bims-tremyl 2025-07-06 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–07–06
39 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Multi-Modal and Data-Driven Assessment of Myeloid Neoplasms Refines Classification Across Disease States.
Impact of transplant conditioning, NPM1 mutations, and measurable residual disease in FLT3-ITD acute myeloid leukemia.
Hematopoietic stem cell transplantation is effective in achieving long-term survival for post-aplastic anemia myeloid neoplasms: the EBMT Severe Aplastic Anemia Report.
Restoring p53 wild-type conformation in TP53-Y220C-mutant acute myeloid leukemia.
Advances in menin inhibition in acute myeloid leukemia.
Functional cure with single agent olutasidenib in relapsed IDH1/NPM1 co-mutated AML.
Systemic Mastocytosis in 910 Patients: Prognostic Contribution of the International Consensus Classification in the Context of the Mayo Alliance Prognostic System.
PTPN11 mutations define a rare but highly adverse subset of myelodysplastic syndromes.
Imbalanced TGFβ signalling and autophagy drive erythroid priming of hematopoietic stem cells in β-thalassemia.
Characterization of E1 enzyme dependencies in mutant-UBA1 human cells reveals UBA6 as a novel therapeutic target in VEXAS syndrome.
Restricted Human CD45 Isoglycoforms Serve as Functional E-selectin Ligands and Delineate Hematopoietic Maturity.
Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation.
ZIP10 as a potential therapeutic target in acute myeloid leukaemia.
Efficacy and safety of luspatercept with or without erythropoiesis-stimulating agent in patients with myelodysplastic neoplasms with ring sideroblasts: A multicentre real-life study by the GFM.
Induction chemotherapy with CPX-351 in acute myeloid leukemia: revisiting the role of early bone marrow assessment.
Disruption of normal stem cell function and transmission of myelodysplastic syndrome by self-renewal of committed myeloid lineage cells.
Asciminib for relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia.
Autophagosome-lysosome mediated secretion of the thrombopoietin receptor is modulated by distinct driver mutations of myeloproliferative neoplasm.
SIRT5 inhibition impairs mitochondrial metabolism and enhances venetoclax-induced elimination of acute myeloid leukemia cells.
A heterozygous CEBPA mutation disrupting the bZIP domain in a RUNX1 and SRSF2 mutational background causes MDS disease progression.
Clusterin drives myeloid bias in aged hematopoietic stem cells by regulating mitochondrial function.
TET2-mutant myeloid cells mitigate Alzheimer's disease progression via CNS infiltration and enhanced phagocytosis in mice.
A phase 1, first-in-human, dose-escalation study of JNJ-74856665 (dihydroorotate dehydrogenase inhibitor) alone or in combination in patients with AML or MDS.
The long-term effects of chemotherapy on normal blood cells.
Histamine dihydrochloride and low-dose interleukin-2 in an emerging landscape of relapse prevention in acute myeloid leukemia.
Disease Trajectories and Glucocorticoid Exposure in VEXAS Syndrome Treated with Cytokine-Directed Therapies.
Modeling mesenchymal stromal cell support to hematopoiesis within a novel 3D artificial marrow organoid system.
15-PGDH inhibition enhances hematopoietic regeneration during aging.
Detecting and quantifying clonal selection in somatic stem cells.
SGK1 repression by WT1 may confer a survival advantage to leukemic cells under stress conditions.
Treatment Free Remission (TFR) in Chronic Phase-Chronic Myeloid Leukemia (CP-CML): Analysis of Predictive Factors and Novel Baseline Scoring System to Predict Molecular Relapse.
Structure-guided design of a methyltransferase-like 3 (METTL3) proteolysis targeting chimera (PROTAC) incorporating an indole-nicotinamide chemotype.
Evaluation of current mouse in vivo models and advanced in vitro models for leukaemia research.
Iron chelation therapy in myelodysplastic syndromes and allogeneic hematopoietic cell transplantation, a delicate balance.
Efficacy and safety of HRS-5965 monotherapy in complement inhibitor-naïve patients with paroxysmal nocturnal haemoglobinuria.
Single-cell transcriptomics reveals BMP4-BMPR2 signaling promotes radiation resistance in hematopoietic stem cells following injury.
Second allogeneic transplantation in relapsed acute leukemia - a risk worth taking?
PROM1/CD133 MARKS A PROLIFERATIVE STEM CELL LIKE POPULATION OF BLASTS IN KMT2A REARRANGED INFANT ALL.
The Somatic Mosaicism across Human Tissues Network.

