bims-tremyl 2026-04-05 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2026–04–05
twenty papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Treatment of TP53-mutated myelodysplastic syndrome and acute myeloid leukemia with lowintensity metronomic decitabine and venetoclax.
Defining remission and relapse after allogeneic hematopoietic cell transplantation in myelodysplastic/myeloproliferative neoplasms and optimization of transplantation outcomes: Recommendations from the EBMT practice harmonisation and guidelines committee.
A phase I open label study of fostamatinib, a SYK inhibitor, in patients with lower-risk myelodysplastic syndrome and chronic myelomonocytic leukemia.
Pharmacological blockade of rho kinase enhances venetoclax responses in translational models of acute myeloid leukemia.
Clinical, Genetic, and Pathologic Variability in Myelodysplastic Syndromes and Precursor Conditions Across Race, Ethnicity, and Sex.
Epigenome editing of human hematopoietic stem cells enables sustained and reversible thrombosis prevention.
Clinical Experience With Venetoclax-Based Combinations for Relapsed/Refractory or MRD-Positive NPM1-Mutated Acute Myeloid Leukemia.
Hematopoietic Stem Cell Senescence and Opportunities for Intervention.
Hypomethylating agents plus venetoclax versus intensive chemotherapy prior to transplant in high-risk acute myeloid leukemia.
Site-specific methylation of SRSF2P95H by SETD2 inhibits MDSC-mediated proinflammatory niche formation in mouse models of myelodysplastic syndrome.
BCR::ABL1 tyrosine kinase inhibitors induce ribosome collisions to activate ZAK-dependent ribotoxic stress and apoptosis in chronic myeloid leukemia.
Enhancement of CD117-targeted bispecific T-cell engagement by CD33-targeted bispecific T-cell co-stimulation in acute myeloid leukemia.
Targeting systemic and tumor metabolic balances with ketogenic diets enhance efficacy of therapy in FLT3-ITD acute myeloid leukemia.
New selective and allosteric FLT3 inhibitors show efficacy against resistant acute myeloid leukemia cells.
The adverse prognostic impact of HMGCLL1 gene variants can be abrogated by frontline second-generation tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia.
Azacitidine for MDS and CMML.
Trisomy 8 alters chromatin conformations and activates Y chromosome genes in stem cells to drive a pre-leukemic state.
Polycythemia vera.
American Society of Hematology 2026 Guidelines for the Diagnosis and Management of Severe Acquired Aplastic Anemia.
Preemptive hematopoietic stem cell transplantation in RUNX1 familial platelet disorder: a shared decision-making framework.

Haematologica. 2026 Apr 02.

Treatment of TP53-mutated myelodysplastic syndrome and acute myeloid leukemia with lowintensity metronomic decitabine and venetoclax.

Mendel Goldfinger, Ioannis Mantzaris, Aditi Shastri, Bradley Rockwell, Yogen Saunthararajah, Shanye Yin, David Levitz, Kira Gritsman, Alejandro R Sica, Noah Kornblum, Lauren C Shapiro, Ridhi Gupta, Stephen Peeke, Nishi Shah, Kith Pradhan, Anne Munoz, Aradhika Dhawan, Jhannine Alyssa Verceles, Karen Fehn, Monica Comas, Lamisha Shah, Yang Shi, Brian A Jonas, Dennis L Cooper, Marina Konopleva, Eric J Feldman, Amit Verma.

Venetoclax (Ven) in combination with hypomethylating agents (HMA) (azacitidine or decitabine) is the standard of care for elderly or unfit patients with acute myeloid leukemia (AML) and is being explored in high-risk myelodysplastic syndrome (HR-MDS). However, currently approved dosing of HMA/Ven is associated with prolonged cytopenias, without a clear improvement in survival for TP53-mutated myeloid malignancies. In order to reduce hospitalizations during COVID, a once-weekly, metronomic schedule of decitabine (0.2 mg/Kg) and venetoclax (400 mg) was developed for patients with MDS and AML. Based on encouraging results, a phase 2 trial was performed. In the current study, we analyzed response rates and survival for all patients with TP53-mutated disease treated on the metronomic schedule. In total, 40 patients with TP53-mutated MDS and AML (26 in a prospective trial and 14 in the retrospective cohort) were included; 26 had HR-MDS and 14 had AML. The median age was 76.5 years, 70% had complex cytogenetics and 82% had bi-allelic TP53 mutations. The ORR for AML (CR+Cri) was 70% and 57% (CR+mCR) for MDS. With a median follow-up of 12.9 months, the median OS for the entire cohort was 11.3 months (11.6 months for AML, 9.9 months for MDS), and median OS in the 31 patients with bi-allelic mutated TP53 was 10.4 months. Transfusion independence was achieved in 58%. Neutropenic fever occurred in 15%, there were no therapy-related fatalities, and the 100-day mortality was 7.5%. A non-cytotoxic metronomic dosing schedule of decitabine/Ven has a low toxicity profile in TP53-mutated myeloid malignancies.

