bims-tremyl 2026-01-25 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2026–01–25
twenty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Single-cell proteogenomic analysis of clonal evolution in PDX models of AML treated with IDH inhibitors.
Immunomodulatory role of megakaryocytes in the hematopoietic niche of myeloproliferative neoplasms.
Impact of Mutational Landscape and Burden on RBC Transfusion Response in Patients With Lower-Risk Myelodysplastic Syndromes (LR-MDS) in the COMMANDS Study.
Highly effective combination of BRG1/BRM inhibitor with BET inhibitor or decitabine for high-risk MECOM-rearranged AML.
Mmrn1 expression defines a novel subset of hematopoietic stem cells and leukemia stem cells with great self-renewal potential.
SKIDA1 sustains MLL::ENL-expressing hematopoietic progenitors during neonatal stages and promotes B-lineage priming.
PRDM16 expression is an independent prognostic factor in AML with the double-mutant NPM1/FLT3-ITD genotype.
Metabolic profiling of measurable residual disease (MRD) in APL: Do MRD cells retain PML::RARα-mediated long-chain fatty acid (LCFA) dependency?
Prognostic value of anemia plus thrombocytopenia in primary myelofibrosis.
ELK1 promotes the progress of myeloid leukemia by hindering the differentiation of neutrophils.
Treatment-free remission after two nilotinib consolidation durations in chronic myeloid leukemia treated with imatinib: Phase 3 ENESTPath results.
Impact of autoimmune diseases or inflammatory manifestations on response and outcome in high-risk myelodysplastic syndromes and chronic myelomonocytic leukemia.
Regulatory role of mTORC1 signaling in osteoblasts in acute myeloid leukemia progression and steady-state hematopoiesis.
Imetelstat improves patient-reported outcomes and quality of life in lower-risk myelodysplastic syndromes: results from the phase III IMerge study.
Red blood cell immunization as an independent predictor of survival in the myelodysplastic syndromes.
Multiomic characterization, early detection, and therapeutic targeting of myeloid sarcoma.
Sequential therapy with allogeneic HCT in patients aged ≥70 years with active AML: a singlecenter retrospective analysis.
Rps19R67∆ mutation creates a model of Diamond-Blackfan anemia and reveals downstream mediators of p53 pathway.
Sequence-dependent splicing dysregulation drives therapy resistance in pediatric AML.
Distal enhancer RNAs regulate alternative promoter usage of MYB and drug resistance in human leukemia cells.
TET1 as a master regulator controlling GPX4-dependent and -independent ferroptosis surveillance in acute myeloid leukemia.

Blood Neoplasia. 2026 Feb;3(1): 100182

Single-cell proteogenomic analysis of clonal evolution in PDX models of AML treated with IDH inhibitors.

Alex C H Liu, Severine Cathelin, Dhanoop Manikoth Ayyathan, Yitong Yang, Farzaneh Aboualizadeh, Amina Abow, Gurbaksh Basi, Lance Li, David L Dai, Abdula Maher, Eric Grignano, Mohsen Hosseini, Vivian Wang, Troy Ketela, Brandon Nicolay, Dylan M Marchione, Adriana E Tron, Andrea Arruda, Mark D Minden, Steven M Chan.

Clonal heterogeneity in acute myeloid leukemia (AML) can drive drug resistance because different clones may respond variably to treatments. Studying the evolution of these clones under the influence of therapeutic selective pressures is important for designing strategies to overcome drug resistance. Here, we used single-cell proteogenomic analysis to monitor the clonal evolution and differentiation of isocitrate dehydrogenase (IDH)-mutated AML in patient-derived xenografts (PDX) treated with IDH inhibitors alone or in combination with other antileukemic therapies. Furthermore, we generated mixed PDX models by coengrafting ≥2 leukemic samples into the same animal and used single-cell DNA sequencing to deconvolute their clonal composition. Using these models, we tracked clonal evolution under selective pressure from IDH inhibitors and combination therapies, identifying an association between WT1 mutations and ivosidenib (IDH1 inhibitor) monotherapy resistance, as well as an antagonism between ivosidenib and enasidenib (IDH2 inhibitor) when tested in IDH1-mutated cells. Our findings demonstrate how single-cell proteogenomic analysis of PDX models can illuminate drug resistance mechanisms and inform therapeutic strategies.

DOI: https://doi.org/10.1016/j.bneo.2025.100182
Haematologica. 2026 Jan 22.

Immunomodulatory role of megakaryocytes in the hematopoietic niche of myeloproliferative neoplasms.

Xiaoxi Yang, Sandy Lee, Kyla Masarik, Tameena Ahmed, Lei Zheng, Huichun Zhan.

Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by dysregulated megakaryopoiesis and expansion of neoplastic hematopoietic stem cells (HSCs). Megakaryocytes (MKs) not only regulate HSC function but also shape immune responses within the marrow niche. Using an aging murine model of MPN with MK-restricted JAK2V617F expression, we investigated the immunomodulatory roles of mutant MKs. Compared to wild-type MKs, aged mutant MKs exhibit enhanced antigen uptake and MHC I presentation, secretion of pro-inflammatory cytokines (PF4, TGFβ, IL-1β), and induction of T cell dysregulation in the marrow niche. In chimeric murine models with co-existing wild-type and JAK2V617F mutant hematopoietic cells, enhanced MK immune activity correlates with mutant cell expansion and MPN development. Single-cell RNA sequencing revealed that aging amplifies JAK2V617F MK-driven immune remodeling. Notably, aged mutant MKs showed marked upregulation of LINE-1 (long-interspersed element-1) retrotransposon transcripts alongside elevated innate immune sensors cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), implicating retrotransposon activity in niche inflammation. In human MPN marrow, immunohistochemistry detected LINE-1-encoded protein ORF1p in MKs from 12 of 13 MPN patients, but not in orthopedic controls (n=5). These findings identify MKs as active immune regulators in MPNs, with JAK2V617F mutation and aging synergizing to reprogram MKs into inflammatory, immunemodulatory niche cells. LINE-1 activation emerges as a potential driver of chronic marrow inflammation and a targetable mechanism in clonal hematopoiesis and MPN progression.

DOI: https://doi.org/10.3324/haematol.2025.288948
Am J Hematol. 2026 Jan 19.

Impact of Mutational Landscape and Burden on RBC Transfusion Response in Patients With Lower-Risk Myelodysplastic Syndromes (LR-MDS) in the COMMANDS Study.

Rami S Komrokji, Sheida Hayati, Manuel Ugidos, Guillermo Garcia-Manero, Matteo Giovanni Della Porta, Amer M Zeidan, Valeria Santini, Uwe Platzbecker, Anita K Gandhi, Rajasekhar N V S Suragani.

  The COMMANDS trial established luspatercept as a first-line treatment for anemia in transfusion-dependent lower-risk (LR) myelodysplastic syndromes (MDS). Here we report red blood cell (RBC) transfusion response analysis based on somatic mutations profile and disease risk for patients treated with luspatercept or epoetin alfa in the COMMANDS trial. Of 350 evaluable patients, 238 (68.0%) had MDS with multiple lineage dysplasia and ring sideroblasts (RS) according to World Health Organization 2016 criteria, and 320 (91.4%) had somatic mutations in ≥ 1 gene (median, 2) with median variant allele frequencies (VAF) of 2%-59%. Mutation profiles were similar in the treatment groups. Luspatercept had superior responses versus epoetin alfa across multiple mutations (risk difference; RD, [95% confidence interval; CI] 0.25 [0.15-0.35]), including in SF3B1-mutated (0.38 [0.25-0.50]) and SF3B1 wild-type (0.09 [-0.11 to 0.30]). Luspatercept demonstrated superior responses in patients with VAF ≥ 10% (random effect, 0.36 [95% CI, 0.28-0.44]), and in those with 1 (63% vs. 40%; p = 0.040), 2 (70% vs. 27%; p < 0.001), and 3 (72% vs. 40%; p = 0.018) mutations, and across the low (75% vs. 38%), moderate low (61% vs. 38%), moderate high (44% vs. 21%), and high (36% vs. 24%) Molecular International Prognostic Scoring System risk groups (summary effect RD, 0.26 [95% CI, 0.14-0.37]). Across most mutations luspatercept responses were superior (random effect, 0.34 [95% CI, 0.24-0.44]) in patients with RS but were similar between treatments in RS-negative patients. Luspatercept represents an effective treatment option in various mutational backgrounds in LR MDS. Trial Registration: ClinicalTrials.gov Identifier: NCT03682536.

Keywords:  ineffective erythropoiesis; luspatercept; mutational landscape; myelodysplastic syndrome; red cell transfusion burden

DOI:  https://doi.org/10.1002/ajh.70171
Hemasphere. 2026 Jan;10(1): e70289

Highly effective combination of BRG1/BRM inhibitor with BET inhibitor or decitabine for high-risk MECOM-rearranged AML.

Warren Fiskus, Christopher P Mill, Jessica Piel, Mike Collins, Murphy Hentemann, Branko Cuglievan, Christine E Birdwell, Kaberi Das, John A Davis, Hanxi Hou, Antrix Jain, Anna Malovannaya, Lauren B Flores, Tapan M Kadia, Naval Daver, Koji Sasaki, Koichi Takahashi, Danielle Hammond, Jian Wang, Sanam Loghavi, Xiaoping Su, Courtney D DiNardo, Ruud Delwel, Kapil N Bhalla.