Blood Cancer Discov. 2025 Jul 03.

Multi-Modal and Data-Driven Assessment of Myeloid Neoplasms Refines Classification Across Disease States.

Curtis A Lachowiez, Georgios Asimomitis, Elsa Bernard, Sean M Devlin, Yanis Tazi, Maria Creignou, Ulrich Germing, Norbert Gattermann, Amanda Gilkes, Ian Thomas, Lars Bullinger, Konstanze Döhner, Luca Malcovati, Jad Othman, Richard Dillon, Ann-Kathrin Eisfeld, Deedra Nicolet, Ghayas C Issa, Naval Daver, Tapan M Kadia, Courtney D DiNardo, Farhad Ravandi, Guillermo Garcia-Manero, Guillermo Montalban-Bravo, Nigel Russell, Mario Cazzola, Hartmut Döhner, Brian Jp Huntly, Robert P Hasserjian, Eva Hellström-Lindberg, Elli Papaemmanuil, Sanam Loghavi.

The World Health Organization (WHO) 5th edition and International Consensus Classification (ICC) for myeloid neoplasms both incorporate empirical numerical thresholds to morphologic and molecular features defining certain disease entities. However, the clinical implications of these thresholds remain unclear. We analyzed a large cohort (N=6,976) of patients with myeloid neoplasms to evaluate the impact of proposed, yet different numerical thresholds for variant allele frequency of genetic mutations or hematologic parameters set forth by WHO 5th and ICC for classification of SF3B1-mutated (SF3B1m) myelodysplastic neoplasms (MDS), NPM1m acute myeloid leukemia (AML), and oligomonocytic-chronic myelomonocytic leukemia (O-CMML). Our analysis demonstrated the clonal burden of SF3B1m in MDS informs biological classification and prognosis, supported the notion that NPM1 mutation should be AML-defining regardless of blast percentage, highlighted the prognostic impact of the cumulative number of myelodysplasia-related mutations in NPM1-mutated AML, and provided evidence that integrating specific molecular signatures could improve accuracy of O-CMML classification.

DOI: https://doi.org/10.1158/2643-3230.BCD-25-0047
Blood Adv. 2025 Jul 01. pii: bloodadvances.2025016306. [Epub ahead of print]

Impact of transplant conditioning, NPM1 mutations, and measurable residual disease in FLT3-ITD acute myeloid leukemia.

Mark J Levis, Mehdi Hamadani, Brent R Logan, Richard J Jones, Anurag K Singh, Mark R Litzow, John R Wingard, Esperanza B Papadopoulos, Alexander E Perl, Robert J Soiffer, Celalettin Ustun, Masumi Ueda Oshima, Geoffrey L Uy, Edmund K Waller, Sumithira Vasu, Melhem M Solh, Asmita Mishra, Lori S Muffly, Hee-Je Kim, Matthias Stelljes, Yuho Najima, Masahiro Onozawa, Kirsty J Thomson, Caroline Chen, Nahla Hasabou, Matt Rosales, Jason E Hill, Stanley C Gill, Rishita Nuthethi, Denise King, Adam M Mendizabal, Steven M Devine, Mary M Horowitz, Yi-Bin Chen.

We conducted a post-hoc analysis of data from BMT CTN 1506 (MORPHO), a randomized trial of gilteritinib versus placebo as post-transplantation maintenance for patients with FLT3-ITD-mutated acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT), focusing the interactions between conditioning regimen intensity, measurable residual disease (MRD), and NPM1 co-mutation status reported from diagnosis. Comparing FLT3-ITD MRD before and after conditioning, there was no difference between myeloablative conditioning (MAC) and reduced intensity conditioning (RIC) in eradication or reduction of FLT3-ITD MRD. For participants who were FLT3-ITD MRD-negative pre-HCT, there was no difference in the cumulative incidence of relapse during follow-up between those receiving MAC versus RIC. NPM1 co-mutation was associated with the largest magnitude of relapse-free survival benefit from post-HCT gilteritinib, and in these participants, post-HCT gilteritinib in the setting of RIC appeared to be as effective as MAC at preventing relapse. Only in participants who were NPM1 wild-type at diagnosis and were FLT3-ITD MRD-positive prior to HCT did MAC appear superior to RIC in preventing relapse. Our findings suggest that only a subset of patients with FLT3-ITD AML undergoing HCT may benefit from myeloablative conditioning, and that, much like AML therapy prior to HCT, the intensity of the HCT regimen should be adapted according to the molecular features of the disease. (NCT02997202).

