bims-tremyl 2025-04-27 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–04–27
29 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Treatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein.
Phosphatidic acid phosphatase LPIN1 in phospholipid metabolism and stemness in hematopoiesis and AML.
Dual targeting of EZH2 and EZH1 drives exit of leukemia stem cells from quiescence and potentiates chemotherapy in acute myeloid leukemia.
Engineered cytokine-expressing MSCs support ex vivo culture of human HSPCs and AML cells.
Safety and efficacy of the combination of azacitidine with venetoclax after hypomethylating agent failure in higher-risk myelodysplastic syndrome.
Abnormal nucleoli architecture and aggregate formation in Nucleophosmin mutated Acute Myeloid Leukaemia.
Allogeneic stem cell transplantation in de novo core-binding factor acute myeloid leukemia in active disease: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1.
RBC Transfusion Dependency Refines the Molecular International Prognostic Scoring System for Myelodysplastic Syndrome.
Orchestration of human multi-lineage hematopoietic cell development by humanized in vivo bone marrow models.
Impact of myelodysplasia-related gene mutations and residual mutations at remission in venetoclax/azacitidine for AML.
Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias.
Protocol for the isolation and characterization of murine hematopoietic stem and progenitor cell-derived extracellular vesicles.
Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice.
Clonal Hematopoiesis as a Driver of Solid Tumors.
Heterogeneity of high-potency multilineage hematopoietic stem cells and identification of 'Super' transplantability.
SETD2 loss of function is a recurrent event in advanced-phase chronic myeloid leukemia and contributes to genomic instability: SETD2 loss in Chronic Myeloid Leukemia.
Cytokine release syndrome: implications for transplant outcomes in haploidentical and HLA-matched HSCT using PTCy.
Prophylactic and pre-emptive donor lymphocyte infusion in patients with acute myeloid leukemia and myelodysplastic syndrome: validation of current recommendations and proposal of a modified outcome assessment.
Which Is the Best Tyrosine Kinase Inhibitor for Newly Diagnosed Chronic Myelogenous Leukemia?
Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids.
Unbiased analysis of NUP98-KDM5A-induced murine leukemia reveals phenotypic heterogeneity recapitulating human disease subtypes.
Loss of NOL10 leads to impaired disease progression of NUP98::DDX10 leukemia.
Ruxolitinib mediated paradoxical JAK2 hyperphosphorylation is due to the protection of activation loop tyrosines from phosphatases.
Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes: a practical guide to diagnosis and management.
Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.
Coordinated regulation of self-renewal and cell cycle during human lympho-myeloid lineage restriction.
Management of liver sinusoidal obstruction syndrome/veno-occlusive disease in adults: a 2025 perspective from an international expert group.
Tumor-Infiltrating Clonal Hematopoiesis.

Nat Biotechnol. 2025 Apr 23.

Treatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein.

Benson M George, Maria Eleftheriou, Eliza Yankova, Jonathan Perr, Peiyuan Chai, Gianluca Nestola, Karim Almahayni, Siân Evans, Aristi Damaskou, Helena Hemberger, Charlotta G Lebedenko, Justyna Rak, Qi Yu, Ece Bapcum, James Russell, Jaana Bagri, Regan F Volk, Malte Spiekermann, Richard M Stone, George Giotopoulos, Brian J P Huntly, Joanna Baxter, Fernando Camargo, Jie Liu, Balyn W Zaro, George S Vassiliou, Leonhard Möckl, Jorge de la Rosa, Ryan A Flynn, Konstantinos Tzelepis.

Immunotherapies for acute myeloid leukemia (AML) and other cancers are limited by a lack of tumor-specific targets. Here we discover that RNA-binding proteins and glycosylated RNAs (glycoRNAs) form precisely organized nanodomains on cancer cell surfaces. We characterize nucleophosmin (NPM1) as an abundant cell surface protein (csNPM1) on a variety of tumor types. With a focus on AML, we observe csNPM1 on blasts and leukemic stem cells but not on normal hematopoietic stem cells. We develop a monoclonal antibody to target csNPM1, which exhibits robust anti-tumor activity in multiple syngeneic and xenograft models of AML, including patient-derived xenografts, without observable toxicity. We find that csNPM1 is expressed in a mutation-agnostic manner on primary AML cells and may therefore offer a general strategy for detecting and treating AML. Surface profiling and in vivo work also demonstrate csNPM1 as a target on solid tumors. Our data suggest that csNPM1 and its neighboring glycoRNA-cell surface RNA-binding protein (csRBP) clusters may serve as an alternative antigen class for therapeutic targeting or cell identification.

DOI: https://doi.org/10.1038/s41587-025-02648-2
Hemasphere. 2025 Apr;9(4): e70118

Phosphatidic acid phosphatase LPIN1 in phospholipid metabolism and stemness in hematopoiesis and AML.

Karin Huber, Swati Garg, Lena Schlautmann, Rui Wang, Lixiazi He, Richard Huth, Alireza Pouya, Christian Rohde, Maike Janssen, Christian Lüchtenborg, Christian Arnold, Pilar M Luque-Navarro, Judith B Zaugg, Simon Raffel, Carsten Müller-Tidow, Irmela Jeremias, Luisa C López-Cara, Britta Brügger, Caroline Pabst.

Targeting metabolism represents a promising approach to eradicate leukemic stem cells (LSCs) that are considered critical drivers of relapse in acute myeloid leukemia (AML). In this study, we demonstrate that the phosphatidic acid phosphatase LPIN1, which regulates the synthesis of diacylglycerol, the key substrate for triacylglycerol, and phospholipid production, is crucial for the function of healthy and leukemic hematopoietic stem and progenitor cells (HSPC and LSC). LPIN1 mRNA was highly expressed in the CD34+ compartment of primary human AML samples. LPIN1 suppression inhibited the proliferation of primary leukemic cells and normal HSPCs in vitro and in xenotransplantation assays. Lipidomics analyses revealed a reduction of phosphatidylcholine (PC) and phosphatidylethanolamine and an upregulation of sphingomyelin upon LPIN1 depletion. Distinct phospholipid composition was associated with genetic AML groups, and targeting PC production by choline kinase inhibitors showed strong anti-leukemic activity. In summary, our data establish a regulatory role of LPIN1 in HSPC and LSC function and provide novel insights into the role of glycerophospholipid homeostasis in stemness and differentiation.

DOI: https://doi.org/10.1002/hem3.70118
Blood Cancer J. 2025 Apr 24. 15(1): 76

Dual targeting of EZH2 and EZH1 drives exit of leukemia stem cells from quiescence and potentiates chemotherapy in acute myeloid leukemia.