In AML with 3q26.2 rearrangements (r) the distal GATA2 hematopoietic enhancer becomes aberrantly relocated leading to activation of EVI1 expression. EVI1 is a transcriptional regulator that plays a role in proliferation and maintenance of a stem cell-like phenotype in AML. BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive ATPases of the BAF (BRG1/BRM-associated factor) chromatin remodeling complexes. They regulate access to enhancers/promoters and gene-expressions orchestrating AML stem/progenitor cell proliferation and differentiation. AML with 3q26.2 rearrangements are clinically challenging and prognosis remains very poor. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induced differentiation and lethality in AML cells with MECOM-r, perturbed chromatin accessibility and depleted expression of EVI1, c-Myc, CD44 and CDK4. Co-treatment with FHD-286 and decitabine, BET inhibitor (BETi) or HAT inhibitor synergistically induced in vitro lethality in patient-derived AML cells with MECOM-r. In patient-derived xenograft (PDX) models of AML with MECOM-r, compared to each drug alone, co-treatment with FHD-286 and BETi OTX015 significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with chromosome 3q26.2 rearrangement and EVI1 overexpression.

DOI: https://doi.org/10.1002/hem3.70289
Haematologica. 2026 Jan 22.

Mmrn1 expression defines a novel subset of hematopoietic stem cells and leukemia stem cells with great self-renewal potential.

Naicheng Chen, Lijing Yang, Fang Chen, Hao Zeng, Xiaoyi Zhong, Yanying Liu, Zijin Chen, Mengying Yao, Yukai Lu, Mingqiang Shen, Mo Chen, Yang Xu, Song Wang, Xi Zhang, Junping Wang, Mengjia Hu.

Hematopoietic stem cells (HSCs) are critical for lifelong blood cell generation. After mutation accumulation and functional disruption, HSCs may transform into leukemic stem cells (LSCs), leading to malignant hematological disorders. However, both HSCs and LSCs are highly heterogeneous, which hinders our comprehensive understanding of their biological characteristics and clinical application. Here, we identified multimerin 1 (Mmrn1) as a reliable marker for the most primitive HSCs and LSCs. We found that Mmrn1 was abundantly present in human and mouse HSCs. Interestingly, HSCs with high levels of Mmrn1 displayed increased quiescence and regenerative capacity, accompanied by megakaryocytic lineage commitment. Importantly, Mmrn1 deficiency gradually impairs HSC self-renewal under stress of transplantation due to reduced quiescence. Additionally, we noticed that Mmrn1 was specifically upregulated in acute myeloid leukemia (AML) cells, and its overexpression predicted poor patient prognosis. Further investigation revealed that Mmrn1 marked a subset of quiescent LSCs responsible for AML initiation and development, and that deletion of Mmrn1 delays AML progression. Collectively, these data broaden our knowledge of stem cell heterogeneity in the context of normal and malignant hematopoiesis and advance the precision diagnosis and therapy of AML in the clinic.

DOI: https://doi.org/10.3324/haematol.2025.287609
Blood Neoplasia. 2026 Feb;3(1): 100185

SKIDA1 sustains MLL::ENL-expressing hematopoietic progenitors during neonatal stages and promotes B-lineage priming.

Jonny Mendoza-Castrejon, Wei Yang, Elisabeth Denby, Rohini Muthukumar, Emily B Casey, Riddhi M Patel, Sarah K Tasian, Jeffrey A Magee.

Infant leukemias arise as B-cell acute lymphoblastic or acute myeloid leukemia. Most are driven by chromosomal rearrangements of the MLL/KMT2A gene (MLLr) and arise in utero, implying a fetal cell of origin. Fetal and neonatal hematopoietic progenitors have unique transcriptomes and epigenomes, raising the question of whether MLL fusion proteins activate distinct target genes during these early stages of life. In this study, we used a transgenic mouse model of MLL::ENL-driven leukemia to identify Skida1 as a target gene that is more highly induced in fetal and neonatal progenitors than in adult progenitors. SKIDA1 is highly expressed in human MLLr leukemias, and the encoded protein associates with the polycomb repressive complex 2. We show that Skida1 is dispensable for normal hematopoiesis, but it promotes B-cell priming and maintains MLL::ENL-expressing hematopoietic stem cells (HSCs) and multipotent progenitor cells during neonatal development. Conditional deletion of Skida1 has no effect on normal HSC function, yet it impairs B-cell production from neonatal MLL::ENL-expressing HSCs while leaving myeloid leukemogenesis unaffected. Temporally restricted targets of MLL fusion proteins, such as SKIDA1, can therefore tune cell fates at different ages, potentially influencing the types MLLr leukemias that arise at different ages.

DOI: https://doi.org/10.1016/j.bneo.2025.100185
Ann Hematol. 2026 Jan 22. 105(2): 49

PRDM16 expression is an independent prognostic factor in AML with the double-mutant NPM1/FLT3-ITD genotype.

Sebastian Stasik, Jan-Niklas Eckardt, Christoph Röllig, Claudia D Baldus, Hubert Serve, Carsten Müller-Tidow, Kerstin Schäfer-Eckart, Martin Kaufmann, Stefan W Krause, Mathias Hänel, Andreas Neubauer, Gerhard Ehninger, Uwe Platzbecker, Martin Bornhäuser, Johannes Schetelig, Jan M Middeke, Christian Thiede.