DOI: https://doi.org/10.1182/bloodadvances.2025016306
Haematologica. 2025 Jul 03.

Hematopoietic stem cell transplantation is effective in achieving long-term survival for post-aplastic anemia myeloid neoplasms: the EBMT Severe Aplastic Anemia Report.

Pedro Henrique Prata, Dirk-Jan Eikema, Brian Piepenbroek, Austin Kulasekararaj, Beatrice Drexler, Jennifer M-L Tjon, Krista Vaht, Mahmoud Aljurf, Patrice Chevallier, Tobias Gedde-Dahl, Ain Kaare, Urpu Salmenniemi, Thomas Schroeder, Jenny Byrne, Jérôme Cornillon, Fiorenza Barraco, Johan Maertens, Eleni Tholouli, Uwe Platzbecker, Nicolaus Kröger, Didier Blaise, Simona Sica, Robert Zeiser, Antonio Maria Risitano, Régis Peffault De Latour.

Aplastic anemia (AA) transformation into myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) is associated with a dismal prognosis. Hematopoietic stem cell transplant offers the sole possibility of cure, but data on long-term survival are scarce. We retrospectively analyzed 270 patients transplanted for MDS, AML, or an isolated cytogenetic abnormality after a diagnosis of AA or paroxysmal nocturnal hemoglobinuria reported to the EBMT. The median age at transplantation was 39 years. The 5-year overall survival (OS) rate was 64%, unaffected by chromosome 7 abnormalities, age at transplant, sex, interval from clonal evolution to transplant, and intensity of conditioning regimen. The 5-year non-relapse mortality rates were 34% (95% CI, 25-42%) for MDS patients and 19% (95% CI, 7-31%) for AML patients and were higher following a myeloablative conditioning regimen. The five-year relapse rate was 12% (95% CI, 6-19%) for MDS and 22% (95% CI, 9-35%) for AML. Our study's survival estimates reflect a younger cohort of patients, considering the bimodal distribution of aplastic anemia. Conditioning regimen intensity did not affect relapse. For MDS patients, pretreating before transplant did not improve survival nor reduce relapse. Transplantation is feasible and effective in achieving long-term survival for transplant-eligible post-AA myeloid neoplasm patients. MDS patients may benefit from upfront RIC transplant, limiting toxicity without higher relapse. Posttransplant maintenance therapies to reduce the relapse incidence among AML patients might be warranted.

DOI: https://doi.org/10.3324/haematol.2024.287205
Blood. 2025 Jul 03. pii: blood.2025028935. [Epub ahead of print]

Restoring p53 wild-type conformation in TP53-Y220C-mutant acute myeloid leukemia.

Bing Z Carter, Po Yee Mak, Edward Ayoub, Xiaogang Wu, Baozhen Ke, Yuki Nishida, Andrew Futreal, Lauren B Ostermann, Andrea D Bedoy, Steffen Boettcher, Courtney D DiNardo, Anna Puzio-Kuter, Masha V Poyurovsky, Arnold J Levine, Michael Andreeff.