Hiroki Akiyama, Yuki Nishida, Kyung Hee Chang, Andrea D Bedoy, Muharrem Muftuoglu, Wencai Ma, Mahesh Basyal, Zoe Hirschi, Daisuke Honma, Shinji Tsutsumi, Jing Wang, Weiguo Zhang, Xuelin Huang, Raajit K Rampal, Olalekan O Oluwole, Dale Lee Bixby, Naval G Daver, Michael Andreeff.

DOI: https://doi.org/10.1038/s41408-025-01266-0
Exp Hematol. 2025 Apr 22. pii: S0301-472X(25)00081-5. [Epub ahead of print] 104790

Engineered cytokine-expressing MSCs support ex vivo culture of human HSPCs and AML cells.

Johannes Foßelteder, Thomas Brauchart, Angelika Schlacher, Tommaso Sconocchia, Erdem Özkaya, Lisa Auinger, Peter Schlenke, Heinz Sill, Armin Zebisch, Andreas Reinisch.

CD34+ human hematopoietic stem and progenitor cells (HSPCs) and primary patient-derived leukemia cells are important tools for basic and translational research. Their limited availability demands additional expansion ex vivo in many cases. The use of either cytokine cocktails or co-cultures with mesenchymal stromal cells (MSCs) has advanced cell expansion but combinations of both have not been addressed extensively so far. Here, we present a novel approach to generate human cytokine-expressing MSCs (ceMSCs) via genetic engineering. Co-culture with ceMSCs and their culture supernatant led to an efficient expansion and maintenance of functional CD34+CD45RA-CD90+CD201+CD49c+ HSCs ex vivo. Similarly, ceMSCs and their culture supernatant support the growth of cytokine-dependent leukemic cell lines in vitro, and improved the survival, maintenance, and expansion of patient-derived acute myeloid leukemia (AML) cells, a cell population very challenging to be cultured ex vivo. ceMSCs even surpass the support provided by wild-type MSCs or external cytokines alone. Therefore, ceMSCs offer a cost-effective, straightforward alternative to traditional cytokine supplementation, enhancing the feasibility of ex vivo studies on healthy and leukemic stem and progenitor cells, including therapeutic drug testing and mechanistic investigations.

DOI: https://doi.org/10.1016/j.exphem.2025.104790
Leuk Res. 2025 Apr 08. pii: S0145-2126(25)00052-9. [Epub ahead of print]153 107692

Safety and efficacy of the combination of azacitidine with venetoclax after hypomethylating agent failure in higher-risk myelodysplastic syndrome.

Julie S Braish, Guillermo Montalban-Bravo, Farhad Ravandi, Nicholas Short, Tapan Kadia, Maro Ohanian, Kelly Chien, Lucia Masarova, Koji Sasaki, Musa Yilmaz, Sanam Logahvi, Naval Daver, Gautam Borthakur, Elias Jabbour, Heather Schneider, Lizabeth T Romero, Hagop Kantarjian, Guillermo Garcia-Manero.

   OBJECTIVE: Therapies for patients with higher-risk myelodysplastic syndromes (HR-MDS) who have failed hypomethylating agents (HMAs) are needed. This Phase I/II study evaluates the safety, tolerability, and efficacy of venetoclax, an orally bioavailable BCL-2 inhibitor, in combination with azacitidine in this population.
METHODS: We conducted a single-center, dose-escalation, Phase I/II trial (NCT04550442) involving 33 patients with HR-MDS or CMML (IPSS ≥ 1.5) who had progressed after prior HMA therapy. Patients received intravenous or subcutaneous azacitidine (SC) (75 mg/m² for 5 days) and venetoclax (100-400 mg for 7-14 days in a 28-day cycle). The primary endpoints were safety/tolerability (Phase 1) and overall response rate (ORR) (Phase 2).
RESULTS: Patients received a median of 3 cycles (range, 1-22). The maximum tolerated dose of venetoclax was 400 mg. Common grade 3-4 adverse events included neutropenia (19 %) and thrombocytopenia (10 %). The 4-week early mortality rate was 9 %. The ORR was 49 %, and the median overall survival (OS) was 7 months (95 % CI, 3.5-10.5). The median progression-free survival (PFS) was 6 months (95 % CI, 3.0-9.0). Four patients (12 %) underwent stem cell transplantation, with 3 of 4 alive at last follow-up (75 %).
CONCLUSION: Combining venetoclax with azacitidine is feasible for HR-MDS and CMML patients who failed prior HMA therapy. However, this combination did not significantly improve clinical outcomes in this patient population.

Keywords:  Azacitidine; Chronic myelomonocytic leukemia; Hypomethylating agent failure; Myelodysplastic syndrome; Venetoclax

DOI:  https://doi.org/10.1016/j.leukres.2025.107692
J Cell Sci. 2025 Apr 22. pii: jcs.263553. [Epub ahead of print]

Abnormal nucleoli architecture and aggregate formation in Nucleophosmin mutated Acute Myeloid Leukaemia.

Martin Grundy, Kellie Lucken, Xiaomeng Xing, Eva L Simpson, Alice Worker, Ahmed Bayyoomi, Alison J Beckett, Ian A Prior, Daniel G Booth, Claire H Seedhouse.

  Mutations in the Nucleophosmin (NPM1) gene represent the most common genetic alteration in Acute Myeloid Leukaemia (AML) and result in mis-localisation of the mutated protein from a predominantly nucleolar localisation to a predominantly cytoplasmic distribution. Here, we use high resolution imaging to demonstrate that NPM1 is critical for maintaining normal nucleoli architecture and specifically the integrity of the enigmatic nucleoli rim, the least understood nucleolar compartment. We demonstrate that cell lines and primary AML patient cells with NPM1 mutations have aberrant nucleoli architecture; intriguingly this abnormal nucleolar phenotype is reversible. Using a surrogate for rRNA synthesis, we show that the aberrant phenotype is associated with differences in nucleolar function, specifically activity is increased in NPM1 mutated cells. Perinucleolar chromatin organisation is also markedly different in NPM1 mutant cells. Finally, we report the novel finding that NPM1 mutated protein forms distinct aggregates and characterise these for the first time. This work reveals how nucleolar organisation contributes to the molecular mechanisms underpinning NPM1 driven AML revealing novel therapeutic vulnerabilities.

Keywords:  Acute Myeloid Leukaemia; Aggregates; Mutations; Nucleoli; Nucleophosmin

DOI:  https://doi.org/10.1242/jcs.263553
Bone Marrow Transplant. 2025 Apr 23.