  PRDM16 (PR Domain Containing 16) is a transcription factor that plays a critical role in hematopoietic stem cell maintenance. In acute myeloid leukemia (AML), PRDM16 overexpression is linked to specific cytogenetic risk groups and poor prognosis. However, in NPM1-mutated AMLs, PRDM16 expression varies widely, with no consensus on its prognostic significance. To understand molecular and clinical associations of PRDM16 expression in this relevant subgroup, we screened 503 adult NPM1-mutant AML patients. High PRDM16 expression was associated with mutations in DNMT3A (57% vs 22%; p < 0.0001) and FLT3-ITD (51% vs 37%; p = 0.0258), and therefore a higher rate of ELN2022 intermediate-risk (42% vs 26%; p = 0.01), compared to low PRDM16 expression. Accordingly, PRDM16 overexpression was not associated with clinical outcome in multivariable analysis adjusting for ELN2022 risk in the unselected NPM1-mutant AML cohort. However, within the double-mutant NPM1/FLT3-ITD subgroup (n = 200), low PRDM16 expression was an independent prognostic factor for longer survival (hazard ratio [95%-CI] 0.467 [0.270-0.807]; p = 0.006). On a molecular level, low PRDM16 expression was associated with mutations in epigenetic regulators (TET2, IDH1/2) and increased PRDM16 promoter methylation, suggesting impaired TET/IDH-mediated DNA-demethylation as underlying mechanism. Notably, IDH1 R132C and IDH2 R140Q alterations particularly contributed to higher PRDM16 promoter methylation and reduced expression. These results suggest an association of PRDM16 overexpression with the NPM1/FLT3-ITD/DNMT3A triple-mutant AML genotype, typically linked to high leukemia stem cell frequencies and poor prognosis. Importantly, within this adverse AML subtype low PRDM16 expression is an independent prognostic marker for favorable outcome, supporting an anti-leukemic mechanism in AMLs with repressed PRDM16 transcription.

Keywords:   PRDM16 expression; Acute Myeloid Leukemia (AML); Clinical Outcome; Molecular associations

DOI:  https://doi.org/10.1007/s00277-026-06767-x
Leukemia. 2026 Jan 22.

Metabolic profiling of measurable residual disease (MRD) in APL: Do MRD cells retain PML::RARα-mediated long-chain fatty acid (LCFA) dependency?

Yu Zheng, Fangyi Dong.

DOI: https://doi.org/10.1038/s41375-025-02837-7
Leukemia. 2026 Jan 22.

Prognostic value of anemia plus thrombocytopenia in primary myelofibrosis.

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

DOI: https://doi.org/10.1038/s41375-026-02860-2
Exp Hematol Oncol. 2026 Jan 20. 15(1): 9

ELK1 promotes the progress of myeloid leukemia by hindering the differentiation of neutrophils.

Yuhan He, Ya Zhou, Dexin Wen, Rongqun Guo, Juan Du, Sizhou Huang, Yong Dong.

   BACKGROUND: The genes controlling lineage determination and differentiation tend to be essential for the development of acute myeloid leukemia (AML). Identifying novel target genes capable of promoting the differentiation and maturation of undifferentiated leukemia cells offers a promising therapeutic strategy for the treatment of AML.
METHODS: We used conditional Elk1 and KrasG12D expression mice, along with Mx1-Cre, Lyz2-Cre and Elane-Cre drive strains (which enable stage specific control of Elk1 or KrasG12D expression), to investigate the function of Elk1 in the hematopoiesis and leukemogenesis. Bone marrow transplantation assay was performed to explore the function of Elk1 in hematopoiesis under stress conditions. Additionally, bulk-cell RNA sequencing, single-cell RNA sequencing and proteomics were performed to reveal the signaling pathways altered by Elk1. Finally, undifferentiated leukemia cells were used to verify whether inhibiting ELK1 could promote the differentiation of these cells into mature neutrophils.
RESULTS: ELK1 is highly expressed in undifferentiated AML cells. Studies using mouse model demonstrated that overexpression of Elk1 accelerates the development of KrasG12D-induced myeloid leukemia by impairing the stemness of hematopoietic stem cells (HSCs) and impeding the differentiation of neutrophils. Furthermore, impeding the maturation of neutrophils independently promotes the development of KrasG12D mutation-induced myeloid leukemia. Meanwhile, our in vitro experiments preliminarily confirmed that inhibiting ELK1 suppresses the proliferation of leukemia cells and induces the differentiation of CD15+CD66b- myeloid progenitor cells into CD15+CD66b+ neutrophils.
CONCLUSIONS: Our study demonstrates that ELK1 is a potential therapeutic target for AML, due to its critical role in regulating neutrophils differentiation.

Keywords:  ELK1; Hematopoiesis; Leukemogenesis; Myeloid leukemia; Neutrophil depletion

DOI:  https://doi.org/10.1186/s40164-025-00742-4
Leukemia. 2026 Jan 19.

Treatment-free remission after two nilotinib consolidation durations in chronic myeloid leukemia treated with imatinib: Phase 3 ENESTPath results.

