bims-tremyl 2025-05-18 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–05–18
28 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Mutant IDH1 cooperates with NPM1c or FLT3ITD to drive distinct myeloid diseases and molecular outcomes.
Ubiquitin-conjugating enzyme UBE2N modulates proteostasis in immunoproteasome-positive acute myeloid leukemia.
Long-Term Transfusion Independence with Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent-Naive, Lower-Risk Myelodysplastic Syndromes in the COMMANDS Trial.
Taurine from tumour niche drives glycolysis to promote leukaemogenesis.
Myeloid Neoplasms With Erythroid Predominance and Excess Blasts in Young Adults Exhibit Distinct Genetic Profiles.
A Machine Learning-Based Strategy Predicts Selective and Synergistic Drug Combinations for Relapsed Acute Myeloid Leukemia.
IRAK1/4/pan-FLT3 Kinase Inhibitors with Reduced hERG Block as Treatments for Acute Myeloid Leukemia.
Inhibition of DOCK1 suppresses Notch signalling pathway and impairs leukaemogenesis.
Transcription factor cooperativity at a GATA3 tandem DNA sequence determines oncogenic enhancer-mediated activation.
Defective neutrophil clearance in JAK2V617F myeloproliferative neoplasms drives myelofibrosis via immune checkpoint CD24.
Discovery of an LSD1 PROTAC degrader.
CLEVER-1 targeting antibody, bexmarilimab, supports HLA-DR expression and alters ex vivo responsiveness to azacitidine and venetoclax in myeloid malignancies.
The evolving landscape of epigenetic target molecules and therapies in myeloid cancers: focus on acute myeloid leukemia and myeloproliferative neoplasms.
The Mutational Landscape in Polycythemia Vera: Phenotype, Genotype, and Prognostic Correlates.
How I Evaluate and Treat Resistance and Relapse in CML.
Erythroid-stimulating agents in VEXAS syndrome: A retrospective study from an Italian multicentre cohort.
Addition of mycophenolate mofetil to a calcineurin inhibitor and post-transplant cyclophosphamide results in lower incidence of extensive chronic graft-versus-host disease in HLA-matched allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia in complete remission: a matched-pair analysis on behalf of the Acute Leukemia Working Party of the EBMT.
Genetic Landscape and Risk Stratification of AML With Hyperdiploid Karyotype.
Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs.
Acute myeloid leukemia stem cells remodel the bone marrow niche via TGF-β-activated Alcam+ bone lining cells, creating a self-sustaining environment.
Conflating polycythemia vera with essential thrombocytosis.
Inhibition of MIF with an Allosteric Inhibitor Triggers Cell Cycle Arrest in Acute Myeloid Leukemia.
Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from the FRENVEX group.
Effect of peri-transplant measurable residual disease clearance in patients with myelodysplastic neoplasm; a referral center experience: Effect of peri-HSCT MRD Clearance in MDS.
Characterization and prognostic implication of pulmonary hypertension among patients with myeloproliferative neoplasms.
Real-world outcomes of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome at a tertiary referral centre.
Prognostic value of measurable residual disease (MRD) for venetoclax in combination with hypomethylating agents in patients diagnosed with acute myeloid leukemia: validation of the ELN-2021 MRD recommendations.
How I approach hematopoietic stem cell transplantation for CML in a TKI world.

Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2415779122

Mutant IDH1 cooperates with NPM1c or FLT3ITD to drive distinct myeloid diseases and molecular outcomes.

Takashi Sakamoto, Julie Leca, Xin Zhang, Cem Meydan, Jonathan Foox, Parameswaran Ramachandran, Liam D Hendrikse, Wenjing Zhou, Thorsten Berger, Jerome Fortin, Steven M Chan, Ming-Feng Chiang, Satoshi Inoue, Wanda Y Li, Mandy F Chu, Gordon S Duncan, Andrew Wakeham, François Lemonnier, Chantal Tobin, Ryan Mcwilliam, Isabelle Colonna, Christophe Bontoux, Soode Moghadas Jafari, Robert L Bowman, Brandon Nicolay, Sebastien Ronseaux, Rohini Narayanaswamy, Ross L Levine, Ari M Melnick, Christopher E Mason, Mark D Minden, Tak W Mak.

  In human acute myeloid leukemia (AML), mutations of isocitrate dehydrogenase-1 (IDH1) often co-occur with NPM1 mutations, and less frequently with FLT3 mutations. To investigate whether the effects of IDH1 mutation differ according to the specific co-occurring mutation, we generated two strains of double knock-in mutant mice. Idh1R132H combined with Npm1c induced overt AML, whereas Idh1R132H plus Flt3ITD resulted in Flt3ITD-driven myelo- or lymphoproliferation that was minimally affected by Idh1R132H and rarely generated AML. Gene expression profiling revealed differences between Idh1R132H;Npm1c cells and Idh1R132H;Flt3ITD cells and suggested altered heme metabolism and immune responses in the former. The profile of Idh1R132H;Npm1c cells corresponded to that of human IDH-mutated AML cells, particularly those resistant to inhibitors of mutant IDH. Compared to treatment with a menin inhibitor, IDH1-targeted therapy of Idh1R132H;Npm1c AML-bearing mice was less efficacious in improving cell differentiation and extending survival. The differential cooperation of Idh1R132H with Npm1c vs. Flt3ITD may have implications for the devising of subtype-specific treatments for human AML.

Keywords:  FLT3; IDH1; NPM1; acute myeloid leukemia; preclinical mouse model

DOI:  https://doi.org/10.1073/pnas.2415779122
J Clin Invest. 2025 May 15. pii: e184665. [Epub ahead of print]135(10):

Ubiquitin-conjugating enzyme UBE2N modulates proteostasis in immunoproteasome-positive acute myeloid leukemia.

Chiharu Ishikawa, Laura Barreyro, Avery M Sampson, Kathleen M Hueneman, Kwangmin Choi, Sophia Y Philbrook, Issac Choi, Lyndsey C Bolanos, Mark Wunderlich, Andrew G Volk, Stephanie S Watowich, Kenneth D Greis, Daniel T Starczynowski.