Allogeneic stem cell transplantation in de novo core-binding factor acute myeloid leukemia in active disease: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Sara Tarantino, Myriam Labopin, Robert Zeiser, Matthias Stelljes, Thomas Schroeder, Nicolaus Kröger, Wolfgang Bethge, Jakob Passweg, Martin Bornhäuser, Christoph Schmid, Johanna Tischer, Matthias Eder, Eolia Brissot, Jordi Esteve, Arnon Nagler, Mohamad Mohty, Fabio Ciceri.

Core-binding factor acute myeloid leukemia (CBF-AML) generally has a favorable prognosis, with allogeneic hematopoietic stem cell transplantation (allo-SCT) recommended for relapsed/ refractory (R/R) cases achieving second complete remission (CR). However, clinical outcomes remain suboptimal for patients who relapse or fail to achieve CR following induction chemotherapy. Allo-SCT in non-CR is a potential strategy for such patients, though supporting evidence in CBF-AML is limited. To assess outcomes and prognostic factors of allo-SCT in R/R CBF-AML with active disease, we conducted a retrospective analysis of 610 patients with CBF-AML in non-CR undergoing allo-SCT from 2010 to 2021 across 174 centers within the European Society for Blood and Marrow Transplantation. Graft sources included matched sibling (MSD, n = 151), unrelated (UD, n = 368), and haploidentical donors (Haplo, n = 91). Among patients, 124 had inv(16), and 486 had t(8;21). Two-year overall survival (OS) and leukemia-free survival (LFS) were 53.6% and 42.7%, respectively. Haplo-SCT showed inferior OS compared to MSD (HR 1.79, p = 0.003) and UD (HR 1.64, p = 0.004) and reduced chronic graft-versus-host disease. Patients with t(8;21) exhibited higher relapse incidence (HR 2.04, p = 0.002) and poorer survival outcomes than those with inv(16). These findings confirm the therapeutic role of allo-SCT in R/R CBF-AML in non-CR, supporting its favorable risk profile.

DOI: https://doi.org/10.1038/s41409-025-02596-0
Nature. 2025 Apr 23.

Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1.

Puneet Agarwal, Avery Sampson, Kathleen Hueneman, Kwangmin Choi, Niels Asger Jakobsen, Emma Uible, Chiharu Ishikawa, Jennifer Yeung, Lyndsey Bolanos, Xueheng Zhao, Kenneth D Setchell, David B Haslam, Jessica Galloway-Pena, John C Byrd, Paresh Vyas, Daniel T Starczynowski.

Clonal haematopoiesis of indeterminate potential (CHIP) involves the gradual expansion of mutant pre-leukaemic haematopoietic cells, which increases with age and confers a risk for multiple diseases, including leukaemia and immune-related conditions1. Although the absolute risk of leukaemic transformation in individuals with CHIP is very low, the strongest predictor of progression is the accumulation of mutant haematopoietic cells2. Despite the known associations between CHIP and increased all-cause mortality, our understanding of environmental and regulatory factors that underlie this process during ageing remains rudimentary. Here we show that intestinal alterations, which can occur with age, lead to systemic dissemination of a microbial metabolite that promotes pre-leukaemic cell expansion. Specifically, ADP-D-glycero-β-D-manno-heptose (ADP-heptose), a biosynthetic bi-product specific to Gram-negative bacteria3-5, is uniquely found in the circulation of older individuals and favours the expansion of pre-leukaemic cells. ADP-heptose is also associated with increased inflammation and cardiovascular risk in CHIP. Mechanistically, ADP-heptose binds to its receptor, ALPK1, triggering transcriptional reprogramming and NF-κB activation that endows pre-leukaemic cells with a competitive advantage due to excessive clonal proliferation. Collectively, we identify that the accumulation of ADP-heptose represents a direct link between ageing and expansion of rare pre-leukaemic cells, suggesting that the ADP-heptose-ALPK1 axis is a promising therapeutic target to prevent progression of CHIP to overt leukaemia and immune-related conditions.

DOI: https://doi.org/10.1038/s41586-025-08938-8
Blood Adv. 2025 Apr 23. pii: bloodadvances.2025016086. [Epub ahead of print]

RBC Transfusion Dependency Refines the Molecular International Prognostic Scoring System for Myelodysplastic Syndrome.

Thomas Wiseman, Michaela Spooner, Shreyas Khanna, Kevin Hung, Carla Toop, Monika M Kutyna, Joanne Yu, Anna L Brown, Hamish S Scott, Christopher N Hahn, Chung Hoow Kok, Devendra K Hiwase.

DOI: https://doi.org/10.1182/bloodadvances.2025016086
Hemasphere. 2025 Apr;9(4): e70120

Orchestration of human multi-lineage hematopoietic cell development by humanized in vivo bone marrow models.

Laurent Renou, Wenjie Sun, Chloe Friedrich, Klaudia Galant, Cecile Conrad, Anne Consalus, Evelia Plantier, Katharina Schallmoser, Linda Krisch, Vilma Barroca, Saryami Devanand, Nathalie Dechamps, Andreas Reinisch, Jelena Martinovic, Alessandra Magnani, Lionel Faivre, Daniel Lewandowski, Julien Calvo, Leila Perie, Olivier Kosmider, Françoise Pflumio.

Hematopoiesis develops in the bone marrow (BM) where multiple interactions regulate the differentiation and preservation of hematopoietic stem and progenitor cells (HSPCs). Immune-deficient murine models have enabled the analysis of molecular and cellular regulation of human HSPCs, but the physiology of these models is questioned as human hematopoietic cells develop in xenogenic microenvironments. In this study, we thoroughly characterized a humanized (h) in vivo BM model, developed from fetal (F/) and post-natal (P-N/) mesenchymal stromal cell (MSC) differentiation (called hOssicles [hOss]), in which human hematopoietic cells are generated following the transplantation of CD34+ cells. Serial isolation and transplant experiments of hMSCs and HSPCs from hOss revealed the dynamic nature of these hBM niches. hOss modified human hematopoietic development by modulating myeloid/lymphoid cell production and HSPC levels, with no major transcriptional changes in HSPCs at the single-cell level. Clonal tracking using genetic barcodes highlighted hematopoietic cell cross-talks between the endogenous murine BM and hOss and differences in clonal myeloid/multipotent cell production between F/hOss and P-N/hOss, uncovering ontogeny-related impact of the BM on human hematopoietic cell production.

DOI: https://doi.org/10.1002/hem3.70120
Leukemia. 2025 Apr 21.

