kinase signaling in acute lymphoblastic and myeloid leukemia. Genetic ablation of CD25 in murine and patient-derived xenograft (PDX) models of acute leukemias reduced clonal fitness, colony formation, and leukemia-initiation capacity in serial transplant recipients. Oncogenic tyrosine kinase signaling in leukemia cells stimulated NF-κB-mediated CD25 expression, whereas PKCδ-mediated phosphorylation of CD25 suppressed oncogenic tyrosine kinase signaling through inhibitory phosphatases, such as PTPN6. Interactome analyses and mass spectrometry-based global phosphoproteomic analyses showed that CD25 deletion abolished the phosphatase activity of PTPN6, resulting in enhanced activation of tyrosine kinases and NF-κB. Four injections of a CD25 antibody-drug conjugate induced complete remission in mice transplanted with PDX refractory leukemia. These findings highlight the dependency of tyrosine kinase-driven leukemias on robust feedback control and the role of PKCδ and CD25 in assembling its components.

DOI: https://doi.org/10.1126/scisignal.adw5054