  Altered protein homeostasis through proteasomal degradation of ubiquitinated proteins is a hallmark of many cancers. Ubiquitination, coordinated by E1, E2, and E3 enzymes, involves up to 40 E2-conjugating enzymes in humans to specify substrates and ubiquitin linkages. In a screen for E2 dependencies in acute myeloid leukemia (AML), ubiquitin conjugating enzyme E2 N (UBE2N) emerged as the top candidate. To investigate UBE2N's role in AML, we characterized an enzymatically defective mouse model of UBE2N, revealing UBE2N's requirement in AML without an impact on normal hematopoiesis. Unlike other E2s, which mediate lysine-48 (K48) polyubiquitination and degradation of proteins, UBE2N primarily synthesizes K63-linked chains, stabilizing or altering protein function. Proteomic analyses and a whole-genome CRISPR-activation screen in pharmacologically and genetically UBE2N-inhibited AML cells unveiled a network of UBE2N-regulated proteins, many of which are implicated in cancer. UBE2N inhibition reduced their protein levels, leading to increased K48-linked ubiquitination and degradation through the immunoproteasome and revealing UBE2N activity is enriched in immunoproteasome-positive AML. Furthermore, an interactome screen identified tripartite motif-containing protein 21 (TRIM21) as the E3 ligase partnering with activated UBE2N in AML to modulate UBE2N-dependent proteostasis. In conclusion, UBE2N maintains proteostasis in AML by stabilizing target proteins through K63-linked ubiquitination and prevention of K48 ubiquitin-mediated degradation by the immunoproteasome. Thus, inhibition of UBE2N catalytic function suppresses leukemic cells through selective degradation of critical proteins in immunoproteasome-positive AML.

Keywords:  Hematology; Leukemias; Oncology; Ubiquitin-proteosome system

DOI:  https://doi.org/10.1172/JCI184665
Adv Ther. 2025 May 16.

Long-Term Transfusion Independence with Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent-Naive, Lower-Risk Myelodysplastic Syndromes in the COMMANDS Trial.

Guillermo Garcia-Manero, Valeria Santini, Amer M Zeidan, Rami S Komrokji, Veronika Pozharskaya, Shelonitda Rose, Karen Keeperman, Yinzhi Lai, Sameer Kalsekar, Barkha Aggarwal, Dimana Miteva, David Valcárcel, Pierre Fenaux, Jake Shortt, Matteo Giovanni Della Porta, Uwe Platzbecker.

   INTRODUCTION: The efficacy of erythropoiesis-stimulating agents (ESAs) for transfusion-dependent (TD) anemia in lower-risk myelodysplastic syndromes (LR-MDS) is limited. Luspatercept achieved significantly greater rates of red blood cell (RBC) transfusion independence (TI) versus epoetin alfa (an ESA) in the phase 3 COMMANDS trial. This analysis assessed long-term RBC-TI, cumulative response, and safety with luspatercept in COMMANDS.
METHODS: Eligible patients aged ≥ 18 years, with ESA-naive, RBC TD LR-MDS were randomized 1:1 to receive luspatercept (1.0 mg/kg, titration to 1.75 mg/kg permitted) or epoetin alfa (450 IU/kg, titration to 1050 IU/kg). Disease assessment was carried out at week 24 (day 169) and every 24 weeks thereafter. Treatment continued until disease progression, lack of clinical benefit, unacceptable toxicity, or consent withdrawal.
RESULTS: At data cutoff (September 22, 2023; median follow-up: luspatercept 21.4 months, epoetin alfa 20.3 months), a greater proportion of patients treated with luspatercept (n = 182) versus epoetin alfa (n = 181) achieved a longest single RBC-TI period ≥ 1 year (44.5% vs. 27.6%; P = 0.0003) and ≥ 1.5 years (30.2% vs. 13.8%; P < 0.0001). Higher rates of RBC-TI ≥ 1.5 years with luspatercept over epoetin alfa were consistent across all prespecified subgroups, including patients with ring sideroblast-negative status and low baseline serum erythropoietin. Longer cumulative RBC-TI response [sum of all durations of RBC-TI for ≥ 12 weeks; week 1 to end of treatment (95% CI)] was observed with luspatercept [154.7 weeks (118.4-NR)] versus epoetin alfa [91.1 weeks (73.1-123.9)]. Rates of treatment-emergent adverse events, including asthenia and hypertension, generally decreased over time in both arms. Progression rates to high-risk MDS and acute myeloid leukemia were similarly low (< 5%) in both treatment arms.
CONCLUSIONS: These data demonstrated sustained, durable clinical benefit across subgroups and support luspatercept as the treatment of choice for anemia in patients with LR-MDS who are TD and ESA-naive.
TRIAL REGISTRATION NUMBER: NCT03682536.

Keywords:  Anemia; Epoetin alfa; Erythroid-stimulating agents; Luspatercept; Myelodysplastic syndromes; Transfusion-independence

DOI:  https://doi.org/10.1007/s12325-025-03208-5
Nature. 2025 May 14.

Taurine from tumour niche drives glycolysis to promote leukaemogenesis.

Sonali Sharma, Benjamin J Rodems, Cameron D Baker, Christina M Kaszuba, Edgardo I Franco, Bradley R Smith, Takashi Ito, Kyle Swovick, Kevin Welle, Yi Zhang, Philip Rock, Francisco A Chaves, Sina Ghaemmaghami, Laura M Calvi, Archan Ganguly, W Richard Burack, Michael W Becker, Jane L Liesveld, Paul S Brookes, Joshua C Munger, Craig T Jordan, John M Ashton, Jeevisha Bajaj.

Signals from the microenvironment are known to be critical for development, stem cell self-renewal and oncogenic progression. Although some niche-driven signals that promote cancer progression have been identified1-5, concerted efforts to map disease-relevant microenvironmental ligands of cancer stem cell receptors have been lacking. Here, we use temporal single-cell RNA-sequencing (scRNA-seq) to identify molecular cues from the bone marrow stromal niche that engage leukaemia stem-enriched cells (LSCs) during oncogenic progression. We integrate these data with our human LSC RNA-seq and in vivo CRISPR screen of LSC dependencies6 to identify LSC-niche interactions that are essential for leukaemogenesis. These analyses identify the taurine-taurine transporter (TAUT) axis as a critical dependency of aggressive myeloid leukaemias. We find that cysteine dioxygenase type 1 (CDO1)-driven taurine biosynthesis is restricted to osteolineage cells, and increases during myeloid disease progression. Blocking CDO1 expression in osteolineage cells impairs LSC growth and improves survival outcomes. Using TAUT genetic loss-of-function mouse models and patient-derived acute myeloid leukaemia (AML) cells, we show that TAUT inhibition significantly impairs in vivo myeloid leukaemia progression. Consistent with elevated TAUT expression in venetoclax-resistant AML, TAUT inhibition synergizes with venetoclax to block the growth of primary human AML cells. Mechanistically, our multiomic approaches indicate that the loss of taurine uptake inhibits RAG-GTP dependent mTOR activation and downstream glycolysis. Collectively, our work establishes the temporal landscape of stromal signals during leukaemia progression and identifies taurine as a key regulator of myeloid malignancies.

DOI: https://doi.org/10.1038/s41586-025-09018-7
Eur J Haematol. 2025 May 15.

Myeloid Neoplasms With Erythroid Predominance and Excess Blasts in Young Adults Exhibit Distinct Genetic Profiles.

Laurène Fenwarth, Benjamin Podvin, Loïc Vasseur, Delphine Lebon, Guillaume Couillez, Céline Berthon, Alexis Caulier, Elise Fournier, Claire Bories, Benjamin Carpentier, Sabine Tricot, Kevin-James Wattebled, Catherine Roche-Lestienne, Valentin Lestringant, Carine Hauspie, Karine Celli-Lebras, Maël Heiblig, Hervé Dombret, Raphael Itzykson, Jean-Pierre Marolleau, Loïc Garçon, Claude Preudhomme, Nicolas Duployez, Thomas Boyer.