DOI: https://doi.org/10.3324/haematol.2026.300534
Bone Marrow Transplant. 2026 Apr 01.

Defining remission and relapse after allogeneic hematopoietic cell transplantation in myelodysplastic/myeloproliferative neoplasms and optimization of transplantation outcomes: Recommendations from the EBMT practice harmonisation and guidelines committee.

Christopher Armstrong, Kavita Raj, Giorgia Battipaglia, Gonzalo Bentolila, Eolia Brissot, Yves Chalandon, Fernando Barroso Duarte, Joanna Drozd-Sokolowska, Vaneuza Funke, Nico Gagelmann, Thierry Guillaume, Carmelo Gurnari, Robert Hasserjian, Juan Carlos Hernández-Boluda, Devendra Hiwase, Andrés Jerez, Michael Loschi, Marin Medjugorac, Mufaddal T Moonim, Francesco Onida, Nicola Polverelli, Micaela Quarchioni, Marie Robin, Christof Scheid, Katja Sockel, Daniel H Wiseman, Annalisa Ruggeri, Isabel Sánchez-Ortega, Natalia Aranguiz Garcia, Mario Cazzola, Fabio Ciceri, Tomasz Czerw, Jaroslaw Maciejewski, Simona Pagliuca, Lisa Pleyer, Patryk Sobieralski, Jurjen Versluis, Maria Teresa Voso, Ibrahim Yakoub-Agha, Donal P McLornan.

Myelodysplastic/myeloproliferative neoplasms (excluding CMML) are rare and heterogenous malignancies with recurrent and overlapping clinicopathological abnormalities. Classification and characterization continue to evolve, but outcomes remain unsatisfactory and allo-HCT is currently the only curative therapy. Experience with these diseases is limited by rarity, accounting for <1% of allo-HCT procedures in Europe annually. Transplant indications have recently been described by this group, however response assessment, post-transplant surveillance and management of poor graft function, splenomegaly and relapse are not well established. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization & Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) collaborated to develop a practical and expert consensus-based guideline. Criteria for remission confirmation are proposed, including timing/thresholds for morphological, molecular, cytogenetic and chimerism analysis, aiming to harmonize comparisons in registry data and between international series. Suggestions for managing poor graft function and splenomegaly are designed to broadly align with those for myelofibrosis and related disorders. Relapse post-transplant remains a frequent challenge and the lack of robust evidence, in both the pre-transplant/post-transplant setting, underpins a need for collaborative clinical trials. This document serves as a framework to model post-transplant care, guide future research and address unresolved questions.

DOI: https://doi.org/10.1038/s41409-026-02843-y
Leuk Lymphoma. 2026 Mar 30. 1-7

A phase I open label study of fostamatinib, a SYK inhibitor, in patients with lower-risk myelodysplastic syndrome and chronic myelomonocytic leukemia.

J Croden, G Garcia-Manero, K Chien, C DiNardo, G Borthakur, D Hammond, P Bose, N Short, L Romero, H Shneider, M Hatfield, S Pierce, X Huang, H Hwang, G Montalban-Bravo.

  Lower-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are commonly managed with erythropoiesis-stimulating agents, luspatercept, or hypomethylating agents. Despite this, the disease often becomes refractory and patients develop transfusion dependence. Preclinical evidence suggests that targeting innate immune signaling, including NF-kB activation, may improve hematopoiesis. Fostamatinib, an oral SYK inhibitor approved for immune thrombocytopenia, was evaluated in a phase 1 open-label study in previously treated lower-risk MDS/CMML. Eleven patients received fostamatinib starting at 100 mg twice daily with dose escalation for lack of response. Patients had received a median of 3 prior therapies and most were transfusion-dependent. Over a median of 5 treatment cycles and 14.4 months of follow-up, no objective responses were observed, although all patients achieved stable disease. Transfusion needs remained largely unchanged. There were no dose-limiting toxicities. Although safe, fostamatinib demonstrated no clinical benefit, underscoring the need for alternative strategies to modulate inflammatory signaling in MDS/CMML.

Keywords:  CMML; MDS; SYK inhibitor; fostamatinib

DOI:  https://doi.org/10.1080/10428194.2026.2650674
Haematologica. 2026 Apr 02.

Pharmacological blockade of rho kinase enhances venetoclax responses in translational models of acute myeloid leukemia.