Impact of myelodysplasia-related gene mutations and residual mutations at remission in venetoclax/azacitidine for AML.

Yoshikazu Ikoma, Nobuhiko Nakamura, Yuto Kaneda, Hiroyuki Takamori, Tomokazu Seki, Nobuhiro Hiramoto, Junichi Kitagawa, Junya Kanda, Kei Fujita, Tetsuji Morishita, Yotaro Ochi, Shigeru Chiba, Nana Sasaki, Michiko Ichii, Kazunori Imada, Mizuki Watanabe, Masakatsu Hishizawa, Yasuko Miyahara, Yoshitomo Maesako, Yasuhiro Tanaka, Satoko Oka, Masaaki Tsuji, Satoshi Yoshihara, Kinuko Mitani, Yasunori Ueda, Toshiyuki Kitano, Mitsumasa Watanabe, Nobuo Sezaki, Tadakazu Kondo, Senji Kasahara, Akifumi Takaori-Kondo, Nobuhiro Kanemura, Seishi Ogawa, Yasuhito Nannya.

Venetoclax plus azacitidine (VEN + AZA) is widely used in acute myeloid leukemia (AML). This study explored the role of static and dynamic profiles of mutational clonal burden to predict outcomes by analyzing marrow samples from 228 VEN + AZA treated AML cases at "Pre-treatment" (n = 228), "Best-response" (n = 105), and "Relapse" (n = 27) phases using targeted-capture sequencing. In a multivariate model, older age, prior AZA, TP53 mutation with variant allele frequency ≥0.10, and RAS-pathway mutations predicted shorter overall survival (OS), while BCORL1 mutation predicted longer OS. Notably, myelodysplasia-related gene mutations, which constitute adverse factors in ELN 2022, predicted favorable survival. Achieving composite complete remission (CRc) significantly predicted longer OS (P < 0.001) but showed residual mutations in 76.2% of the cases. Among CRc cases, relapse-free survival was stratified by molecular clearance of mutations other than DNMT3A, ASXL1, and TET2 (P = 0.04). In addition, 37% of relapsed cases showed a change of major clones, with 40% having potential targets of molecular-targeting treatment. This study revealed the novel prognostic role of myelodysplasia-related gene mutations and established the importance of molecular response assessment in CRc phase.

DOI: https://doi.org/10.1038/s41375-025-02625-3
Cell. 2025 Apr 21. pii: S0092-8674(25)00399-X. [Epub ahead of print]

Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias.

Won Jun Kim, Edie I Crosse, Emma De Neef, Inaki Etxeberria, Erich Y Sabio, Eric Wang, Jan Philipp Bewersdorf, Kuan-Ting Lin, Sydney X Lu, Andrea Belleville, Nina Fox, Cynthia Castro, Pu Zhang, Takeshi Fujino, Jennifer Lewis, Jahan Rahman, Beatrice Zhang, Jacob H Winick, Alexander M Lewis, Robert F Stanley, Susan DeWolf, Brigita Meškauskaitė Urben, Meril Takizawa, Tobias Krause, Henrik Molina, Ronan Chaligne, Priya Koppikar, Jeffrey Molldrem, Mathieu Gigoux, Taha Merghoub, Anthony Daniyan, Smita S Chandran, Benjamin D Greenbaum, Christopher A Klebanoff, Robert K Bradley, Omar Abdel-Wahab.

  Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here, we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-major histocompatibility complex (MHC) dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8+ T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing SRSF2 mutant-induced neoantigens arising from mis-splicing events in CLK3 and RHOT2 resulted in specific recognition and cytotoxicity of SRSF2-mutant leukemia. These data identify recurrent RNA mis-splicing events as sources of actionable public neoantigens in myeloid leukemias and provide proof of concept for genetically redirecting T cells to recognize these targets.

Keywords:  RNA splicing; SF3B1; SRSF2; T cell receptor; U2AF1; ZRSR2; acute myeloid leukemia; immunotherapy; myelodysplastic syndromes; neoantigen

DOI:  https://doi.org/10.1016/j.cell.2025.03.047
STAR Protoc. 2025 Apr 17. pii: S2666-1667(25)00184-4. [Epub ahead of print]6(2): 103778

Protocol for the isolation and characterization of murine hematopoietic stem and progenitor cell-derived extracellular vesicles.

Federica Zanotti, Ilaria Zanolla, Massimo Bonora, Claudia Morganti, Barbara Zavan, Letizia Ferroni, Paolo Pinton, Keisuke Ito.

  Hematopoietic stem cells (HSCs) maintain their self-renewal capacity in an autocrine manner through hematopoietic stem and progenitor cell (HSPC)-derived extracellular vesicles (EVs). Here, we present a protocol for the isolation and characterization of EVs from HSPCs starting from an in vivo murine model. We describe steps for murine bone marrow isolation, HSPC staining and sorting, HSPC-derived EV isolation, size and concentration characterization, and EV visualization and marker description. For complete details on the use and execution of this protocol, please refer to Bonora et al.1.

Keywords:  Cell Biology; Cell isolation; Flow Cytometry; Metabolism; Stem Cells

DOI:  https://doi.org/10.1016/j.xpro.2025.103778
Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00380-8. [Epub ahead of print]44(5): 115609

Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice.

Netherlands Brain Bank

  Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment that resists seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles. Due to their hematopoietic stem cell (HSC) derivation, monocyte-derived microglia (MoMg) are unlike yolk-sac-derived cells, targets of clonal hematopoiesis (CH). Indeed, using a chimeric transfer model, we show that the hematopoietic expression of DNMT3AR882H, a prominent human CH variant, renders MoMg pathogenic and promotes motor deficits resembling atypical Parkinsonian disorders. Collectively, we establish that MoMg progressively seed the brain of healthy aging mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can cause brain pathology.

Keywords:  ARCH; CH; CHIP; CP: Immunology; CP: Neuroscience; DNMT3A R882H; HSC; brain macrophages; clonal hematopoiesis; microglia; monocytes

DOI:  https://doi.org/10.1016/j.celrep.2025.115609
N Engl J Med. 2025 Apr 24. 392(16): 1654-1656

Clonal Hematopoiesis as a Driver of Solid Tumors.

Lachelle D Weeks, Benjamin L Ebert.

DOI: https://doi.org/10.1056/NEJMe2504775
Blood. 2025 Apr 21. pii: blood.2024027872. [Epub ahead of print]

Heterogeneity of high-potency multilineage hematopoietic stem cells and identification of 'Super' transplantability.