  The evolution of acute myeloid leukemia (AML) classifications has progressively shifted the diagnostic focus toward genetic criteria. Nevertheless, morphology remains a key element in clinical practice, often serving as the initial trigger for additional molecular investigations. The diagnosis of acute erythroleukemia (AEML), initially defined by the FAB group, is no longer recognized as a distinct entity in the latest WHO and ICC classifications. Some studies have indicated that AEML shares similarities with myelodysplastic neoplasms, including a high frequency of TP53 mutations and adverse karyotypes. Here, we conducted a retrospective analysis in adults with AEML defined using historical morphologic criteria (≥ 50% erythroid precursors and ≥ 20% blasts among non-erythroid cells). In contrast to older patients, young adults (18-60 years) exhibit unique genetic profiles including a high prevalence of normal karyotypes (65%), NPM1 (35%) and UBTF (23%) mutations. AEML morphology in NPM1-mutated cases did not impact clinical outcomes but was associated with specific molecular features, including an enrichment of WT1 and cohesin gene mutations. In this age group, our findings support that morphologically defined AEML often corresponds to AML according to current genetic criteria, consistent with recent classification systems that prioritize molecular features over morphology.

Keywords:  AML; NPM1; UBTF; classification; erythroleukemia

DOI:  https://doi.org/10.1111/ejh.14435
Cancer Res. 2025 May 12.

A Machine Learning-Based Strategy Predicts Selective and Synergistic Drug Combinations for Relapsed Acute Myeloid Leukemia.

Yingjia Chen, Liye He, Aleksandr Ianevski, Kristen Nader, Tanja Ruokoranta, Nora Linnavirta, Juho J Miettinen, Markus Vähä-Koskela, Ida Vänttinen, Heikki Kuusanmaki, Mika Kontro, Kimmo Porkka, Krister Wennerberg, Caroline A Heckman, Anil K Giri, Tero Aittokallio.

Combination therapies are one potential approach to improve the outcomes of patients with refractory or relapsed disease. However, comprehensive testing in scarce primary patient material is hampered by the many drug combination possibilities. Furthermore, inter- and intra-patient heterogeneity necessitates personalized treatment optimization approaches that effectively exploit patient-specific vulnerabilities to selectively target both the disease- and resistance-driving cell populations. Here, we developed a systematic combinatorial design strategy that uses machine learning to prioritize the most promising drug combinations for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). The predictive approach leveraged single-cell transcriptomics and single-agent response profiles measured in primary patient samples to identify targeted combinations that co-inhibit treatment resistant cancer cells individually in each AML patient sample. Cell type compositions evolved dynamically between the diagnostic and R/R stages uniquely in each patient, hence requiring personalized drug combination strategies to target therapy-resistant cancer cells. Cell population-specific drug combination assays demonstrated how patient-specific and disease stage-tailored combination predictions led to treatments with synergy and strong potency in R/R AML cells, while the same combinations elicited non-synergistic effects in the diagnostic stage and minimal co-inhibitory effects on normal cells. In preliminary experiments on clinical trial samples, the approach predicted clinical outcomes to venetoclax-azacitidine combination therapy in patients with AML. Overall, the computational-experimental approach provides a rational means to identify personalized combinatorial regimens for individual AML patients with R/R disease that target treatment-resistant leukemic cells, thereby increasing their likelihood for clinical translation.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3840
ACS Med Chem Lett. 2025 May 08. 16(5): 887-895

IRAK1/4/pan-FLT3 Kinase Inhibitors with Reduced hERG Block as Treatments for Acute Myeloid Leukemia.

Scott B Hoyt, Chris J Finocchio, Elizabeth Croll, Gregory J Tawa, Mingliang Zhang, Jiangong Wang, Huixi Li, Li Ma, Kaikai Li, Xiaohu Zhang, Xin Xu, Pranav Shah, Yuhong Fang, Lyndsey C Bolanos, Gabriel Gracia-Maldonado, Amal Kolt, Christina Robinson, Jessica Free, Elijah F Edmondson, Simone Difilippantonio, LaQuita M Jones, Ashley E Culver-Cochran, Jan S Rosenbaum, Daniel T Starczynowski, Craig J Thomas.

We report the optimization of a series of IRAK1/4/pan-FLT3 kinase inhibitors. These efforts have produced a key compound 27 that displays potent and selective inhibition of IRAK1, IRAK4, and FLT3, reduced block of hERG, and good pharmacokinetic properties. In a mouse xenograft model of acute myeloid leukemia (AML), 27 produces survival prolongation superior to that of gilteritinib, the leading FDA-approved FLT3 inhibitor currently used to treat AML.

DOI: https://doi.org/10.1021/acsmedchemlett.5c00147
Br J Haematol. 2025 May 12.

Inhibition of DOCK1 suppresses Notch signalling pathway and impairs leukaemogenesis.

Ming-En Lin, Yueh-Chwen Hsu, Hsueh-Ling Chiu, Chi-Yuan Yao, Chia-Hua Liu, Chein-Jun Kao, Chang-Tsu Yuan, Chia-Lang Hsu, Yi-Tsung Yang, Hsin-An Hou, Wen-Chien Chou, Hwei-Fang Tien.

  Dedicator of cytokinesis 1 (DOCK1), a guanine nucleotide exchange factor for the small GTPase Rac, has been implicated in various biological processes, but its pathological roles in acute myeloid leukaemia (AML) remain unexplored. In this study, we analysed the clinical impacts of DOCK1 expression in 341 patients with de novo non-M3 AML treated with standard chemotherapy. The results showed that high DOCK1 expression is an independent adverse prognostic factor. Consistent with this, experiments using cell lines, xenografts and Dock1 conditional-knockout mice all demonstrated the pro-survival effects of DOCK1 in AML cells. This observation was corroborated by findings that the absence of Dock1 ameliorated the MN1-induced AML phenotypes. Transcriptome analyses demonstrated an association between DOCK1 expression and upregulated Notch signalling, and the causal relationship was supported by cell line experiments. Furthermore, single-cell RNA sequencing of MN1-induced mouse AML cells revealed a unique cluster with upregulated stem cell functions and Hes1, a Notch target, in the Dock1 wild type but not knockout background. These findings underscore the clinical and pathogenic significance of DOCK1 in AML and support its potential as a therapeutic target.

Keywords:  DOCK1; acute myeloid leukaemia; leukaemogenesis; notch; survival

DOI:  https://doi.org/10.1111/bjh.20140
Cell Rep. 2025 May 14. pii: S2211-1247(25)00476-0. [Epub ahead of print]44(5): 115705

Transcription factor cooperativity at a GATA3 tandem DNA sequence determines oncogenic enhancer-mediated activation.