TP53-Y220C is a recurrent hotspot mutation in cancers and leukemias. It is observed predominantly in acute myeloid leukemia (AML)/myelodysplastic syndromes among hematological malignancies and is associated with poor outcome. The mutation creates a structural pocket in the p53 protein. PC14586 (rezatapopt) is a small molecule designed to bind to this pocket and thus restore a p53-wild type (p53-WT) conformation. We demonstrate that PC14586 converts p53-Y220C into a p53-WT conformation and activates p53 transcriptional targets, but surprisingly induces limited/no apoptosis in TP53-Y220C AML. Mechanistically, MDM2 induced by PC14586-activated conformational p53-WT and the nuclear exporter XPO1 reduce the transcriptional activities of p53, which are fully restored by inhibition of MDM2 and/or XPO1. Importantly, p53-WT protein can bind to BCL-2, competing with BAX in the BH3 binding pocket of BCL-2 and also binds to BCL-xL and MCL-1. However, such binding by PC14586-activated conformational p53-WT is not detected. Pharmacological inhibition of the BCL-2/BAX interaction with venetoclax fully compensates for this deficiency, induces massive cell death in AML cells and stem/progenitor cells in vitro and prolongs survival of TP53-Y220C AML xenografts in vivo. Collectively, we identified transcription-dependent and -independent mechanisms that limit the apoptogenic activities of reactivated conformational p53-WT and suggest approaches to optimize apoptosis induction in TP53-mutant leukemia. A clinical trial of PC14586 in TP53-Y220C AML/myelodysplastic syndromes has recently been initiated (NCT06616636).

DOI: https://doi.org/10.1182/blood.2025028935
Trends Cancer. 2025 Jul 03. pii: S2405-8033(25)00144-X. [Epub ahead of print]

Advances in menin inhibition in acute myeloid leukemia.

Leora Boussi, Sheng F Cai, Eytan M Stein.

  Menin has emerged as a promising therapeutic target in acute myeloid leukemia (AML). The menin-MLL1 interaction promotes an oncogenic transcriptional program that drives leukemogenesis in HOX-mediated acute leukemias, including KMT2A-rearranged (KMT2Ar), nucleophosmin 1-mutated (NPM1m), and NUP98-rearranged (NUP98r) AML, prompting development of menin inhibitors for treatment of these subtypes. Successes in clinical investigation have led to recent FDA approval of revumenib for KMT2Ar AML, with numerous trials examining menin inhibitors as monotherapy and in combination with other antileukemic drugs ongoing. Although menin inhibitors represent a major advancement in AML treatment, acquired resistance is an evolving barrier to efficacy. Here, we examine the biological rationale for menin inhibition and discuss the landscape of clinical trials and resistance mechanisms associated with menin inhibitors.

Keywords:  KMT2A; NPM1; acute myeloid leukemia; menin inhibitors

DOI:  https://doi.org/10.1016/j.trecan.2025.06.002
NPJ Precis Oncol. 2025 Jul 01. 9(1): 211

Functional cure with single agent olutasidenib in relapsed IDH1/NPM1 co-mutated AML.

Justin Watts, Tiffany Nong, Katarina Micin, Deborah Soong, Ellen Madarang, Maurizio Affer, Shefali Mehra, Jessica Alvarez Lesmes, Jennifer Chapman, Yi Zhou, Amber Thomassen, Terrence Bradley, Tulasigeri Totiger, Ronan Swords, Justin Taylor.

Olutasidenib is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) that was recently approved by the US FDA for adult patients with relapsed or refractory acute myeloid leukemia (AML) harboring mutant IDH1. In the pivotal Phase II trial of olutasidenib, the median duration of complete response (CR) was 28.1 months. Here we report the first patient in the world to receive olutasidenib, for relapsed NPM1 and IDH1 co-mutated AML, who remains in continuous CR for over 7 years on olutasidenib monotherapy. We detail the clinical course as well as the pathologic and genomic evolution of the disease. Furthermore, using a novel single cell measurable residual disease assay and digital PCR and qPCR for the detection of IDH1 and NPM1 mutations, we found no evidence of residual detectable leukemia. To our knowledge, this is the first report of an AML patient functionally cured by IDH1 inhibitor monotherapy.

DOI: https://doi.org/10.1038/s41698-025-01013-5
Am J Hematol. 2025 Jul 03.

Systemic Mastocytosis in 910 Patients: Prognostic Contribution of the International Consensus Classification in the Context of the Mayo Alliance Prognostic System.

Fnu Aperna, Maymona G Abdelmagid, Mahesh Kumar, Joseph H Butterfield, Thanai Pongdee, Cecilia Y Arana Yi, Mrinal S Patnaik, Daniel A Arber, Attilio Orazi, Dong Chen, Kaaren K Reichard, Naseema Gangat, Animesh Pardanani, Ayalew Tefferi.