Fang Dong, Sen Zhang, Caiying Zhu, Zining Yang, Lisha Wang, Yao Ma, Jiayi Lu, Xialin Li, Xiaofang Wang, Nini Wang, Shanshan Zhang, Miner Xie, Jinhong Wang, Xiaobing Zhang, Yawei Zheng, Shihui Ma, Hideo Ema, Hui Cheng, Sha Hao, Toshio Suda, Yu Lan, Bing Liu, Ping Zhu, Junren Chen, Tao Cheng.

Hematopoietic stem cells (HSCs) are heterogeneous, and the quality of HSCs - that is, 'transplantability' - is a key determinant for posttransplant hematopoietic reconstitution. However, molecular modalities of high-potency HSCs with superior transplantability still remain poorly understood. Here, we conducted large-scale single-clone serial-transplant experiments and tracked descendant cells of 288 HSC clones to quantify their intrinsic capability for hematopoietic reconstitution. Using integrated single-cell transcriptional, immunophenotypical, and Bayesian dynamic analyses, we uncovered three classes of HSC clones - 'Super', 'Flash', and 'Trickle' - that had higher output in the 1st generation but exhibited markedly different behavior in later generations. The 'Super'-class HSC clones comprised 4% of the HSCs and manifested persistent superior transplantability and balanced myeloid/lymphoid lineage outputs across generations in serial transplants. The 'Super'-class HSCs had a unique molecular signature, including low expression of CD27, that was distinct from previously known 'Classical HSC' signatures. Validation experiments indicated that CD27- HSCs had superior transplantability compared to CD27+ HSCs. Our study asserted an operational definition for 'Super' transplantability of HSCs, defined its molecular program, and suggested new directions for enriching high-potency HSCs in grafts.

DOI: https://doi.org/10.1182/blood.2024027872
Clin Transl Med. 2025 Apr;15(4): e70163

SETD2 loss of function is a recurrent event in advanced-phase chronic myeloid leukemia and contributes to genomic instability: SETD2 loss in Chronic Myeloid Leukemia.

Manuela Mancini, Sara De Santis, Cecilia Monaldi, Fausto Castagnetti, Miriam Iezza, Alessandra Iurlo, Daniele Cattaneo, Sara Galimberti, Marco Cerrano, Isabella Capodanno, Massimiliano Bonifacio, Maura Rossi, Claudio Agostinelli, Manja Meggendorfer, Torsten Haferlach, Michele Cavo, Gabriele Gugliotta, Simona Soverini.

  The SETD2 tumour suppressor encodes a histone methyltransferase that specifically trimethylates histone H3 on lysine 36 (H3K36me3), a key histone mark implicated in the maintenance of genomic integrity among other functions. We found that SETD2 protein deficiency, mirrored by H3K36me3 deficiency, is a nearly universal event in advanced-phase chronic myeloid leukemia (CML) patients. Similarly, K562 and KCL22 cell lines exhibited markedly reduced or undetectable SETD2/H3K36me3 levels, respectively. This resulted from altered SETD2 protein turnover rather than mutations or transcriptional downregulation, and proteasome inhibition led to the accumulation of hyper-ubiquitinated SETD2 and to H3K36me3 rescue suggesting that a functional SETD2 protein is produced but abnormally degraded. We demonstrated that phosphorylation by Aurora-A kinase and ubiquitination by MDM2 plays a key role in the proteasome-mediated degradation of SETD2. Moreover, we found that SETD2 and H3K36me3 loss impinges on the activation and proficiency of homologous recombination and mismatch repair. Finally, we showed that proteasome and Aurora-A kinase inhibitors, acting via SETD2/H3K36me3 rescue, are effective in inducing apoptosis and reducing clonogenic growth in cell lines and primary cells from advanced-phase patients. Taken together, our results point to SETD2/H3K36me3 deficiency as a mechanism, already identified by our group in systemic mastocytosis, that is reversible, druggable, and BCR::ABL1-independent, able to cooperate with BCR::ABL1 in driving genetic instability in CML. KEY POINTS: Virtually all CML patients in blast crisis display SETD2 loss of function. SETD2 loss seems to be accomplished at the posttranslational level rather than being the result of genetic/genomic hits or transcriptional repression. Phosphorylation by Aurora kinase A and ubiquitination by MDM2 contribute to SETD2 proteasome-mediated degradation in blast crisis CML patients. Loss of SETD2 results in increased DNA damage.

Keywords:  Aurora kinase A; H3K36me3; MDM2; SETD2; genomic instability

DOI:  https://doi.org/10.1002/ctm2.70163
Bone Marrow Transplant. 2025 Apr 23.

Cytokine release syndrome: implications for transplant outcomes in haploidentical and HLA-matched HSCT using PTCy.

Rafael Benavente, Juan Montoro, Aitana Balaguer-Roselló, Marta Villalba, Pedro Chorão, Pedro Asensi, Pablo Granados, Pilar Lloret, Inés Gómez-Seguí, Pilar Solves, Marta Santiago, Brais Lamas, Ana Bataller, Juan Eirís, David Martinez, Alberto Louro, Paula Rebollar, Aurora Perla, Javier de la Rubia, Miguel Á Sanz, Jaime Sanz.

This study assessed 552 allogeneic hematopoietic cell transplantation (HCT) recipients with posttransplant cyclophosphamide (PTCy) to evaluate the incidence, characteristics, risk factors, and impact of early posttransplant cytokine release syndrome (CRS) on outcomes. The cohort included 36% matched sibling donors (MSD), 34% matched unrelated donors (MUD), 27% haploidentical donors, and 4% mismatched unrelated donors (MMUD). CRS was observed in 182 patients, with the highest incidence in haploidentical transplants (80%) compared to MMUD (32%), MUD (23%), and MSD (8%). Most CRS cases were mild, with 93% classified as grade 1 and 6% as grade 2, with only one severe case of grade 3. In haploidentical transplants, CRS was linked to a lower risk of severe chronic graft-versus-host disease (GVHD) and non-relapse mortality (NRM), leading to improved overall survival. In contrast, among HLA-matched recipients (MSD and MUD), there were no significant differences in outcomes between those with or without CRS. However, subgroup analysis revealed that CRS in patients with myeloid malignancies, including acute myeloid leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms, was associated with a reduced relapse rate, improving survival outcomes. In conclusion, while CRS is typically mild and short-lived, it significantly impacts survival, particularly in haploidentical transplants and HLA-matched patients with myeloid malignancies.

DOI: https://doi.org/10.1038/s41409-025-02594-2
Haematologica. 2025 Apr 24.