Upendarrao Golla, Riya Bhalodia, Charyguly Annageldiyev, Satyam Patel, Vishnu Sravan Bollu, Su-Fern Tan, Myles C Cabot, David J Feith, Thomas P Loughran, Ross L Levine, Shin Mineishi, Hong Zheng, Kentaro Minagawa, Jeremy Hengst, Giselle L Saulnier Sholler, Dhimant Desai, Sinisa Dovat, Kelsey H Fisher-Wellman, David F Claxton, Arati Sharma.

Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy requiring concomitant targeting of critical cellular survival pathways due to resistance and frequent relapse with monotherapies. Venetoclax (VEN), a BCL-2 inhibitor, is one such promising clinical agent best utilized in combination therapies due to transient responses and acquired resistance. Given the involvement of the Rho/ROCK pathway in VEN activity, we combined Rho-associated coiled-coil-containing protein kinase inhibitors (ROCKi))with VEN to achieve superior antileukemic activity. The ROCKi (Fasudil, DJ4, GSK269962A) synergized with VEN to enhance cytotoxicity in both VEN-sensitive and VEN-resistant cell lines in vitro. Among the three ROCKi, GSK269962A (GSK) was best-tolerated in combination with VEN and effectively inhibited leukemia growth across multiple AML cell line-derived xenograft models in vivo. The GSK+VEN combination exhibited additive to synergistic cytotoxicity in primary AML patient cells ex vivo and enhanced antileukemic activity in a patientderived xenograft model. Additionally, the GSK+VEN combination significantly decreased the clonogenicity of primary AML cells, relatively sparing normal cells. Functional assays demonstrated enhanced apoptosis (Annexin V, caspase-3/7), elevated reactive oxygen species, and mitochondrial depolarization in both VENsensitive and VEN-resistant AML cells following combination treatment. Mechanistically, GSK augmented venetoclax responses by downregulating anti-apoptotic proteins (BCL2, MCL1) and inducing pro-apoptotic mediators (NOXA, MCL1 short isoforms), including in VEN-resistant AML cells. Together, these findings across multiple preclinical AML models demonstrate synergistic antileukemic activity and support combining VEN with ROCKi as a promising therapeutic strategy for AML.

DOI: https://doi.org/10.3324/haematol.2025.289041
Am J Hematol. 2026 Mar 29.

Clinical, Genetic, and Pathologic Variability in Myelodysplastic Syndromes and Precursor Conditions Across Race, Ethnicity, and Sex.

Nancy Gillis, Christelle Colin-Leitzinger, Yi-Han Tang, Michael Otterstatter, Seth Sherman, Ling Zhang, Lynn C Moscinski, Mary Ellen Walker, Jeffrey S Painter, Gregory A Abel, Tareq Al Baghdadi, H Joachim Deeg, James M Foran, Steven D Gore, Alexandra M Harrington, Steven H Kroft, Jane Jijun Liu, Wael Saber, Shamsuddin Virani, Rafael Bejar, R Coleman Lindsley, Eric Padron, Matthew J Walter, Rami Komrojki, Amy E DeZern, Mikkael A Sekeres.

The epidemiology of myelodysplastic syndromes/neoplasms (MDS) is challenging to define due to inconsistent reporting, complex diagnostic procedures, and evolving diagnostic criteria. Using the National MDS Natural History Study-a prospective cohort with centrally adjudicated histopathology and genetic variant review-we characterized the landscape of MDS across the United States and identified differences across demographics. Among 2115 participants, 64% (1346) had an MDS spectrum condition, including MDS (24%), MDS/myeloproliferative neoplasm (5%) and precursor conditions-clonal cytopenia of undetermined significance (22%) and idiopathic cytopenia/dysplasia of undetermined significance (13%). The median age was 74 years, and participants were predominantly male (66%), White (91%), and Non-Hispanic (92%). Myeloid-associated variants were detected in 68% of participants, most commonly in TET2, DNMT3A, ASXL1, SF3B1, and SRSF2. Black, compared to White, participants were younger at diagnosis (69 vs. 74 years, p = 0.01), had equal or increased prevalence of higher-risk MDS, lower hemoglobin, and higher peripheral blood blasts, yet were less likely to receive MDS-directed therapy (14% vs. 42%, p = 0.008). Black and Hispanic participants had fewer detectable gene mutations than White participants. Females had lower variant allele frequencies and fewer RNA splicing gene mutations than males. After multivariable adjustment, TP53 mutations, MDS diagnosis, and higher-risk disease were associated with worse progression-free and overall survival; age was also associated with overall survival. Black race trended toward improved progression-free survival. These findings highlight the need for enhanced understanding of MDS pathogenesis across patient groups and refined prognostic tools to improve personalized management of MDS spectrum conditions. Trial Registration: ClinicalTrials.gov identifier: NCT02775383.