Joana R Costa, Yang Li, Nurkaiyisah Zaal Anuar, David O'Connor, Sunniyat Rahman, Tanya Rapoz-D'Silva, Kent T M Fung, Rachael Pocock, Zhaodong Li, Stephen Henderson, Lingyi Wang, Mateja E Krulik, Sara Hyseni, Nivedita Singh, George Morrow, Yanping Guo, Daisy O F Gresham, Javier Herrero, Richard G Jenner, A Thomas Look, Dennis Kappei, Marc R Mansour.

  The TAL1 oncogene driving T cell lymphoblastic leukemia is frequently activated through mutated cis-regulatory elements, whereby small insertions or deletions (indels) create a binding site for the transcription factor MYB. Unraveling how non-coding mutations create oncogenic enhancers is key to understanding cancer biology and can provide important insights into fundamental mechanisms of gene regulation. Utilizing a CRISPR-Cas9 screening approach, we identify GATA3 as the key transcriptional regulator of enhancer-mediated TAL1 overexpression. CRISPR-Cas9 engineering of the mutant enhancer reveals a tandem GATA3 site that is required for binding of GATA3, chromatin accessibility, and MYB recruitment. Reciprocally, MYB binding to its motif is required for GATA3 recruitment, consistent with a transcription factor cooperativity model. Importantly, we show that GATA3 stabilizes a TAL1-MYB interaction and that complex formation requires GATA3 binding to DNA. Our work sheds light on the mechanisms of enhancer-mediated oncogene activation, where key transcription factors cooperate to achieve maximal transcriptional output, thereby supporting leukemogenesis.

Keywords:  CP: Cancer; CP: Molecular biology; DNA binding domain; GATA3; MYB; T cell acute lymphoblastic leukemia; T-ALL; TAL1; cooperativity; enhancer; motif; oncogene; transcription factor

DOI:  https://doi.org/10.1016/j.celrep.2025.115705
Blood. 2025 May 15. pii: blood.2024027455. [Epub ahead of print]

Defective neutrophil clearance in JAK2V617F myeloproliferative neoplasms drives myelofibrosis via immune checkpoint CD24.

Eman Khatib-Massalha, Christian Andrea Di Buduo, Agathe L Chédeville, Ya-Hsuan Ho, Yexuan Zhu, Elodie Grockowiak, Yuki Date, Lam Tan Khuat, Zijian Fang, Jose Quesada-Salas, Eva Carrillo Félez, Matteo Migliavacca, Isabel Montero, José Antonio Pérez-Simón, Alessandra Balduini, Simón Méndez-Ferrer.

Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell-driven malignancies marked by excessive myelopoiesis and high risk of myelofibrosis, which remains therapeutically challenging. Senescent neutrophils home daily to the bone marrow (BM) to be cleared by macrophages. This avoids their accumulation, which can increase the risk of chronic inflammation or oncogenesis. Neutrophils carrying the most common oncogenic MPN driver (JAK2V617F) are protected from apoptosis, which may prolong their lifespan and enhance their pro-inflammatory activity. On the other hand, abnormal interactions of neutrophils with megakaryocytes ("emperipolesis") have been associated with BM fibrosis in disparate hematological disorders, including MPN and grey platelet syndrome; however, the underlying pathophysiology remains unclear. We investigated neutrophil homeostasis and cellular interactions in MPN. We found that senescent neutrophils evade homeostatic clearance and accumulate in JAK2V617F MPN, but not in MPN caused by the second most prevalent mutations affecting Calreticulin (CALR) gene. This is explained by GM-CSF-JAK2-STAT5-dependent upregulation of the "don't-eat-me" signal CD24 in neutrophils. Mechanistically, JAK2V617F CD24hi neutrophils evade efferocytosis, invade megakaryocytes and increase active TGF-b. Collectively, JAK2V617F neutrophil-megakaryocyte interactions promote platelet production in a humanized bioreactor and myelofibrosis in mouse models. Notably, chronic antibody blockade or genetic loss of CD24 restores clearance of senescent neutrophils, reduces emperipolesis and active TGF-b. Consequently, CD24 blockade improves thrombocytosis and prevents myelofibrosis in MPN mice. Taken together, these findings reveals defective neutrophil clearance as a cause of pathogenic microenvironmental interactions of inflammatory neutrophils with megakaryocytes, associated with myelofibrosis in MPN. Our study postulate CD24 as a candidate innate immune checkpoint in MPN.

DOI: https://doi.org/10.1182/blood.2024027455
Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2425812122

Discovery of an LSD1 PROTAC degrader.

Amir Hosseini, Xing Qiu, Yan Xiong, Ki Him Nicholas Chiang, Jerrel Catlett, Ines Kaltheuner, Zhijie Deng, Sudipta Ghosh, Yang Shi, Jian Jin.

  Aberrant expression of lysine-specific demethylase 1 (LSD1) has been implicated in various cancers, including acute myeloid leukemia (AML). Recent studies have revealed both catalytic and noncatalytic oncogenic functions of LSD1, which cannot be effectively addressed by traditional small-molecule inhibitors. Therefore, to remove LSD1 and mitigate its oncogenic activity, we utilized the proteolysis-targeting chimera (PROTAC) approach and developed an LSD1 PROTAC degrader MS9117, which recruits the E3 ligase cereblon (CRBN). MS9117 induces LSD1 degradation in a concentration-, time-, CRBN-, and proteasome-dependent manner. Importantly, MS9117 effectively degrades LSD1 and demonstrates superior antiproliferative effects in AML cells, compared to the existing pharmacological LSD1 inhibitors. Furthermore, MS9117 also sensitized nonacute promyelocytic leukemia AML cells to all-trans retinoic acid treatment. Moreover, we developed two negative controls of MS9117, MS9117N1 and MS9117N2, which do not degrade LSD1 or inhibit leukemia cell growth, further confirming the mechanism of action of MS9117. Overall, MS9117 serves as a valuable chemical tool and a potential therapeutic to target both the catalytic and scaffolding functions of LSD1. With several LSD1 inhibitors already in clinical development, the LSD1 degraders such as MS9117 offer an additional option for future clinical studies.

Keywords:  AML; ATRA; LSD1; PROTAC; degrader

DOI:  https://doi.org/10.1073/pnas.2425812122
Sci Rep. 2025 May 14. 15(1): 16775

CLEVER-1 targeting antibody, bexmarilimab, supports HLA-DR expression and alters ex vivo responsiveness to azacitidine and venetoclax in myeloid malignancies.

Sofia Aakko, Arno Ylitalo, Heikki Kuusanmäki, Jenna H Rannikko, Mari Björkman, Jami Mandelin, Caroline A Heckman, Mika Kontro, Maija Hollmén.

  Treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) requires new therapy options, especially for patients uneligible for intense chemotherapy or with relapsed or refractory disease. CLEVER-1 is a myeloid checkpoint protein, which can be targeted with a therapeutic function blocking antibody, bexmarilimab. Bexmarilimab has shown clinical efficacy in different solid tumors. Here, we show preclinical data demonstrating expression of CLEVER-1 on immature malignant myeloid cells and their derivates in MDS and AML bone marrow samples and AML cell lines. Highest CLEVER-1 levels were observed in AML with monocytic differentiation. Ex vivo treatment of AML/MDS bone marrow samples with bexmarilimab led to an increase in antigen-presenting human leukocyte antigen DR isotype (HLA-DR) molecule expression. Combination of bexmarilimab with current standard-of-care (SoC) drugs, azacitidine and venetoclax, showed potential for HLA-DR induction and enhanced killing of leukemic cells, respectively. Our non-clinical findings support the feasibility of CLEVER-1 inhibition in AML/MDS to induce antigen presentating molecule expression and potentially, an anti-leukemic effect together with SoC. Therapeutic targeting of CLEVER-1 with bexmarilimab is currently undergoing clinical investigation in the BEXMAB trial (NCT05428969).

Keywords:  Acute myeloid leukemia; Bexmarilimab; CLEVER-1; Immunotherapy; Myelodysplastic syndrome; Stabilin-1

DOI:  https://doi.org/10.1038/s41598-025-01675-y
Leukemia. 2025 May 15.

The evolving landscape of epigenetic target molecules and therapies in myeloid cancers: focus on acute myeloid leukemia and myeloproliferative neoplasms.

Michael W M Kühn, Naveen Pemmaraju, Florian H Heidel.

Research on myeloid neoplasms, a field that has been driving scientific advances in cancer for over 50 years, has yielded many discoveries that have fundamentally reshaped our understanding of cancer biology. These insights, often the product of leukemia research, have been instrumental in developing more mechanism-based treatments in the early 2000s [1]. Recognizing epigenetic dysregulation as a common disease mechanism in myeloid cancers has been groundbreaking regarding recent treatment developments that exploit chromatin-based oncogenic mechanisms. In the case of acute myeloid leukemia (AML), sequencing studies aimed at assessing the complement of genetic alterations demonstrated that more than 60% of AML cases harbored disease-driving mutations in epigenetic regulators. This high prevalence underscores the importance of epigenetic dysregulation in AML pathogenesis [2, 3]. Chromatin regulators commonly control disease-specific transcriptional programs, making them attractive therapeutic targets to manipulate neoplastic gene expression programs, particularly in myeloid neoplasms. Several drugs targeting epigenetic mechanisms and exploiting myeloid disease-specific dependencies have recently been approved for treating myeloid neoplasms. Many additional drugs are currently being investigated in clinical trials, and numerous new compound developments are being studied in preclinical studies. This manuscript will review (1) chromatin-based disease mechanisms, such as DNA methylation, chromatin regulatory complexes, and histone modifications, currently investigated for therapeutic exploitation in myeloid malignancies, and (2) therapeutic developments already approved or investigated for treating these diseases.

DOI: https://doi.org/10.1038/s41375-025-02639-x
Am J Hematol. 2025 May 15.

The Mutational Landscape in Polycythemia Vera: Phenotype, Genotype, and Prognostic Correlates.

Masooma S Rana, Moazah Iftikhar, Yamna Jadoon, Maymona Abdelmagid, David S Viswanatha, Rong He, Kaaren K Reichard, Animesh D Pardanani, Naseema Gangat, Ayalew Tefferi.

  Polycythemia vera (PV) is invariably associated with a JAK2 mutation, with over 50% of patients harboring additional non-JAK2 mutations. In the current study, 319 patients with PV underwent NGS at diagnosis or in chronic phase PV (Group A: N = 270, 85%) or at the time of fibrotic (Group B; N = 37, 12%) or leukemic (Group C; N = 12, 4%) transformation. Mutational frequencies involving TP53/SRSF2/IDH1/U2AF1 were significantly (p < 0.05) different between patients in the mutually exclusive Groups A (2%/4%/2%/0.4%), B (8%/0%/0%/5%), and C (50%/25%/17%/8%). Analyses on phenotype/genotype associations and prognostic impact on overall (OS), leukemia-free (LFS), and myelofibrosis-free (MFFS) survival were limited to Group A patients. ASXL1MUT was associated with younger age (p < 0.01), SRSF2MUT with older age and leukocytosis (p < 0.01), and TP53MUT with leukocytosis (p < 0.01). Mutation co-segregation was apparent between ASXL1 and IDH2 (p < 0.01) or SRSF2 (p < 0.01), SRSF2 and IDH2 (p < 0.01), and TP53 and NRAS (p = 0.01). Multivariable analysis identified SRSF2MUT (p < 0.01; HR, 4.2, 1.9-9.5), IDH2MUT (p = 0.01; HR, 5.3, 1.8-15.3), ASXL1MUT (p = 0.04; HR, 2.0, 1.1-3.7), leukocyte count ≥ 15 × 109/L (p < 0.01; HR 2.0, 1.3-3.1), and advanced age (p < 0.01) as risk factors for OS. Median OS in the presence (N = 235; 87%) or absence (N = 35; 13%) of any adverse mutation (i.e., SRSF2MUT, ASXL1MUT, or IDH2MUT) was 8.8 versus 17.8 years (p = 0.01; HR 1.8, 1.1-2.9). In addition, ASXL1MUT (p = 0.02; HR, 1.6-24.9), SRSF2MUT (p = 0.06; HR, 11.9, 1.1-126.2), and advanced age (p = 0.04) were associated with inferior LFS, and SRSF2MUT (p < 0.01; HR, 24.0, 5.5-103.8) and abnormal karyotype (p < 0.01; HR 3.8, 1.6-8.9) with inferior MFFS. The number of non-JAK2 mutations was significant in predicting outcome in univariate but not multivariable analysis. The observations from the current study highlight the prognostic significance of non-JAK2 mutations in PV and the prospect of their inclusion in future prognostic models.

Keywords:  JAK2; NGS; cytogenetic; myeloproliferative; sequencing

DOI:  https://doi.org/10.1002/ajh.27717
Blood. 2025 May 15. pii: blood.2024026511. [Epub ahead of print]

How I Evaluate and Treat Resistance and Relapse in CML.

Simona Soverini, Fausto Castagnetti.

As evidenced by the excellent survival outcomes, chronic myeloid leukemia (CML) treatment in the era of tyrosine kinase inhibitors (TKIs) is often successful. However, when response milestones are not met or lost, treatment decision-making may be challenging. The availability for first-, second- or subsequent-line use of six different TKIs, each with definite and often non-overlapping features in terms of mechanism of action, potency, activity against resistance mutations and tolerability profile provides a reassuring opportunity to rescue an optimal response, but it must be exploited carefully to avoid hasty or inappropriate choices. When and how to sequence TKIs, and if and when to consider transplant are very important issues. 'One for all' rules cannot be formulated, since for each individual patient the decision process requires investigation and integration of a series of clinical and biological factors. After discussing how resistance is defined, we here aim to provide practical guidance to therapeutic reassessment, discussing which laboratory investigations should be performed, how they should be interpreted, which additional clinical considerations are mandatory, and how these factors should be weighed and reasonably concur to the final decision.