Delphine Rea, Slawomira Kyrcz-Krzemien, Paolo Sportoletti, Jiří Mayer, Arpad Illes, Anna Angona Figueras, Alexander Kiani, Aude Charbonnier, Theodoros Marinakis, Leif Stenke, Juan Luis Steegmann, Giuseppe Saglio, Andrzej Hellmann, Dietger Niederwieser, Peter Schuld, Gianantonio Rosti.

The phase 3 ENESTPath study investigated treatment-free remission (TFR) rates in patients with chronic Philadelphia chromosome-positive (Ph+) and/or BCR::ABL1+ chronic myeloid leukemia who had not achieved deep molecular response (DMR) after >2 years of imatinib treatment and were switched to nilotinib 300 mg twice daily (BID). After 24 months of treatment, patients with a stable DMR were randomized to either enter the TFR phase (Arm 1) or continue nilotinib consolidation for an additional 12 months and then enter the TFR phase if in stable DMR (Arm 2). The primary endpoint was the proportion of patients who remained in TFR (≥MR4.0 [BCR::ABL1IS ≤ 0.01%]) without molecular relapse at the end of 12 months. Of the 620 patients enrolled, 239 (38.5%) achieved stable MR4.0 and were randomized to Arm 1 (n = 120) or Arm 2 (n = 119). In the TFR phase, MR4.0 rates at 12 months (Arm 1: 31.9%, Arm 2: 37.5%; p = 0.383) and 24 months (Arm 1: 29.4%, Arm 2: 30.8%) revealed no differences in TFR success between 2 and 3 years of nilotinib. Irrespective of the consolidation duration, switching to nilotinib 300 mg BID provided the opportunity to achieve TFR if patients were unable to reach stable DMR with first-line imatinib.

DOI: https://doi.org/10.1038/s41375-025-02847-5
Leuk Res. 2026 Jan 16. pii: S0145-2126(26)00012-3. [Epub ahead of print]161 108168

Impact of autoimmune diseases or inflammatory manifestations on response and outcome in high-risk myelodysplastic syndromes and chronic myelomonocytic leukemia.

Rinzine Sammut, Antoine Benichou, Chen Wang, Michael Loschi, Sami Benachour, Valentine Richez-Olivier, Edmond Chiche, Rami Komrokji, Corinne Ferrero-Vacher, Neila De Pooter, Joy Mouanes-Abelin, Bérengere Dadone-Montaudie, David A Sallman, Thomas Cluzeau.



Keywords:  AIM; AZA; CMML; MDS

DOI:  https://doi.org/10.1016/j.leukres.2026.108168
iScience. 2026 Jan 16. 29(1): 114533

Regulatory role of mTORC1 signaling in osteoblasts in acute myeloid leukemia progression and steady-state hematopoiesis.

Kazuya Fukasawa, Kazuya Tokumura, Makoto Yoshimoto, Koki Sadamori, Ioanna Mosialou, Yoshiaki Harakawa, Kazuto Isawa, Shohei Tsuji, Haruhiko Inufusa, Atsushi Hirao, Stavroula Kousteni, Eiichi Hinoi.

  Acute myeloid leukemia (AML) is widely recognized for its intrinsic leukemic-cell-driven regulation as well as its extrinsic niche-driven regulation. Despite mounting evidence that bone-forming osteoblasts provide an endosteal niche for AML cells, the precise mechanism remains to be elucidated. The cell-autonomous mammalian target of rapamycin complex 1 (mTORC1) is involved in the onset and progression of AML. Here, we found that mTORC1 signaling was activated in the osteoblasts of an AML murine model and clinical AML specimens. Osteoblast-specific mTORC1 activation in mice promotes AML growth, whereas mTORC1 inactivation suppresses it. Interleukin-6 (IL-6) was identified through screening as a downstream factor in mTORC1-regulated AML progression. Genetic ablation of the IL-6 receptor in AML cells significantly attenuated AML growth in osteoblast-specific mTORC1-activated mice. Collectively, our results suggest that the mTORC1/IL-6 axis in osteoblastic niche non-autonomously contributes to the AML progression, suggesting a viable therapeutic target for AML.

Keywords:  cancer; cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.114533
Haematologica. 2026 Jan 22.

Imetelstat improves patient-reported outcomes and quality of life in lower-risk myelodysplastic syndromes: results from the phase III IMerge study.

Mikkael A Sekeres, Amer M Zeidan, Valeria Santini, Rami S Komrokji, Pierre Fenaux, Michael R Savona, Yazan F Madanat, David Valcárcel, Antoine Regnault, Kristin Creel, Libo Sun, Ying Wan, Shyamala Navada, Tymara Berry, Faye Feller, Uwe Platzbecker, María Díez-Campelo, Esther Natalie Oliva.