DOI: https://doi.org/10.1002/ajh.70279
bioRxiv. 2026 Mar 29. pii: 2026.03.27.714536. [Epub ahead of print]

Epigenome editing of human hematopoietic stem cells enables sustained and reversible thrombosis prevention.

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

Thrombosis remains a major cause of cardiovascular and cerebrovascular diseases, driven in large part by platelet activation and aggregation. Because platelets are continuously produced from hematopoietic stem cells (HSCs), durable reprogramming of HSC output offers a unique opportunity for a one-time antithrombotic intervention. Here, we show that DNA methylation-based epigenome editors delivered transiently as RNA result in stable, heritable gene silencing in primary human HSCs that persists through long-term self-renewal and megakaryocytic differentiation, while remaining reversible through targeted demethylation. Targeting the platelet integrin β3 ( ITGB3 ), this approach achieves robust, sustained repression and yields platelets with impaired aggregation. Extending this framework to additional genetically-nominated platelet targets establishes HSC epigenome editing as a durable and reversible strategy to modulate thrombotic risk and highlights broader opportunities to engineer hematopoiesis.

DOI: https://doi.org/10.64898/2026.03.27.714536
Am J Hematol. 2026 Apr 01.

Clinical Experience With Venetoclax-Based Combinations for Relapsed/Refractory or MRD-Positive NPM1-Mutated Acute Myeloid Leukemia.

Matteo Piccini, Naseema Gangat, Francesco Mannelli, Barbara Scappini, Gaia Ciolli, Francesca Crupi, Andrea Pasquini, Jessica Caroprese, Giorgio Cannetti, Chiara Lucarelli, Silvia Querceto, Giada Rotunno, Fabiana Pancani, Niccolò Bartalucci, Paola Guglielmelli, Ayalew Tefferi, Alessandro Maria Vannucchi.



Keywords:  NPM1; leukemia; myeloid; refractory; relapse; venetoclax

DOI:  https://doi.org/10.1002/ajh.70313
Exp Hematol. 2026 Mar 30. pii: S0301-472X(26)00058-5. [Epub ahead of print] 105425

Hematopoietic Stem Cell Senescence and Opportunities for Intervention.

Aditya Barve, Preeti Dabas, Terri Cain, Shannon McKinney-Freeman.

How the cellular state of senescence manifests in hematopoietic stem cells (HSCs) is currently poorly understood and likely orchestrated by a complex interplay of intrinsic and extrinsic factors, such as genetic instability, epigenetic reprograming, alterations in the stem cell niche and metabolic dysregulation. Accumulating senescence may contribute to the age-related functional decline of HSCs, which manifests as reduced self-renewal, impaired differentiation, altered hematopoietic regenerative potential, expansion of dysfunctional HSC clones, and increased susceptibility to hematological disorders. Recent work has advanced our understanding of the molecular hallmarks and signaling pathways that contribute to HSC senescence, nominating promising therapeutic targets to ameliorate age-associated hematopoietic dysfunction and malignancy. Here, we review the intrinsic and extrinsic factors that likely contribute to HSC senescence during homeostasis and pathological conditions. We further summarize senescence targeting strategies that may be leveraged to mitigate HSC senescence and restore hematopoietic function during aging or hematologic disease.

DOI: https://doi.org/10.1016/j.exphem.2026.105425
Haematologica. 2026 Apr 02.

Hypomethylating agents plus venetoclax versus intensive chemotherapy prior to transplant in high-risk acute myeloid leukemia.

Guillaume Berton, Jan Philipp Bewersdorf, Julia Gilhodes, Alexandre Iat, Amel Soua, Daniel J DeAngelo, Leora Boussi, Rory M Shallis, Andrius Žučenka, Rebecca P Bystrom, Kelly Ling, Luis E Aguirre, Richard M Stone, Marlise R Luskin, Jacqueline S Garcia, Eric S Winer, Evan C Chen, Martha Wadleigh, Lourdes Mendez, Nikolai Podoltsev, Urbain Tauveron-Jalenques, Luca Lanino, Eytan Stein, Amer M Zeidan, Edouard Forcade, Thomas Cluzeau, Pierre-Yves Dumas, Mael Heiblig, Raynier Devillier, Shai Shimony, Aaron D Goldberg, Maximilian Stahl, Sylvain Garciaz.

Not available.

DOI: https://doi.org/10.3324/haematol.2025.300202
Sci Transl Med. 2026 Apr;18(843): eadv1065

Site-specific methylation of SRSF2P95H by SETD2 inhibits MDSC-mediated proinflammatory niche formation in mouse models of myelodysplastic syndrome.