  The current study includes 910 patients with systemic mastocytosis (SM) seen at the Mayo Clinic from 1968 to 2024. The primary objective was to examine the prognostic contribution of the International Consensus Classification (ICC), in the context of the Mayo Alliance Prognostic System (MAPS) for SM. World Health Organization classification (WHO-HAEM5) subcategories included (i) indolent/smoldering SM (ISM/SSM; N = 518), (ii) SM associated with another hematological neoplasm (SM-AHN; N = 273), with the latter including both myeloid and lymphoid neoplasms, (iii) aggressive SM (ASM; N = 106), and (iv) WHO-defined mast cell leukemia (MCL; N = 13), which included mast cells with both "mature" and "immature" morphology. The ICC-defined subcategories were mostly similar with the exception that SM-AHN was replaced by SM associated with another myeloid neoplasm (SM-AMN; N = 235) and WHO-defined MCL was replaced by ICC-defined MCL (N = 8), which included only those with immature MC morphology. Overall survival (OS) was similar between WHO-defined MCL (median 1.8 years) vs. SM-AHN (median 2.3 years; p = 0.3) but significantly different between ICC-defined MCL (median 0.08 years) vs. SM-AMN (median 2.0 years; p < 0.01). Significant difference in OS was also apparent between ICC-defined SM-AMN and SM associated with lymphoid neoplasm (SM-ALN; median 8.1 years; HR 3.4; p < 0.01). Multivariable analysis confirmed the inter-independent prognostic contributions of both ICC-defined morphologic subcategories and MAPS risk variables, including age > 60 years, anemia, alkaline phosphatase > ULN, and platelet count < 150 × 109/L (p < 0.03 in all instances); the same was not true for WHO-HAEM5-defined SM subcategories. The addition of mutational information into the multivariable model resulted in ousting anemia and inclusion of ASXL1 (p < 0.01), SRSF2 (p = 0.01), and NRAS (p = 0.01) mutations as additional risk factors. Classification of SM by ICC is prognostically more accurate, compared to WHO-HAEM5, and strengthens the prognostic contribution of morphology to current clinical and molecular risk models.

Keywords:  advanced; aggressive; indolent; leukemia; smoldering

DOI:  https://doi.org/10.1002/ajh.27764
Haematologica. 2025 Jul 03.

PTPN11 mutations define a rare but highly adverse subset of myelodysplastic syndromes.

Alexandre Bazinet, Alex Bataller, Guillermo Montalban-Bravo, Kelly Chien, Koji Sasaki, Wei Ying Jen, Mahesh Swaminathan, Tapan Kadia, Courtney DiNardo, Farhad Ravandi, Guillermo Garcia-Manero, Hagop Kantarjian.

Not available.

DOI: https://doi.org/10.3324/haematol.2025.287874
Nat Commun. 2025 Jul 01. 16(1): 5639

Imbalanced TGFβ signalling and autophagy drive erythroid priming of hematopoietic stem cells in β-thalassemia.

Maria Rosa Lidonnici, Giulia Chianella, Nicole Mende, Hugo P Bastos, Matteo Barcella, Ivan Merelli, Mariangela Storto, Valentina Romeo, Francesca Tiboni, Samantha Scaramuzza, Claudia Rossi, Laura Raggi, Annamaria Aprile, Stefania Crippa, Deena Iskander, Irene Roberts, Anastasios Karamiditris, Julia Keith, Christophe Lechauve, Mitchell J Weiss, Nicola K Wilson, Berthold Göttgens, Maria Ester Bernardo, Fabio Ciceri, Alessandro Aiuti, Sarah Marktel, Elisa Laurenti, Giuliana Ferrari.