DOI: https://doi.org/10.1182/blood.2024026511
Br J Haematol. 2025 May 13.

Erythroid-stimulating agents in VEXAS syndrome: A retrospective study from an Italian multicentre cohort.

E Diral, C Campochiaro, G Furnari, F Moretti, J Ferrari, C Elena, G Battipaglia, S Barbato, A Vitale, M Frigeni, F Crisafulli, M Frassi, C Papayannidis, A D Romagnoli, C Cattaneo, A D'Ambrosio, E Morsia, P Musto, G Rivoli, M E Dragani, C Toffalori, G M Bergonzi, G Scorpio, A Tomelleri, M T Voso, C Gurnari, L Vago, L Dagna, F Ciceri.



Keywords:  VEXAS; erythropoietin; macrocytic anaemia; myelodysplastic neoplasms

DOI:  https://doi.org/10.1111/bjh.20157
Bone Marrow Transplant. 2025 May 13.

Addition of mycophenolate mofetil to a calcineurin inhibitor and post-transplant cyclophosphamide results in lower incidence of extensive chronic graft-versus-host disease in HLA-matched allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia in complete remission: a matched-pair analysis on behalf of the Acute Leukemia Working Party of the EBMT.

Giorgia Battipaglia, Myriam Labopin, Aleksandr Kulagin, Jurgen Versluis, Goda Choi, Ellen Meijer, Montserrat Rovira, Gwendolyn van Gorkom, Mi Kwon, Yener Koc, Jan Vydra, Patrizia Chiusolo, Amit Patel, Simona Piemontese, Jaime Sanz, Annalisa Ruggeri, Arnon Nagler, Fabio Ciceri, Mohamad Mohty.

Whether one or two agents added to post-transplant cyclophosphamide (PTCy) are needed in HLA-matched allogeneic hematopoietic stem cell transplantation (allo-HSCT) with peripheral blood stem cells (PBSC) is debated. We retrospectively compared PTCy in association with a calcineurin inhibitor (PTCy+CNI) or with a CNI plus mycophenolate mofetil (PTCy+CNI+MMF) in adult patients transplanted for acute myeloid leukemia in first complete remission and receiving PBSC in the period from 2010 to 2020. Propensity score matching was performed using exact matching for donor type (related or unrelated) and the nearest neighbor for other variables (i.e. age, adverse cytogenetics, Karnofsky performance status, patient and donor cytomegalovirus serology, conditioning intensity). Each group comprised 146 patients, with 63% in total undergoing matched unrelated-allo-HSCT. Median follow up was longer for PTCy+CNI (36 [IQR 31-39] months versus 25 [IQR 19-30] months for PTCy+CNI+MMF, p < 0.01). At 2 years, PTCy+CNI was associated with a higher incidence of extensive chronic GVHD (16% [95% CI 10-22] versus 6% [95% CI 3-12] for PTCy+CNI+MMF, p < 0.03) while no differences were observed for all the other transplant outcomes. Addition of MMF to PTCy and CNI may help to prevent extensive chronic GVHD in HLA-matched allo-HSCT with PBSC.

DOI: https://doi.org/10.1038/s41409-025-02610-5
Eur J Haematol. 2025 May 12.

Genetic Landscape and Risk Stratification of AML With Hyperdiploid Karyotype.

Ehsan Bahrami Hezaveh, Jiong Yan, Davidson Zhao, Collins Wangulu, Winnie Lo, Cuihong Wei, Hong Chang.

  Hyperdiploid karyotype (HK) (49-65 chromosomes) in acute myeloid leukemia (AML) is rare. Recently, HK-AML with only numerical changes has been reclassified into an intermediate risk group in the updated 2022 European LeukemiaNet (ELN) risk classification, which has historically been classified into an adverse risk group. However, there are limited data in the literature concerning whether these new exclusion criteria are appropriate, and the genetic landscape of HK-AML remains unclear. We retrospectively analyzed a cohort of HK-AML diagnosed at our institution. Among 124 cases, 72 (58.1%) had concurrent adverse risk cytogenetic abnormalities (HK-ADV), 33 (26.6%) had other concurrent structural abnormalities (HK-STR) and 19 (15.3%) had numerical changes alone (HK-NUM). The most frequently gained chromosomes were chromosomes 8, 22, 21, and 19. TP53 mutation was associated with HK-ADV, and a higher frequency of mutations in DNA methylation genes was present in HK-NUM and HK-STR. Patients with HK-NUM had significantly longer overall survival (OS) and event-free survival (EFS) compared to those with HK-ADV. In the adjusted model accounting for confounders, the HK-STR outcome was superior to that of HK-ADV but was not significantly different from that of HK-NUM. In addition, patients with a modal chromosome number of 49-53 had more favorable survival than those with ≥ 54 chromosomes. Our data support the reclassification of HK-NUM patients in the intermediate risk group and suggest that HK-STR might also be more appropriately classified into the intermediate risk group.

Keywords:  acute myeloid leukemia; complex karyotype; cytogenetics; gene mutation; hyperdiploid karyotype; prognosis

DOI:  https://doi.org/10.1111/ejh.14434
Nat Commun. 2025 May 13. 16(1): 4451

Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs.

Julie A I Thoms, Feng Yan, Henry R Hampton, Sarah Davidson, Swapna Joshi, Jesslyn Saw, Chowdhury H Sarowar, Xin Ying Lim, Andrea C Nunez, Purvi M Kakadia, Golam Sarower Bhuyan, Xiaoheng Zou, Mary Nguyen, Elaheh S Ghodousi, Forrest C Koch, Fatemeh Vafaee, I Richard Thompson, Mohammad M Karimi, Russell Pickford, Mark J Raftery, Sally Hough, Griselda Buckland, Michelle Bailey, Yuvaraj Ghodke, Noorul Absar, Lachlin Vaughan, Leonardo Pasalic, Chun Y Fong, Melita Kenealy, Devendra K Hiwase, Rohanna I Stoddart, Soma Mohammed, Linda Lee, Freda H Passam, Stephen R Larsen, Kevin J Spring, Kristen K Skarratt, Patricia Rebeiro, Peter Presgrave, William S Stevenson, Silvia Ling, Campbell Tiley, Stephen J Fuller, Fernando Roncolato, Anoop K Enjeti, Dirk Hoenemann, Charlotte Lemech, Christopher J Jolly, Stefan K Bohlander, David J Curtis, Jason W H Wong, Ashwin Unnikrishnan, Mark Hertzberg, Jake Olivier, Mark N Polizzotto, John E Pimanda.