Zi-Juan Li, Mu-Ying Zhao, Roujia Wang, Na Liu, Cheng-Long Hu, Binhe Chang, Fang Hu, Xi-Ya Li, Chun-Hui Xu, Ping Liu, Bing-Yi Chen, Shu-Bei Chen, Yong Wang, Qi-Jing Li, Bu-Sheng Xue, Chuhan Deng, Xinchi Chen, Yiyi Ren, Jia-Cheng Jin, Xiao Yan, Yuanliang Zhang, Robert Peter Gale, Jianfei Fu, Qun-Ling Zhang, Xiaoning Wang, Qiuhua Huang, Yan Liu, Ju Qiu, Jun Qin, Xueshi Ye, Jin Zhang, Yang Liang, Zhu Chen, Sai-Juan Chen, Peng-Cheng He, Chun-Kang Chang, Xiao-Jian Sun, Lan Wang.

Patients with myelodysplastic syndrome (MDS) harboring SRSF2 (serine and arginine rich splicing factor 2) mutations exhibit poor prognosis and aberrant inflammatory activation, underscoring an urgent need for therapies. Here, we reveal that low messenger RNA expression of SETD2 (SET domain containing 2) in hematopoietic stem and progenitor cells (HSPCs) from patients with MDS carrying SRSF2P95 mutations (SRSF2P95-Mut MDS) correlates with adverse outcomes and increased inflammation. Multivariate analysis confirmed the correlation between low SETD2 expression and poor prognosis in patients with SRSF2P95-Mut MDS. Furthermore, Setd2 loss in the Srsf2P95H/+ mouse model resulted in lethal MDS with hyperinflammation and expansion of myeloid-derived suppressor cells (MDSCs). Mechanistically, SETD2 methylates SRSF2P95H at lysine-17 and lysine-65 to inhibit aberrant splicing of CEACAM1-4 (isoforms of carcinoembryonic antigen cell adhesion molecule), which enhances interleukin-1β (IL-1β) signaling through Slc7a11 (solute carrier family 7 member 11)-mediated cystine uptake, thereby promoting HSPC differentiation into MDSCs, establishing an IL-1β-driven immunosuppressive microenvironment. These findings identify the SRSF2P95HK17me1K65me2-CEACAM1-4 signaling axis as a promising therapeutic target in SRSF2P95-Mut MDS.

DOI: https://doi.org/10.1126/scitranslmed.adv1065
Leukemia. 2026 Mar 30.

BCR::ABL1 tyrosine kinase inhibitors induce ribosome collisions to activate ZAK-dependent ribotoxic stress and apoptosis in chronic myeloid leukemia.

Jumin Park, Soo-Hyun Kim, Jongmin Park, Heeju Park, Hongtae Kim, Dong-Wook Kim, Chunghun Lim.

Ribosome collisions act as molecular sensors of cellular stress, yet their role in disease physiology remains unclear. Here, we demonstrate that inhibition of the oncogenic kinase BCR::ABL1 in chronic myeloid leukemia (CML) cells induces ribosome collisions and activates the ribotoxic stress response (RSR). Clinical analyses revealed that CML progression from the chronic phase to the aggressive blast phase correlated with elevated expression of the RSR-initiating kinase ZAK. Although ZAK sustained CML cell proliferation by promoting AKT activity, loss of ZAK function paradoxically reduced the cytotoxic effects of BCR::ABL1 inhibitors. Mechanistically, BCR::ABL1 inhibition promoted phosphorylation of eukaryotic translation elongation factor 2 (EEF2) via the mTOR-EEF2K pathway, slowed translation elongation, and generated nuclease-resistant collided ribosomes that triggered ZAK-dependent p38 activation and apoptosis. Furthermore, pharmacological modulation of translation flux fine-tuned the efficacy of BCR::ABL1 inhibitors, including in primary patient cells. These findings define a ribosome-based stress pathway crucial for CML apoptosis and highlight ZAK-dependent RSR as a therapeutic vulnerability.

DOI: https://doi.org/10.1038/s41375-026-02916-3
Cancer Res Commun. 2026 Mar 30.

Enhancement of CD117-targeted bispecific T-cell engagement by CD33-targeted bispecific T-cell co-stimulation in acute myeloid leukemia.

Mara Hofstetter, Laura Volta, Christian Koch, Melanie Granados Rey, Monique Maurer, Nagihan Gönüllü, Christian Pellegrino, Celeste Gobbi, Florin Schneiter, Francesco Manfredi, Chiara F Magnani, Abdullah Elsayed, Timm Schroeder, Dario Neri, Markus G Manz.