The hematopoietic stem cell and multipotent progenitor (HSC/MPP) pool dynamically responds to stress to adapt blood output to specific physiological demands. In β-thalassemia (Bthal), severe anemia and ineffective erythropoiesis generate expansion of erythroid precursors and a chronic stress status in the bone marrow (BM) microenvironment. However, the response to the BM altered status at the level of the HSC/MPP compartment in terms of lineage commitment has not been investigated. Bulk and single-cell RNA-sequencing reveal that Bthal HSCs/MPPs are expanded and activated with enhanced priming along the whole Ery differentiation trajectory. Consistently, HSC/MPP showed an altered TGFβ expression and autophagy transcriptional signatures along with a declined dormancy state. We discovered that the altered TGFβ signaling fosters the Ery potential of HSCs by reducing their autophagic levels, and in vivo stimulation of autophagy is sufficient to rescue the imbalance of the HSC compartment. Our findings identify the interplay between TGFβ and HSC autophagy as a key driver in the context of non-malignant hematopoiesis.

DOI: https://doi.org/10.1038/s41467-025-60676-7
Leukemia. 2025 Jun 30.

Characterization of E1 enzyme dependencies in mutant-UBA1 human cells reveals UBA6 as a novel therapeutic target in VEXAS syndrome.

Courtnee A Clough, Claire Cunningham, Sophia Y Philbrook, Kathleen M Hueneman, Avery M Sampson, Kwangmin Choi, Kenneth D Greis, Daniel Starczynowski.

VEXAS syndrome is a clonal hematopoietic disorder characterized by hyperinflammation, bone marrow failure, and high mortality. The molecular hallmark of VEXAS is somatic mutations at methionine 41 (M41) in the E1 ubiquitin enzyme, UBA1. These mutations induce a protein isoform switch, but the mechanisms underlying disease pathogenesis remain unclear. Here, we developed a human cell model of VEXAS syndrome by engineering the male monocytic THP1 cell line to express the common UBA1M41V mutation. We found that mutant UBA1M41V cells exhibit aberrant UBA1 isoform expression, increased vacuolization, and upregulation of the unfolded protein response, recapitulating key features of VEXAS. Moreover, proteomic analyses revealed dysregulated ubiquitination and proteotoxic stress in UBA1M41V cells, with alterations in inflammatory and stress-response pathways. Functional studies demonstrated that UBA1M41V cells were highly sensitive to genetic or pharmacological inhibition of E1 ubiquitin enzymes. Treatment with the E1 enzyme inhibitor TAK-243 preferentially suppressed colony formation of UBA1M41V cells as compared to WT cells. Moreover, UBA1M41V cells exhibited greater sensitivity to TAK-243 in competition assays and showed increased apoptosis. Interestingly, TAK-243 preferentially inhibited UBA6 activity over UBA1, suggesting that UBA6 may compensate for UBA1 dysfunction in UBA1M41V cells. Targeting UBA6 using shRNA or the UBA6-specific inhibitor phytic acid further revealed an acquired dependency on UBA6 in UBA1M41V cells. Phytic acid selectively impaired growth and colony formation in UBA1M41V cells while sparing WT cells, highlighting a potential therapeutic vulnerability. Together, these findings establish a novel human model of VEXAS syndrome, identify key roles for UBA1 and UBA6 in disease pathogenesis, and demonstrate that UBA6 inhibition represents a promising therapeutic strategy for selectively targeting UBA1 mutant clones.

DOI: https://doi.org/10.1038/s41375-025-02671-x
J Biol Chem. 2025 Jul 01. pii: S0021-9258(25)02281-1. [Epub ahead of print] 110431

Restricted Human CD45 Isoglycoforms Serve as Functional E-selectin Ligands and Delineate Hematopoietic Maturity.

Evan Ales, Robert Sackstein.

  CD45 is the most abundant glycoprotein on the surface of all nucleated hematopoietic-lineage cells, comprising multiple isoforms generated by alternative splicing of three exons ("A", "B", "C") that are exquisitely restricted across hematopoietic development. Despite CD45's ubiquitous expression on hematopoietic cells, its function(s) remain rather obscure. Here, we report that discrete CD45 isoforms expressed uniquely by immature human hematopoietic cells are distinguished as functional glycoforms ("isoglycoforms") that bind E-selectin. Moreover, our studies indicate that "CD45RA", a marker of human acute myeloid leukemia (AML) cells, identifies a distinct isoglycoform of CD45 containing all splice exon-encoded peptides. This isoglycoform, "CD45RABC-E", is directly upregulated by AML cells and demarcates these malignant cells from mature human leukocytes and the native human hematopoietic stem cell. Further analyses revealed that treatment-resistant AML highly expresses CD45RABC-E. Our findings thus unveil heretofore unrecognized functions of CD45 and define a novel CD45 isoglycoform that delineates AML cells from life-sustaining human hematopoietic cells.