Hypomethylating agents are frontline therapies for myelodysplastic neoplasms (MDS), yet clinical responses remain unpredictable. We conducted a phase 2 trial comparing injectable and oral azacitidine (AZA) administered over one or three weeks per four-week cycle, with the primary objective of investigating whether response is linked to in vivo drug incorporation or DNA hypomethylation. Our findings show that injection results in higher drug incorporation, but lower DNA demethylation per cycle, while global DNA methylation levels in mononuclear cells are comparable between responders and non-responders. However, hematopoietic stem and progenitor cells (HSPCs) from responders exhibit distinct baseline and early treatment-induced CpG methylation changes at regulatory regions linked to tissue patterning, cell migration, and myeloid differentiation. By cycle six-when clinical responses typically emerge-further differential hypomethylation in responder HSPCs suggests marrow adaptation as a driver of improved hematopoiesis. These findings indicate that intrinsic baseline and early drug-induced epigenetic differences in HSPCs may underlie the variable clinical response to AZA in MDS.

DOI: https://doi.org/10.1038/s41467-025-59796-x
Leukemia. 2025 May 13.

Acute myeloid leukemia stem cells remodel the bone marrow niche via TGF-β-activated Alcam+ bone lining cells, creating a self-sustaining environment.

Ngan Thi Kim Nguyen, Hisayuki Yao, Kentaro Hosokawa, Yuki Esaki, Ryosuke Yuta, Shunichi Adachi, Fumio Arai.

DOI: https://doi.org/10.1038/s41375-025-02640-4
Blood Adv. 2025 May 09. pii: bloodadvances.2025016843. [Epub ahead of print]

Conflating polycythemia vera with essential thrombocytosis.

Jerry L Spivak.

DOI: https://doi.org/10.1182/bloodadvances.2025016843
ACS Omega. 2025 May 06. 10(17): 17441-17452

Inhibition of MIF with an Allosteric Inhibitor Triggers Cell Cycle Arrest in Acute Myeloid Leukemia.

Georgios Pantouris, Leepakshi Khurana, Pathricia Tilstam, Alison Benner, Thomas Yoonsang Cho, Martin Lelaidier, Mathieu Perrée, Zoe Rosenbaum, Lin Leng, Francine Foss, Vineet Bhandari, Amit Verma, Richard Bucala, Elias J Lolis.

Macrophage migration inhibitory factor (MIF) is a key modulator of innate and adaptive immunity that has been extensively reported to promote tumor cell survival, proliferation, and metastasis. A recent study focusing on the microenvironment of acute myeloid leukemia (AML) showed that pharmacological inhibition of MIF signaling, in vitro as well as in vivo, reduces AML cell survival. Such data highlights the crucial role of MIF in AML pathogenesis and support the efforts for developing selective MIF modulators. Here, we report the identification and crystallographic characterization of a MIF inhibitor (compound 1) with an allosteric binding motif. Single point screening of 1 against a panel of National Cancer Institute (NCI) 60 human tumor cell lines revealed a selective antitumor activity for the AML cell line HL-60. After confirming the protein's expression in multiple AML cell lines, we utilized 1 to extract mechanistic insights into MIF action. Our findings demonstrate that AML cells utilize an MIF-dependent proliferation mechanism, which upon inhibition triggers a G0/G1 cell cycle arrest of the malignant cells. Complementary analysis of the MIF receptors utilizing neutralizing antibodies and selective small molecule antagonists associates this effect with inhibition of CD74 activation. The collection of data presented herein highlights the important role of MIF in proliferation of AML cells and points to the need of developing small molecule anticancer therapeutics that target MIF signaling.

DOI: https://doi.org/10.1021/acsomega.4c10969
Blood. 2025 May 15. pii: blood.2024028133. [Epub ahead of print]

Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from the FRENVEX group.

Vincent Jachiet, Olivier Kosmider, Maxime Beydon, Jerome Hadjadj, Lin-Pierre Zhao, Vincent Grobost, Valentin Lacombe, Guillaume Le Guenno, Yann Nguyen, Jean Benoit Arlet, Jeremie Dion, Mael Heiblig, Alice Garnier, Maxime Samson, Achille Aouba, Sylvain Thepot, Sophie Dimicoli-Salazar, Fabien Dutasta, Benoit Faucher, Estibaliz Lazaro, Veronique Morel, Antoine Neel, Roderau Outh, Holy Bezanahary, Julien Rossignol, Anne-Sophie Alary, Audrey Bidet, Pauline Blateau, Anne Bouvier, Guilaine Boursier, Matthieu Decamp, Benjamin Lebecque, Yannick Le Bris, Pierre Sujobert, Alice Marceau-Renaut, Cedric Pastoret, David Rizzo, Nathalie Boiret-Dupré, Lara Boucher, Stéphanie Dulucq, Franck Genevieve, Cassandra Jadeau, Pierre Lemaire, Romain Vazquez, Jean Baptiste Rieu, Olivier Fain, Sophie Anne Georgin-Lavialle, Lucie Rigolot, Lise Larcher, Pierre Hirsch, Benjamin Terrier, Pierre Fenaux, Arsène M Mékinian, Thibault Comont.

VEXAS (Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic) syndrome is a severe monogenic disorder caused by somatic UBA1 mutations, characterized by inflammation, cytopenias and frequent association with myelodysplastic neoplasms (MDS). Steroid dependence is common, and targeted therapies have demonstrated limited efficacy. Azacitidine (AZA), a hypomethylating agent used in MDS, has shown potential in VEXAS but data remain limited. This multicenter retrospective study assessed AZA efficacy and safety in 88 genetically confirmed VEXAS patients from the FRENVEX (French VEXAS) group, 80% meeting WHO 2022 MDS criteria. Inflammatory response rates were 41% at 6 months and 54% at 12 months, regardless of MDS status. A total of 50 (61%) patients achieved inflammatory response, with 70% occurring at 6 months, suggesting a delayed median response. Among responders, relapse-free survival on AZA was 90% at 1 year and 85% at 5 years. Of the 12 responders who discontinued AZA, 9 relapsed after a median of 3.1 years (range: 0.4-5.6), with effective re-exposure in 4 of 5 patients. Hematological responses included red blood cell transfusion independence in 65% and platelet improvement in 77% of patients. Molecular response, defined as a ≥25% reduction in UBA1 variant allele frequency (VAF), was observed in 65% of patients, all of whom achieved inflammatory and hematological responses; and VAF dropped below 2% in 43% of cases. Infections (34%) and cytopenias (36%) were common, particularly during the first three cycles. This study establishes AZA as an effective therapy for VEXAS, improving inflammation, cytopenias, and UBA1 clonal burden, warranting larger prospective trials.

DOI: https://doi.org/10.1182/blood.2024028133
Exp Hematol. 2025 May 10. pii: S0301-472X(25)00090-6. [Epub ahead of print] 104799

Effect of peri-transplant measurable residual disease clearance in patients with myelodysplastic neoplasm; a referral center experience: Effect of peri-HSCT MRD Clearance in MDS.