Acute Myeloid Leukemia (AML) originates from the hematopoietic stem and progenitor cell compartment and is associated with an overall poor clinical outcome. T-cell engaging bispecific antibodies (TCEs), binding to a tumor-associated antigen and to CD3, redirect T-cells to the target-antigen expressing cells in an MHC/TCR-independent fashion. The development of TCEs for clinical application is facing several challenges. Firstly, it is difficult to identify a tumor-selective, non-MHC-presented tumor target, not expressed on the tissue of tumor origin, thus limiting specificity. Secondly, CD3-directed TCEs do not provide a second, T-cell activating signal, such as the stimulation of CD28 or 41BB, thus possibly limiting T-cell efficacy. To address both aspects, we generated a CD33xCD28 IgG4-scFv2 with CD28 agonistic activity and tested it in combination with a previously by us reported CD117xCD3 TCE in AML. Combining these two bispecific antibodies significantly improved T-cell mediated lysis of AML cell lines and primary AML samples by enhancing T-cell activation, proliferation and cytokine release in vitro. Furthermore, the addition of CD33xCD28 IgG4-scFv2 showed faster time to cell attachment, increased lytic events, and improved specificity towards double-target expressing cells. In summary, the data indicate that combining co-stimulation via a second tumor-associated antigen to CD3-TCEs enhances T-cell lytic activity and simultaneously increases specificity against double-target expressing AML cells.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0672
Cell Rep. 2026 Mar 28. pii: S2211-1247(26)00263-9. [Epub ahead of print]45(4): 117185

Targeting systemic and tumor metabolic balances with ketogenic diets enhance efficacy of therapy in FLT3-ITD acute myeloid leukemia.

Léa Goupille, Alexandre Boudet, Laura Lauture, Ambrine Sahal, Guillaume Gautier-Renard, Emeline Chu-Van, Anvi Laetitia Nguyen, Céline Chollet, Coralie Alcazar, Isabelle Bernard, François Vergez, Véronique de Mas, Christian Récher, Tony Kaoma, Paolo Gallipoli, Vilma Dembitz, Irene Basili, Flavia Bernardi, Olivier Ayrault, Carine Joffre, Florence Castelli, Benoit Colsch, Nathalie Bourgès-Abella, Fanny Granat, Jean-Emmanuel Sarry.

  FMS-like tyrosine kinase 3 (FLT3) mutations in acute myeloid leukemia (AML) are associated with adverse prognosis. FLT3 inhibitors (FLT3i) improve therapeutic response; however, diverse resistance mechanisms, such as adaptations in lipid metabolism, have been identified. We hypothesized that a lipid-rich ketogenic diet (KD) might alter both host and tumoral lipid metabolism, enhancing responses to FLT3i. In FLT3-mutated AML mouse models, 3 weeks of lard- or plant-based KD improved the efficacy of FLT3i by 2-fold reduction of engraftment and tumor burden. KD increased ketone bodies and lipid accumulation in plasma, liver, and AML cells and also induced a polyunsaturated fatty acid:monounsaturated fatty acid (PUFA:MUFA) imbalance. KD impacted pentoses, hexoses, and amino acid metabolism, enhancing sugar phosphates and vitamins in the host. Mechanistically, KD rewired anabolism toward fatty acid oxidation and glycine-utilizing pathways, modulated the expression of FLT3 signaling pathways and lipid biosynthesis, and promoted tumor cell differentiation. In conclusion, this study shows that KD reduces FLT3i resistance, offering a promising therapeutic solution.

Keywords:  CP: cancer; CP: metabolism; FLT3-ITD mutations; acute myeloid leukemia; ketogenic diet; metabolism; therapy resistance

DOI:  https://doi.org/10.1016/j.celrep.2026.117185
iScience. 2026 Apr 17. 29(4): 115219

New selective and allosteric FLT3 inhibitors show efficacy against resistant acute myeloid leukemia cells.

Shuai-Shuai Ge, Qiao-Cheng Qiu, Jingsheng Hua, Jun Wang, Minfeng Yang, Jiahui Du, Yuan-Hong Huang, Chao-Ling Wan, Ling-Ling Liu, Hai-Ping Dai, Maofeng Zhang, Binghui Shen, Sheng-Li Xue, Fang Chen, Song-Bai Liu.

  Activating FLT3 mutations confer a poor prognosis in acute myeloid leukemia (AML). FLT3 inhibitors significantly improved the clinical outcomes of FLT3-mutated AML. However, all clinically approved inhibitors target the ATP-binding pocket of FLT3. The acquired FLT3 mutations in the ATP-binding pocket, including mutations at D835 and F691, are common mechanisms of leukemia relapse. Using druggable site prediction (DSP) and high-throughput virtual screening, we revealed that the predicted site 1 region was promising for allosteric inhibitor development, and F-17 was identified as the first potential allosteric FLT3 inhibitor. F-17 exhibited high affinity for site 1 in an ATP non-competitive manner. KINOMEscan analysis showed that F-17 was significantly selective toward FLT3 over other homologous kinases of the RTK family. Moreover, F-17 showed potent selectivity and inhibition activity for FLT3-mutated cells both in vitro and in vivo. Collectively, the work provided a new insight for FLT3 inhibitor development.