Red blood cell (RBC) transfusions for anemia associated with lower-risk myelodysplastic syndromes/neoplasms (LR-MDS) often contribute to reduced quality of life (QOL). Thus, reduction in RBC transfusion dependency (TD) is a primary therapeutic goal. Imetelstat is a firstin-class, competitive telomerase inhibitor approved to treat certain adult patients with LR-MDS with RBC-TD anemia who have not responded to, have lost response to, or are ineligible for erythropoiesis-stimulating agents. In the phase III IMerge study (NCT02598661), treatment with imetelstat resulted in clinically meaningful, statistically significant increases in the primary endpoint of ≥8-week RBC transfusion independence (TI) versus placebo. Because patients with LR-MDS experience detrimental effects on numerous facets of QOL (physical, emotional, social, and functional), these exploratory analyses assessed patient-reported outcomes using the Functional Assessment of Chronic Illness Therapy-Fatigue, Quality of Life in Myelodysplasia Scale, and Functional Assessment of Cancer Therapy-Anemia questionnaires as part of the phase III IMerge study. Nominal P values were reported. Fewer imetelstat-treated patients experienced deterioration in fatigue and more imetelstat-treated patients experienced sustained improvement in fatigue and QOL versus placebo. In the imetelstat group, 8-week, 24-week, and 1-year RBC-TI responders had sustained improvements in predefined significance thresholds versus nonresponders for fatigue (70%, 73%, and 88%, respectively, vs. 37%, 41%, and 44%, respectively; P.

DOI: https://doi.org/10.3324/haematol.2025.288956
Br J Haematol. 2026 Jan 20.

Red blood cell immunization as an independent predictor of survival in the myelodysplastic syndromes.

Alexandra Pedraza, Sandra Castaño, Arturo Pereira, Meritxell Nomdedeu, Carlos Ruiz, Marc Esteva, Marina Díaz-Beya, Cristina Sanz.

  Despite red blood cell (RBC) immunization being a frequent complication of chronic transfusion in myelodysplastic syndromes (MDS), its prognostic significance remains unclear. We analysed 486 transfused patients diagnosed with MDS. Prognostic impact of RBC immunization (allo- or autoantibodies) was evaluated as a time-dependent covariate. Competing risk methods were applied to estimate the cumulative incidence of immunization. Sixty-nine patients (14.2%) developed RBC immunization, most commonly anti-K and anti-E, which was more frequent in patients transfused before MDS diagnosis (subhazard ratio [SHR]: 2.9, 95% confidence interval [CI]: 1.6-5.4; p = 0.001) and Rh(D)-negative blood group (SHR: 1.9, 95% CI: 1.1-3.2; p = 0.026). RBC immunization was associated with a significant and independent reduction in remaining survival (hazard ratio: 11.9, 95% CI: 7.3-19.6; p = 0.001), without differences between auto- and alloantibodies. RBC immunization was followed by increased transfusion intensity, but transfusion requirements also rose in non-immunized patients over time. RBC immunization did not predict progression to acute myeloid leukaemia (AML). A trend towards fewer new antibodies was observed during hypomethylating therapy. RBC immunization is independently associated with reduced survival in transfusion-dependent patients with MDS, irrespective of AML progression. These findings highlight the potential prognostic relevance of RBC antibodies and call for further investigation into the mechanisms linking immunization, transfusion burden and survival outcomes.

Keywords:  alloimmunization; blood transfusion; myelodysplastic syndromes; prognosis; survival

DOI:  https://doi.org/10.1111/bjh.70330
bioRxiv. 2025 Dec 05. pii: 2025.12.04.689069. [Epub ahead of print]

Multiomic characterization, early detection, and therapeutic targeting of myeloid sarcoma.

Bettina Nadorp, Audrey Lasry, Sanam Loghavi, Ravi Patel, Hager Mansour, Benjamin J Kelly, Christopher J Walker, Jill Buss, Isaiah Boateng, Wafa Al-Santli, Zoe Ciantra, Rebecca Austin, Adrienne Heyrosa, Helee Desai, Andrea Laganson, Hasan Abaza, Linda Procell, Tejas Patel, Benjamin Kaffenberger, Saranga Wijeratne, Maria Guillamot, Maria Velegraki, Luis Chiriboga, Zihai Li, Lynne V Abruzzo, Daniel A Pollyea, Christine McMahon, Arwa Shana'ah, John C Byrd, Alan Shih, Ross L Levine, Eirini P Papapetrou, Aristotelis Tsirigos, Elaine R Mardis, Alice S Mims, Iannis Aifantis, Ann-Kathrin Eisfeld.