Kittika Poonsombudlert, Sarah Mott, Ratdanai Yodsuwan, Andrew Vegel, Aditya Ravindra, Prajwal Dhakal, Grerk Sutamtewagul, Margarida Magalhaes-Silverman.

  Peri-allogeneic stem cell transplant (peri-HSCT) measurable residual disease (MRD) is increasingly recognized as a prognostic marker. However, the MRD status in myelodysplastic neoplasm (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN), are less well-established compared to B-Acute Lymphoblastic Leukemia. We reviewed the charts of adults who underwent HSCT for MDS or MDS/MPN between 2012-2023 and evaluated the effect of pre-HSCT MRD status on relapse-free and overall survival (RFS and OS). A conditional analysis of outcomes based on day+90 post-HSCT MRD status was also performed. There were 38 and 55 patients in MRD- and MRD+ cohorts respectively. Baseline patient characteristics, including age, Revised and Molecular International Prognostic Scores (IPSS-R & IPSS-M), and HSCT-related factors were similar between MRD+ and MRD- cohort. The MRD+ cohort had inferior RFS (HR: 1.84, 95% CI: 1.09-3.12, p=0.02) but a statistically significant difference in OS was not evidenced (HR: 1.52, 95% CI: 0.88-2.61, p=0.14). After adjusting for % blasts at diagnosis, and conditioning intensity, MRD+ patients were found to be at 1.92 times increased risk of relapse or death (95% CI: 1.12-3.28, p=0.02). Additionally, increasing IPSS-M score was associated with poorer RFS (HR: 1.27, 95% CI: 1.01-1.59, p=0.04) and OS (HR: 1.52, 95% CI: 1.20-1.91, p<0.01). Among patients who were alive and in remission until day +90 post-HSCT, the pre-HSCT MRD status did not confer a statistically significant difference in RFS and OS if they became MRD- by day +90 post-HSCT. Pre- and peri-HSCT MRD testing could offer valuable prognostic information in patients with MDS and MDS/MPN. Teaser Abstract: Not overall survival (OS) but relapse free survival (RFS) can be affected by pre-allogeneic stem cell transplant (pre-HSCT) measurable residual disease (MRD) clearance in patients with myelodysplastic neoplasm (MDS) but more importantly, there is no significant difference in OS and RFS in patients who achieve MRD negative complete remission by day+90 post-HSCT. Graft-versus-tumor effect may exert its effect later in the HSCT course, and clearance of MRD pre-HSCT alone may not reliably predict HSCT outcomes. Post-HSCT MRD surveillance should be performed routinely in MDS patients.

Keywords:  Myelodysplastic neoplasm (MDS); allogeneic stem cell transplant (HSCT); measurable residual disease (MRD)

DOI:  https://doi.org/10.1016/j.exphem.2025.104799
Haematologica. 2025 May 15.

Characterization and prognostic implication of pulmonary hypertension among patients with myeloproliferative neoplasms.

Orly Leiva, Steven Soo, Olivia Liu, Nathaniel R Smilowitz, Harmony Reynolds, Binita Shah, Samuel Bernard, Joan How, Michelle Hyunju Lee, Gabriela Hobbs.

Pulmonary hypertension (PH) is a frequent complication of Philadelphia-negative myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). However, its prognostic significance is understudied, thus we aimed to evaluate the effect of PH identified by echocardiography on risk of progression to secondary MF or acute leukemia in MPN patients. We conducted a multicenter, retrospective cohort study of MPN patients with ≥ 1 echocardiogram from 2010-2023. PH was defined as pulmonary artery systolic pressure (PASP) ≥ 40 mmHg. Outcomes were progression to secondary myelofibrosis or leukemia, major adverse cardiovascular event (MACE) and all-cause death. Multivariable Fine-Gray competing-risk regression was used to estimate subhazard ratio (SHR) of hematologic progression and MACE. 555 patients were included (42.7% PV, 41.1% ET, 16.2% MF) or which 195 (35.1%) had PH. Over a median follow-up period of 51.2 months, PH was associated with increased risk of secondary MF progression (aSHR 2.40, 95% CI 1.25-4.59), leukemia progression (aSHR 3.06, 95% CI 1.13 - 8.25), and MACE (aSHR 1.59, 95% CI 1.01- 2.49) but not all-cause death (aHR 1.48, 95% CI 0.96-2.26). Among patients with PH, absence of left heart disease (LHD) was associated with higher risk of secondary MF progression among patients with ET or PV (aSHR 2.76, 95% CI 1.19 - 6.38) and leukemia progression among patients with MF (aSHR 7.18, 95% CI 1.59-32.46). Prospective studies are needed to assess the role of echocardiography on MPNspecific prognostication.

DOI: https://doi.org/10.3324/haematol.2025.287497
Br J Haematol. 2025 May 13.

Real-world outcomes of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome at a tertiary referral centre.

Lucia Lee, Eric J Zhao, Robert Schmidt, Alym Abdulla, Gayatri Sreenivasan, Kimberley Ambler, Megan Hiltz, Lynda Foltz, Vicki Chan, Alexandra Legge, Maggie Yuen, Lauren Lee, Paul Yenson, Thomas J Nevill, Luke Y C Chen, Ryan J Stubbins.



Keywords:  JAK inhibition; UBA1; VEXAS syndrome; autoinflammation; myelodysplastic syndromes

DOI:  https://doi.org/10.1111/bjh.20153
Blood Cancer J. 2025 May 14. 15(1): 94

Prognostic value of measurable residual disease (MRD) for venetoclax in combination with hypomethylating agents in patients diagnosed with acute myeloid leukemia: validation of the ELN-2021 MRD recommendations.

Spanish CETLAM Group

DOI: https://doi.org/10.1038/s41408-025-01298-6
Blood. 2025 May 12. pii: blood.2024026512. [Epub ahead of print]

How I approach hematopoietic stem cell transplantation for CML in a TKI world.

Yves Chalandon, Federico Simonetta, Stavroula Masouridi-Levrat.

Following the introduction of tyrosine kinase inhibitors (TKI), the number of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic phase chronic myeloid leukemia (CP-CML) has dramatically decreased. Imatinib was the 1st TKI introduced into the clinical arena, predominantly utilized in the 1st line setting. In cases of insufficient response, resistance, or intolerance, CML patients can subsequently be treated with a 2nd, 3rdor 4th generation TKI. However, despite the approval of 1st, 2nd, 3rd, 4th generation TKI allo-HSCT still remains indicated for a minority of CML patients. Here, we discuss the indications in the era of TKI through different cases representing the clinical situations for which allo-HSCT remains the best option. We also propose our transplant strategy to decrease transplant-related morbidity, particularly graft-versus-host disease (GvHD), and mortality in the particular context of CML, a disease that is one of the most sensitive to immune cellular therapy, allowing the use of a combination of donor lymphocyte infusion (DLI) and TKI for post-transplant molecular progression.

DOI: https://doi.org/10.1182/blood.2024026512