Prophylactic and pre-emptive donor lymphocyte infusion in patients with acute myeloid leukemia and myelodysplastic syndrome: validation of current recommendations and proposal of a modified outcome assessment.

Giuliano Filippini Velázquez, Jan Frederic Weller, Anna Rubeck, Tobias Arndt, Stefan Schiele, Markus Mezger, Claudia Lengerke, Wolfgang Bethge, Martin Trepel, Gernot Müller, Maximilian Christopeit, Christoph Schmid.

Prophylactic and pre-emptive donor lymphocyte infusion (pro/preDLI) is used to prevent haematological relapse of AML and MDS after allogeneic stem cell transplantation. For lack of prospective trials, outcome reports, risk factor analyses and published recommendations for DLI administration had to rely on registry studies, frequently limited by inconsistent reporting and missing data. Therefore, we performed an extensive chart review on recipients of pro/preDLI in two German centers to investigate the clinical applicability of current guidelines in a well-defined cohort. Beyond, as outcome after pro/preDLI is unsatisfactorily described by conventional parameters, we constructed a model for treatment success, defined as leukaemia-free survival (LFS) without intensive immunosuppressive treatment for Graft-versus-Host-Disease (GvHD). Eighty-three patients had received proDLI (n=36), preDLI for incomplete chimerism (preDLIIC, n=27) or for persisting minimal residual disease/molecular relapse (preDLI-MRD, n=20). According to current guidelines concerning initial T cell doses and timing of DLI, 42% of patients had received DLI as recommended (standard-intensity), whereas 30%/28% had received DLI in lower/higher cell doses and/or at a later/earlier time point (low-/highintensity). Two-year rates of overall survival (OS), LFS, relapse incidence and non-relapse mortality within the entire cohort were 80%/67%/27%/8%. One-year rates of high-grade acute/chronic GvHD were 34%/27% among all patients and 53%/33% after high-intensity DLI. One-year treatment success rate were 72%/69% after low-/standard intensity, in contrast to 34% after high-intensity DLI. Apart from advanced disease at alloSCT, high-intensity DLI was the major risk factor for lower OS (HR=6.12), LFS (HR=5.43), higher aGvHD (HR=2.51), and lower treatment success (HR=0.41), supporting adherence to current recommendations.

DOI: https://doi.org/10.3324/haematol.2024.287206
Am Soc Clin Oncol Educ Book. 2025 Jun;45(3): e473082

Which Is the Best Tyrosine Kinase Inhibitor for Newly Diagnosed Chronic Myelogenous Leukemia?

Naranie Shanmuganathan, Michael Osborn, Timothy P Hughes.

The choice of frontline therapy for a patient with chronic phase chronic myeloid leukemia (CP-CML) can have a profound effect on the long-term clinical outcome. Currently, five tyrosine kinase inhibitors (TKIs-imatinib, dasatinib, nilotinib, bosutinib, and asciminib) are available for frontline therapy, but no single TKI is optimal for all patients. EUTOS long-term survival (ELTS) risk score, comorbidities, and treatment-free remission (TFR) priority are the key determinants of frontline TKI selection. Higher ELTS score, low age and comorbidity score, and a high priority for achievement of TFR would all favor the frontline use of a more potent TKI than imatinib. However, no TKI has improved survival compared with imatinib. In children with CP-CML, imatinib, dasatinib, and nilotinib have similar long-term efficacy, with ease of administration and impact of toxicities on quality of life being key considerations. Recent adult trials of reduced-dose dasatinib frontline showed that efficacy may be equivalent to standard-dose dasatinib with a better tolerability and safety profile, but experience is limited in patients with high-risk ELTS scores. The ASC4FIRST trial has confirmed that tolerability and molecular response with asciminib are superior to those with both imatinib and the second-generation (2G)-TKIs. While the overall treatment failure rate was lower with asciminib, the rate of BCR::ABL1 mutations that emerged with asciminib appeared to be higher. The risk of emergent mutations appears to be highly associated with the presence of ASXL1 mutations in the CML cells at diagnosis, but more work is needed to understand the implications of this finding.

DOI: https://doi.org/10.1200/EDBK-25-473082
Cell Death Dis. 2025 Apr 22. 16(1): 327

Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids.

Feng Yin, Jing Yang, Hao Luo, Tiantian Yu, Wenhua Lu, Mingyue Zhao, Hongli Du, Shijun Wen, Peng Huang, Yumin Hu.

FMS-like tyrosine kinase 3-internal tandem duplication (FLT3/ITD) is a common driver mutation that presents with a high leukemic burden and its impact on metabolic homeostasis remains to be further investigated. Here, we revealed that the oncogenic activation of FLT3/ITD induced upregulation of target genes of sterol regulatory element-binding proteins (SREBPs) in vivo and in acute myeloid leukemia patients. Quizartinib is a second-generation FLT3 inhibitor that selectively inhibits the activating FLT3 mutations. We demonstrated the critical role of SREBP1 degradation in conferring the response of FLT3/ITD cells to quizartinib. Mechanistically, quizartinib facilitated degradation of the precursor form of SREBP1 via the FLT3/AKT/GSK3 axis and reduced protein levels of its target gene fatty acid synthase (FASN). Lipidomics analysis by Liquid Chromatography Mass Spectrometry (LC-MS) demonstrated that inhibition of FLT3 altered global levels of phospholipids including reduction of cardiolipin, leading to subsequent loss of mitochondrial membrane potential. Pharmacological inhibition of SREBP1 or FASN sensitized FLT3/ITD leukemia cells to quizartinib. Quizartinib combined with SREBP inhibitor fatostatin or FASN inhibitor orlistat provided substantial therapeutic benefit over monotherapies in the murine FLT3/ITD leukemia model. Our results indicated the mechanistic link between FLT3/ITD and SREBP degradation and suggested the combination therapy via targeting FLT3/SREBP/FASN axis.

DOI: https://doi.org/10.1038/s41419-025-07661-6
Exp Hematol. 2025 Apr 19. pii: S0301-472X(25)00082-7. [Epub ahead of print] 104791

Unbiased analysis of NUP98-KDM5A-induced murine leukemia reveals phenotypic heterogeneity recapitulating human disease subtypes.

Marilaine Fournier, Marion Dubuissez, Mathieu Neault, Jean-Sébastien Delisle, Frédérick A Mallette, Heather J Melichar.