Myeloid sarcoma, an aggressive extramedullary subtype of acute myeloid leukemia (AML), occurs in ∼10% of patients, and has not yet been included in large-scale genomic studies. The critical biological changes that drive tumor evolution are unknown, its detection in asymptomatic patients remains a clinical challenge, and treatment options are limited as patients are often excluded from clinical trials, rendering it a neglected disease entity. Based on comprehensive multi-omic profiling, we demonstrate that myeloid sarcoma evolves from medullary AML with distinct sitespecific clonal evolution patterns. Additionally, we show that circulating tumor DNA sequencing can serve as a non-invasive method for molecular profiling of myeloid sarcoma, offering a novel avenue in molecular diagnostics. We characterize unique transcriptional profiles of myeloid sarcoma, reflecting immune evasion and adaptation to an extramedullary microenvironment. We provide evidence for a key role of RAS pathway activation and demonstrate in murine models of myeloid sarcoma that RAS inhibition effectively reduces tumor burden. Overall, our data highlight key differences between medullary AML and myeloid sarcoma including universal molecular evolution and RAS pathway activation as hallmarks of the disease and nominate RAS inhibition as a promising therapeutic strategy for patients with myeloid sarcoma.

DOI: https://doi.org/10.64898/2025.12.04.689069
Haematologica. 2026 Jan 22.

Sequential therapy with allogeneic HCT in patients aged ≥70 years with active AML: a singlecenter retrospective analysis.

Odelia Amit, Gil Fridberg, Yakir Moshe, Inna Ospovat, Yehonatan Sherf, Dina Tshernichovsky, Chen Karni, Irit Avivi, Ron Ram.

Patients ≥ 70 years with relapsed/refractory acute myeloid leukemia (AML) have an extremely poor prognosis. we adopted a sequential therapy approach, aiming to proceed directly to allogeneic hematopoietic cell transplantation (HCT) despite active disease. We analyzed results of all consecutive patients aged over 70 years and diagnosed with primary refractory/relapsed AML who underwent HCT with sequential therapy approach (FITCy regimen) in the Aviv Sourasky Medical Center. 51 patients (median age 72 years, primary refractory, n=42/relapse, n=9). Median follow-up was 35 (range, 12-91) months. Incidences of overall and grade 3-4 acute GVHD were 39.2% (95% CI, 25.6-52.8%), and 5.9% (95% CI, 0.0-12.5%), respectively. Incidences of overall and moderate-severe chronic GVHD were 40.0% (95% CI, 25.7%-57.1%) and 29.4% (95% CI, 13.2%-46.9%), respectively. Non-relapse mortality at 3 years was 36% (95%CI 22%-49%).42/51 patients (82.4%) had CR on d+30 post HCT. Relapse incidence at 3 years was 27.8% (95% CI 14.3%-41.2%). GVHD-free relapse-free and overall survival (OS) at 3-years were 30% (95%CI 19%-47%) and 31% (95% CI 17%-55%), respectively. Multivariable analysis showed that worse ELN-2022 score, relapsed AML (vs. primary-refractory), not receiving ATG, and lower albumin prior to conditioning, were associated with higher mortality. We developed a model to predict OS that showed median OS in the low-, intermediate-, and high-risk group, not reached, 32.9 months, and 2.1 months, respectively, p.

DOI: https://doi.org/10.3324/haematol.2025.300184
Hemasphere. 2026 Jan;10(1): e70302

Rps19R67∆ mutation creates a model of Diamond-Blackfan anemia and reveals downstream mediators of p53 pathway.

Juraj Kokavec, Tereza Turková, Björn Schuster, Jan Prochazka, František Spoutil, Kristína Jamrichová, Markéta Holečková, Karel Chalupský, Inken M Beck, Jesús Ruberte, Matilde Vale, Lukáš Čermák, Tomáš Stopka, Radislav Sedlacek.

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure syndrome accompanied by cardiovascular, skeletal, and urogenital abnormalities. Most of the affected individuals carry mutations in ribosomal proteins, including RPS19, a component of the 40S ribosomal subunit. We developed a transgenic Rps19 mouse model harboring a deletion of conserved R67 that displays a variable phenotype ranging from mild hematopoietic defects to severe anemia and a set of other skeletal, muscular, and cardiac abnormalities with shorter survival. This mouse model exhibited an activation of the p53 signaling pathway in red blood cell committed hematopoietic stem and progenitor cells, affecting erythroid lineage development. Competitive transplantation assays using Rps19 R67∆ bone marrow progenitor cells confirmed that short-term repopulating hematopoietic stem cells (HSCs) and their progenitor lineages were affected, while their differentiation was rescued after deletion of the tumor suppressor Trp53. Rps19 R67∆ mutation leads to pre-ribosomal RNA (pre-rRNA) accumulation coupled with activation of p53, even at relatively immature hematopoietic stages. In conclusion, we present a mouse model that represents a powerful tool for exploring new therapeutic options for the treatment of ribosomal disorders, including DBA.

DOI: https://doi.org/10.1002/hem3.70302
Cell Rep Med. 2026 Jan 20. pii: S2666-3791(25)00615-9. [Epub ahead of print]7(1): 102542

Sequence-dependent splicing dysregulation drives therapy resistance in pediatric AML.

Yue Huang, Peifang Xiao, Lei Qin, Li Gao, Yang Zhao, Jingru Sui, Wenting Hu, Lei Zhou, Nan Han, Xuan Lv, Kunying Chen, Yu Liu, Hanhong Lin, Shuhong Shen, Omar Abdel-Wahab, Shaoyan Hu, Zhaoqi Liu, Qianfei Wang.