Keywords:  Cancer; Pharmacology; Structural biology

DOI:  https://doi.org/10.1016/j.isci.2026.115219
Leukemia. 2026 Mar 30.

The adverse prognostic impact of HMGCLL1 gene variants can be abrogated by frontline second-generation tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia.

Maria Agustina Perusini, Katia Pagnano, Carolina Pavlovsky, Daniela Žáčková, Jiří Mayer, Beatriz Moiraghi, Ana Ines Varela, Michele Bianchini, Ana Beatriz Pascoal Lopes, Gislaine Duarte, Carmino Antonio de Souza, Ivana Ježíšková, Anežka Kvetková, Tomáš Jurček, Hye Won Lee, Myung Hee Chang, Jessie J F Medeiros, Sagi Abelson, Dennis Dong Hwan Kim.

DOI: https://doi.org/10.1038/s41375-026-02921-6
Haematologica. 2026 Apr 01. 111(4): 1147-1148

Azacitidine for MDS and CMML.

Emma St Martin, Mrinal M Patnaik.

DOI: https://doi.org/10.3324/haematol.2026.289398
Oncogene. 2026 Apr 04.

Trisomy 8 alters chromatin conformations and activates Y chromosome genes in stem cells to drive a pre-leukemic state.

Jie Bai, Kimi Araki, Daisuke Kurotaki, Eerdunduleng, Supannika Sorin, Kei Hiramatsu, Narumi Uno, Ai Hamashima, Mihoko Iimori, Kenta Kikuchi, Minoru Terashima, Sho Kubota, Kensaku Kohrogi, Gang Huang, Minetaro Ogawa, Mitsuo Oshimura, Yasuhiro Kazuki, Goro Sashida.

The mechanistic role of trisomy 8 in the development of myelodysplastic syndrome (MDS) remains poorly defined. Here, we generated a trisomy 8 mouse model by transferring a human chromosome 8 into murine embryonic stem cells and prospectively examined the effects on hematopoietic stem cells (HSC) by trisomy 8. The expression of inflammatory genes was enhanced, and hematopoietic programs mediated by transcription factors and polycomb repressive complex 2 (PRC2) were dysregulated in trisomy 8 HSC, which impaired their self-renewal and balanced differentiation. Trisomy 8 HSC altered the chromatin accessibility and conformations and activated Y chromosome genes, such as Uty/Kdm6c epigenetic modifier, which is known to demethylate histone H3K27me3 modification. The Uty gene facilitated the activation of PRC2-target and Runx1-target genes in leukemogenesis and drove the proliferation of human trisomy 8 leukemic cells. Since the RUNX1 gene is frequently mutated in patients with trisomy 8 MDS, its deletion attenuated the enhanced expression of inflammatory genes and mitigated the impaired self-renewal of trisomy 8 HSC in mice. Our findings reveal that trisomy 8 altered the transcriptional programs and chromatin conformations in HSC and drove a pre-malignant state through activating the expression of Uty, suggesting a route for the development of trisomy 8 MDS.

DOI: https://doi.org/10.1038/s41388-026-03763-3
Mayo Clin Proc. 2026 Mar 28. pii: S0025-6196(26)04329-6. [Epub ahead of print]

Polycythemia vera.

Martin H Ellis, Tiziano Barbui, Ayalew Tefferi.

Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm arising from acquired JAK2 mutations (V617F or exon 12), resulting in constitutive activation of the JAK-STAT pathway and panmyelosis. This comprehensive review of the disease is based on relevant publications retrieved from a PubMed search using the terms polycythemia vera and epidemiology or pathophysiology or molecular pathology or clinical trials from inception to June 2025 and a review of abstracts submitted to the American Society of Hematology for annual meetings in 2023 and 2024. Polycythemia vera manifests as erythrocytosis, often accompanied by leukocytosis and thrombocytosis, and symptoms include pruritus, headache, dizziness, and fatigue. Thromboembolism is the most important complication, and transformation to myelofibrosis or acute myeloid leukemia is a rare long-term complication. Diagnosis is guided by international consensus criteria, incorporating hematocrit levels, bone marrow morphology, and JAK2 mutation status, alongside subnormal erythropoietin levels. Risk stratification for thrombosis is crucial and is currently primarily based on age and prior thrombosis. Management aims to maintain hematocrit levels below 45% and prevent thrombotic events. Established therapies include phlebotomy, low-dose aspirin, and cytoreductive agents such as hydroxyurea. Ropeginterferon alfa-2b has shown efficacy in achieving hematologic remission and JAK2 V617F allele burden reduction. Ruxolitinib, a JAK1/JAK2 inhibitor, is effective for patients intolerant or resistant to hydroxyurea, improving hematocrit control, spleen volume, and symptoms. Novel agents targeting hepcidin for iron restriction and epigenetic modifiers are under investigation. Despite recent advances, PV remains incurable, and future research aimed at early detection of disease may allow the application of disease-modifying treatments and improve long-term outcomes.