  NUP98-KDM5A (NK5) is an oncogenic fusion protein implicated in the development of several types of acute myeloid leukemia (AML) in humans, including rare pediatric acute megakaryoblastic leukemia (AMKL). NK5 expression in murine hematopoietic progenitor cells can induce AML in mice. However, the limited number of animals and phenotypic markers used in previous studies preclude the full characterization of the AML subtypes that develop. We used NK5-transduced hematopoietic progenitor cells from murine fetal liver to generate a large cohort of mice, assessed the expression of a panel of myeloid markers to characterize the lineage of leukemic blasts by flow cytometry, and used bioinformatic tools to perform an unbiased analysis assessing the extensive mouse-to-mouse heterogeneity in leukemic cellular phenotypes. We were able to identify phenotypically distinct sub-groups among the NK5 leukemias that segregated predominantly based on expression of the AMKL-associated marker CD41. Our results suggest that NK5 expression in fetal liver cells gives rise to heterogenous types of leukemia similar in proportion to that observed in human pediatric patients. The heterogeneity and mixed phenotypes observed might explain the difficulty in accurately diagnosing leukemia in some patients carrying the NK5 fusion. In addition, this approach may enable identification of the molecular or cellular basis of the diverse NK5-driven AML types. TEASER ABSTRACT: NUP98-KDM5A (NK5) gives rise to a variety of leukemia types in human, including rare pediatric AMKL. The development of curative treatments for NK5+ AMKL is hindered by the lack of animal models that recapitulate human disease. Using unbiased clustering of phenotypic data, we confirm that NK5+ leukemia can be modeled in mice and identify a population of NK5+ AMKL-like leukemias in similar proportion to that observed in human patients. The model will enable identification of the molecular mechanisms driving NK5 leukemias as well as the testing of tailored treatment approaches.

Keywords:  Acute Megakaryoblastic Leukemia; NUP98-KDM5A; Non-biased analysis

DOI:  https://doi.org/10.1016/j.exphem.2025.104791
Leukemia. 2025 Apr 22.

Loss of NOL10 leads to impaired disease progression of NUP98::DDX10 leukemia.

Yutaka Shima, Kazutsune Yamagata, Yoko Kuroki, Kazuki Sasaki, Yukiko Aikawa, Issay Kitabayashi.

NUP98 rearrangements associated with acute myeloid leukemia and myelodysplastic syndromes generate NUP98-fusion proteins. One such fusion protein, NUP98::DDX10, contains the putative RNA helicase DDX10. The molecular mechanism by which NUP98::DDX10 induces leukemia is not well understood. Here, we show that 24 amino acids within the DDX10 moiety of NUP98::DDX10 are crucial for cell immortalization and leukemogenesis. NOL10, nucleolar protein 10, interacts with the 24 amino acids, and NOL10 is a critical dependency of NUP98::DDX10 leukemia development. Studies in a mouse model of NUP98::DDX10 leukemia showed that loss of Nol10 impaired disease progression and improved survival. We also identified a novel function of NOL10 in that it acts cooperatively with NUP98::DDX10 to regulate serine biosynthesis pathways and stabilize ATF4 mRNA. Collectively, these findings suggest that NOL10 is a critical regulator of NUP98::DDX10 leukemia and that targeting NOL10 (or the serine synthesis pathway regulated by NOL10) may be an effective therapeutic approach.

DOI: https://doi.org/10.1038/s41375-025-02607-5
Leukemia. 2025 Apr 23.

Ruxolitinib mediated paradoxical JAK2 hyperphosphorylation is due to the protection of activation loop tyrosines from phosphatases.

Sivahari P Gorantla, Lorenz Oelschläger, Gerin Prince, Jasmin Osius, Suresh Babu Kolluri, Yamil Maluje, Anke Fähnrich, Nancy Ernst, Alanis Barbosa Gulde, Ralf Joachim Ludwig, Timo Gemoll, Stephanie Fliedner, Wencke Walter, Torsten Haferlach, Niklas Gebauer, Hauke Busch, Justus Duyster, Nikolas von Bubnoff.

Myelofibrosis (MF) in 50% of cases is driven by an activating JAK2 mutation, mostly V617F. Ruxolinitib is approved for the treatment of MF. Responses to ruxolitinib in MF are of limited duration. Unexpectedly, treatment of JAK2-V617F expressing cells with ruxolitinib causes paradoxical hyperphosphorylation of JAK2 at activation loop Tyr1007/Tyr1008. The significance of ruxolitinib-induced JAK2 hyperphosphorylation is not well understood. We found that a ruxolitinib-resistant JAK2 variant (V617F + L983F) and a kinase dead mutant (JAK2-V617F + K882R) did not show paradoxical hyperphosphorylation after ruxolitinib treatment indicating that it is an intrinsic mechanism. Antibodies against pTyr1007/1008 failed to immunoprecipitate native JAK2-V617F in the presence of ruxolitinib, although JAK2-V617F was hyperphosphorylated at these sites, suggesting that in the presence of ruxolitinib the JAK2 activation loop is buried within the kinase domain. This stabilization of the activation loop conformation resulted in the protection of pTyr1007/1008 sites from phosphatases. Mutation of Arg975 and Lys999 to Ala reduced the phosphorylation at both Tyr1007/Tyr1008 residues, and notably, ruxolitinib treatment did not lead to JAK2 hyperphosphorylation. Importantly, hyperphosphorylated JAK2 after ruxolitinib dissociation displayed excess rebound activation of STAT5 target gene PIM kinase. Our results suggest a novel mode of kinase regulation by modulating kinase activity through conformational changes induced by ruxolitinib.Subject categories: JAK2-V617F, Ruxolitinib, JAK2 hyperphosphorylation, Phosphatases action, PIM kinases.

DOI: https://doi.org/10.1038/s41375-025-02594-7
Leukemia. 2025 Apr 19.

Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes: a practical guide to diagnosis and management.

Douglas Tremblay, Robert P Hasserjian, Raajit K Rampal.

Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes are a rare group of biologically and clinically connected hematologic malignancies that includes chronic myelomonocytic leukemia (CMML), the most common subtype, as well as atypical chronic myeloid leukemia, MDS/MPN with SF3B1 and thrombocytosis, and MDS/MPN, not otherwise specified. Given their rarity and overlapping clinical features, accurate diagnosis and risk stratification presents a significant challenge. Therapeutic approaches are largely borrowed from either MDS or MPN and the only curative option for appropriate patients is allogeneic stem cell transplantation. Recent advances have started to uncover the pathobiologic basis for these diseases, leading to novel clinical trials for MDS/MPN overlap syndromes, in particular CMML. This review is a practical guide for the diagnosis and management of MDS/MPN overlap syndromes and presents novel therapeutics being specifically designed for these diseases to improve their historically poor outcomes.