  Despite improvements in pediatric acute myeloid leukemia (AML) prognosis, about 30% of patients relapse after initial chemotherapy and have poor survival. However, the genetic basis of resistance remains unclear for most patients. To better understand the mechanistic basis and overcome treatment resistance, we analyze RNA sequencing (RNA-seq) data from 702 pediatric AML patients. This effort uncovers a sequence-dependent splicing dysregulation in 36% of children linked to worse prognosis and a lower rate of complete remission. Surprisingly, this change in RNA splicing matches that induced by SRSF2 mutations, which are common in adult AML. Instead, we identify U2AF2 dysregulation as the driver of aberrant splicing in pediatric AML. The pathologic splicing changes are characterized by "weak" polypyrimidine tracts and are susceptible to modest U2AF2 reduction. These outcomes can be improved by pharmacologic modulation of PRMT enzymes. Overall, these findings highlight the importance of modulating splicing defects to improve treatment response in pediatric AML.

Keywords:  PRMT enzymes; U2AF2 downregulation; pediatric acute myeloid leukemia; splicing dysregulation; therapy resistance

DOI:  https://doi.org/10.1016/j.xcrm.2025.102542
Leukemia. 2026 Jan 22.

Distal enhancer RNAs regulate alternative promoter usage of MYB and drug resistance in human leukemia cells.

Yucheng Wang, Xiang Wang, Mengjia Li, Hongkuan Song, Chao Liu, Mengjie Shi, Xiaoxiao Tao, Siyu Shen, Xinyu Li, Huiying Fang, Zhenhua Zhou, Junfang Zhang, Bingshe Han.

MYB is a master transcription factor for the hematopoietic system, and its dysregulation drives the development and therapy resistance of leukemia. However, the mechanisms of MYB regulation and MYB-related therapy resistance are still unclear. Here, we identified two bidirectional enhancer RNAs (eRNAs), MY34UE-AS and MY34UE-S, transcribed from the -34 kb enhancer region of MYB. Both eRNAs promote MYB transcription, proliferation, and migration in human leukemia cells, although through different MYB promoters. MY34UE-AS physically interacts with PURB that binds near MYB TSS2, promoting long-range looping between downstream -34 kb enhancer elements and TSS2, ultimately activating TSS2. While MY34UE-S facilitates DNA looping between upstream -34 kb enhancer elements and TSS1, promoting TSS1 transcription. TSS2, but not TSS1, activity increases in drug resistant leukemia cells, resulting increased expression of N-terminally truncated MYB (ΔN MYB) when total MYB remains unaltered. Compared to full-length MYB, ΔN MYB more potently promotes drug resistance through FTH1 and EZH2 pathway, and targeting MY34UE-AS more efficiently alleviates drug resistance than targeting MY34UE-S. The above relationship of MY34UE-AS/MY34UE-S, TSS2/TSS1, and prognosis was also verified in clinical leukemia samples. For the first time we provide the mechanisms underlying promoter usage of MYB and MYB TSS2 mediated drug resistance in human leukemia.

DOI: https://doi.org/10.1038/s41375-026-02862-0
Nat Commun. 2026 Jan 20.

TET1 as a master regulator controlling GPX4-dependent and -independent ferroptosis surveillance in acute myeloid leukemia.

Lingling Yang, Jun Lu, Weina Yun, Xinquan Yang, Jie Sun, Chaodong Ge, Fei Han, Xiang Li, Junxia Min, He Huang, Fudi Wang, Xi Jiang.

Ferroptosis, an iron-dependent, lipid peroxidation-driven programmed cell death, holds substantial promise for cancer therapy, yet its translational potential is hindered by widespread intrinsic resistance. While glutathione peroxidase 4 (GPX4) is a well-established ferroptosis suppressor, the epigenetic circuitry coordinating GPX4-related mechanisms remains elusive. Here, via genome-wide screening, we identify ten-eleven translocation 1 (TET1)-a key mediator of DNA 5-hydroxymethylation-as a master controller of cancer cell ferroptosis susceptibility. In acute myeloid leukemia (AML), TET1 enhances 5hmC deposition at the glutamate-cysteine ligase catalytic subunit (GCLC) promoter to activate glutathione/γ-glutamyl-peptide metabolism, fortifying GPX4-dependent defense. Concurrently, TET1 activates NFκB signaling to upregulate GTP cyclohydrolase-1 (GCH1), conferring GPX4-independent ferroptosis resistance. Critically, co-targeting TET1/GCLC/GCH1 with low-dose ferroptosis inducers exhibits potent therapeutic effects against both ferroptosis-sensitive and -resistant AML. Our work positions TET1 as a pivotal epigenetic hub governing ferroptosis surveillance, and provides a translatable strategy to overcome ferroptosis resistance in cancer, with AML as a paradigm.

DOI: https://doi.org/10.1038/s41467-026-68509-x