DOI: https://doi.org/10.1016/j.mayocp.2026.01.008
Blood Adv. 2026 Mar 24. pii: bloodadvances.2025019051. [Epub ahead of print]

American Society of Hematology 2026 Guidelines for the Diagnosis and Management of Severe Acquired Aplastic Anemia.

Phillip Scheinberg, Debra A O'Neal, Ana Lisa Basquiera, Michael T Byrne, Rodrigo T Calado, Ruchi Desai, Amy E DeZern, Carlo Dufour, Emma M Groarke, Hyojeong Han, Kohei Hosokawa, Rina Kansal, Austin G Kulasekararaj, Sherif Beniameen Mossad, Petra Muus, Bhumika J Patel, Antonio M Risitano, Hubert Schrezenmeier, Akshay Sharma, Akiko Shimamura, Kristin A Shimano, Fernando Tortosa, Camila Avila, Martin Ragusa, Ariel Izcovich, Ignacio Neumann.

BACKGROUND: Aplastic anemia is a rare, life-threatening condition marked by pancytopenia and bone marrow hypocellularity. Despite therapeutic advances, clinical practice remains variable, and uncertainties persist regarding diagnosis and optimal management. To address these gaps, the American Society of Hematology (ASH) developed evidence-based guidelines to provide standardized, patient-centered recommendations.
OBJECTIVE: The recommendations are intended to support patients, clinicians and other health care professionals in their decisions about the management and diagnosis of severe and very severe immune acquired aplastic anemia.
METHODS: ASH formed a multidisciplinary guideline panel of content experts, methodologists and a patient representative. An evidence synthesis team supported the guideline development process by conducting systematic evidence reviews. The panel prioritized clinical questions and used the GRADE approach, including the Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment.
RESULTS: The panel agreed on 33 recommendations and 4 good practice statements addressing the use of diagnostic tests, treatment strategies and supportive care. Additional recommendations covered the incorporation of eltrombopag into immunosuppressive regimens and the use of antimicrobial prophylaxis in high-risk patients. For most clinical questions, the certainty of the evidence was rated as low or very low, largely due to the reliance on small, non-randomized studies.
CONCLUSIONS: Recommendations emphasize prioritizing hematopoietic cell transplantation for younger individuals with an available matched sibling or unrelated donor and as a second-line option following failure of immunosuppressive therapy. The panel also recommended adding eltrombopag to immunosuppressive regimens and using antibiotic and antifungal prophylaxis in neutropenic patients.

DOI: https://doi.org/10.1182/bloodadvances.2025019051
Haematologica. 2026 Apr 02.

Preemptive hematopoietic stem cell transplantation in RUNX1 familial platelet disorder: a shared decision-making framework.

Timothy S Olson, Katrin Ericson, Joseph H Antin, Laura Babbitt, Monica Babich, Natalie T Deuitch, Courtney DiNardo, Paul J Ford, Esther A Obeng, Brittany L Stewart, Wenbin Xiao, Akiko Shimamura.

RUNX1 familial platelet disorder (RUNX1-FPD) is associated with a 35% to 50% lifetime risk of hematologic malignancy (HM), and like all germline HM predisposition syndromes, can only be cured with allogeneic hematopoietic stem cell transplantation (HSCT). Current genetic screening techniques allow for early detection of germline predisposition, and consequently, the opportunity for HSCT before overt development of HM (ie, preemptive HSCT). However, there is not yet a consensus on the use of preemptive HSCT for RUNX1-FPD. Described here is the case of an individual with RUNX1-FPD and a family history of HM who underwent preemptive HSCT. We introduce a shared decision-making framework designed to support individuals with RUNX1-FPD, their families, and their multidisciplinary clinical teams in evaluating whether and when to pursue preemptive HSCT versus continued surveillance. The framework reviews key medical factors that influence HSCT timing decisions, including germline and somatic variants, clonal changes over time, familial history of HM, early morphologic or hematologic features, bleeding-related quality of life impacts, and donor availability. The framework also summarizes the major risks and uncertainties potentially associated with preemptive HSCT while highlighting the associated ethical challenges. Together, the case and framework provide a structured, patient-centered approach for navigating the complex clinical decision of preemptive HSCT. Ongoing collaborative efforts to define cytogenetic and clonal changes preceding malignant transformation in RUNX1-FPD will refine the framework and bolster individualized treatment strategies aimed at preventing HM and improving the quality of life of individuals with RUNX1-FPD.

DOI: https://doi.org/10.3324/haematol.2025.300403