DOI: https://doi.org/10.1038/s41375-025-02620-8
Nat Cell Biol. 2025 Apr 21.

Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.

Dohun Kim, Rushendhiran Kesavan, Kevin Ryu, Trishna Dey, Austin Marckx, Cameron Menezes, Prakash P Praharaj, Stewart Morley, Bookyong Ko, Mona H Soflaee, Harrison J Tom, Harrison Brown, Hieu S Vu, Shih-Chia Tso, Chad A Brautigam, Andrew Lemoff, Marcel Mettlen, Prashant Mishra, Feng Cai, Doug K Allen, Gerta Hoxhaj.

Nicotinamide adenine dinucleotide phosphate (NADPH) is a vital electron donor essential for macromolecular biosynthesis and protection against oxidative stress. Although NADPH is compartmentalized within the cytosol and mitochondria, the specific functions of mitochondrial NADPH remain largely unexplored. Here we demonstrate that NAD+ kinase 2 (NADK2), the principal enzyme responsible for mitochondrial NADPH production, is critical for maintaining protein lipoylation, a conserved lipid modification necessary for the optimal activity of multiple mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex. The mitochondrial fatty acid synthesis (mtFAS) pathway utilizes NADPH for generating protein-bound acyl groups, including lipoic acid. By developing a mass-spectrometry-based method to assess mammalian mtFAS, we reveal that NADK2 is crucial for mtFAS activity. NADK2 deficiency impairs mtFAS-associated processes, leading to reduced cellular respiration and mitochondrial translation. Our findings support a model in which mitochondrial NADPH fuels the mtFAS pathway, thereby sustaining protein lipoylation and mitochondrial oxidative metabolism.

DOI: https://doi.org/10.1038/s41556-025-01655-4
Blood. 2025 Apr 21. pii: blood.2024026936. [Epub ahead of print]

Coordinated regulation of self-renewal and cell cycle during human lympho-myeloid lineage restriction.

Fangwu Wang, Laura Gonzalez, Qiuyu Lian, Colin A Hammond, Yasmine Y M Lau, Benjamin D Simons, Martin Hirst, Connie J Eaves.

Recent studies indicate the human lympho-myeloid restriction process to be a different and more heterogeneous one than historically inferred. Here we describe the development of bulk and clonal culture systems that efficiently support early B-lymphoid differentiation and its use to elucidate the biological and molecular changes that accompany their initial restriction from subsets of CD34+ human cord blood cells with lympho-myeloid-limited potential. Analyses of these changes revealed that the acquisition of B-lymphoid- and neutrophil/monocyte (NM)-restricted properties are accompanied by a concomitantly accelerated and lineage-shared cell cycling activity and loss of self-renewal potential. Single-cell transcriptome analysis identified reduced expression of multiple self-renewal-associated genes and an accompanying heterogeneous activation of lineage-regulatory modules during the production of B, NM and dendritic cell precursors. By applying a novel culture system that supports early human lymphoid differentiation, we uncover a shared mechanism of proliferation control, along with persistent biological and transcriptional heterogeneity in cells undergoing B and NM lineage restriction.

DOI: https://doi.org/10.1182/blood.2024026936
Bone Marrow Transplant. 2025 Apr 22.

Management of liver sinusoidal obstruction syndrome/veno-occlusive disease in adults: a 2025 perspective from an international expert group.

Marion Larue, Florent Malard, Ahmed S Alaskar, Mahmoud Aljurf, Mutlu Arat, Marie Balsat, Frédéric Baron, Grzegorz Basak, Ali Bazarbachi, Francesca Bonifazi, Eolia Brissot, Fabio Ciceri, Selim Corbacioglu, Fiona Dignan, Anne Huynh, Michelle Kenyon, Jürgen Kuball, Silvy Lachance, Tamas Masszi, Arnon Nagler, Shinichiro Okamoto, Antonio Pagliuca, Annalisa Ruggeri, Tapani Ruutu, Ibrahim Yakoub-Agha, Yishan Ye, Rafael F Duarte, Zinaida Perić, Enric Carreras, Mohamad Mohty.

Sinusoidal obstruction syndrome (SOS) formerly known as Veno-occlusive disease (VOD) is a potentially fatal complication that occurs mainly after haematopoietic cell transplantation, especially allogeneic transplantation. The liver is the principal organ affected, though other organs, such as the lungs, may also be involved to a lesser extent. The condition is characterised by obstruction of the hepatic venules, leading to sinusoidal congestion, hepatic ischaemia and, in severe cases, fulminant liver failure. Recent refined diagnostic criteria, published by the European Society for Blood and Marrow Transplantation in 2023, provide a more accurate method of detecting SOS/VOD, allowing earlier intervention and better stratification of patients according to the severity of their disease. This article focuses on liver SOS/VOD and discussing key risk factors, new diagnostic methods and therapeutic strategies, with an emphasis on the early use of defibrotide, which remains the reference treatment for severe SOS/VOD.

DOI: https://doi.org/10.1038/s41409-025-02598-y
N Engl J Med. 2025 Apr 24. 392(16): 1594-1608

Tumor-Infiltrating Clonal Hematopoiesis.

Oriol Pich, Elsa Bernard, Maria Zagorulya, Andrew Rowan, Constandina Pospori, Ramy Slama, Hector Huerga Encabo, Jennifer O'Sullivan, Despoina Papazoglou, Panayiotis Anastasiou, Chrysante S Iliakis, Sally-Ann Clark, Krijn K Dijkstra, Vittorio Barbè, Chris Bailey, Aaron J Stonestrom, Katey S S Enfield, Mary Green, Charlotte K Brierley, Alastair Magness, David R Pearce, Robert E Hynds, Rija Zaidi, Jayant K Rane, Ángel F Álvarez-Prado, Kerstin Thol, Rachel Scott, Supreet Kaur Bola, Elena Hoxha, Steve K Harris, Karl S Peggs, Sergio A Quezada, Allan Hackshaw, Simone Zaccaria, Johanna A Joyce, Ilaria Malanchi, Michael F Berger, Mariam Jamal-Hanjani, Andreas Wack, Julian Downward, William Grey, Cristina Lo Celso, Eva Grönroos, Charles M Rudin, Adam J Mead, Dominique Bonnet, Elli Papaemmanuil, Charles Swanton.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear.
METHODS: We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors.
RESULTS: Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth.
CONCLUSIONS: TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).

DOI: https://doi.org/10.1056/NEJMoa2413361