Keywords:  CD15s; CD45; CD45 isoform; E-selectin; E-selectin ligand; isoglycoform; sLeX; sialyl Lewis X; translational glycobiology

DOI:  https://doi.org/10.1016/j.jbc.2025.110431
Nat Genet. 2025 Jul 01.

Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation.

Hidetaka Uryu, Koichi Saeki, Hiroshi Haeno, Chiraag Deepak Kapadia, Ken Furudate, Jyoti Nangalia, Michael Spencer Chapman, Li Zhao, Joanne I Hsu, Chong Zhao, Shujuan Chen, Tomoyuki Tanaka, Zongrui Li, Satoko Ogata, Sarah Hanache, Hui Yang, Courtney DiNardo, Naval Daver, Naveen Pemmaraju, Nitin Jain, Farhad Ravandi, Jianhua Zhang, Xingzhi Song, Erika Thompson, Hongli Tang, Latasha Little, Curtis Gumbs, Robert Z Orlowski, Muzaffar Qazilbash, Kapil Bhalla, Simona Colla, Hagop Kantarjian, Rashmi Kanagal-Shamanna, Carlos Bueso-Ramos, Daisuke Nakada, Gheath Al-Atrash, Jeffery Molldrem, P Andrew Futreal, Elizabeth Shpall, Margaret Goodell, Guillermo Garcia-Manero, Koichi Takahashi.

The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal hematopoiesis is not well defined. We conducted whole-genome sequencing on 1,276 single-cell-derived hematopoietic stem and progenitor cell (HSPC) colonies from ten patients with multiple myeloma treated with chemotherapies and six normal donors. Melphalan treatment significantly increased the mutational burden, producing a distinctive mutation signature, whereas other chemotherapeutic agents had minimal effects. Consequently, the clonal diversity and architecture of post-treatment HSPCs resemble those observed in normal elderly individuals, particularly through the progression of oligoclonal hematopoiesis, thereby suggesting that chemotherapy accelerates clonal aging. Integrated phylogenetic analysis of matched therapy-related myeloid neoplasm samples traced their clonal origin to a single-HSPC clone among multiple competing clones, supporting a model of oligoclonal to monoclonal transformation. These findings underscore the need for further systematic research on the long-term hematological consequences of cancer chemotherapy.

DOI: https://doi.org/10.1038/s41588-025-02235-w
Br J Haematol. 2025 Jun 30.

ZIP10 as a potential therapeutic target in acute myeloid leukaemia.

Benjamin Rolles, Nicolas Chatain, Richard Görg, Margherita Vieri, Nora Tillmann-Tröster, Marcel G Bourgeois, Deborah Christen, Jeanette Walter, Addison C Hillerbrand, Kyle A Romine, Kathryn M Taylor, Jens Bertram, Edgar Jost, Steffen Koschmieder, Fabian Beier, Maximilian Stahl, Tim H Brümmendorf, Lothar Rink, Inga Wessels.

  Acute myeloid leukaemia (AML) is a haematopoietic malignancy that continues to demonstrate lapses in current treatment modalities as evidenced by therapy refractory disease, disease relapse and high rates of lethality. The influence of nutritional factors, including trace elements, on disease development and progression is not yet well understood. We utilized AML cell lines and patient samples to further investigate zinc homeostasis and the dependency of leukaemic cells on zinc. Compared to control individuals, we found significantly increased zinc levels in malignant blasts with concomitant serum hypozincaemia. Increased cellular zinc levels were accompanied by the upregulation of zinc influx transporters such as ZIP6, ZIP9 and ZIP10. Subsequent in vitro experiments showed the importance of zinc for myeloid cell proliferation, survival and block of differentiation. We validated our results with data from the Leukemia Mile (n = 542) and the BeatAML2.0 study (n = 805). Importantly, we identified ZIP10 (as one of the highly upregulated zinc transporters in malignant blasts) which, when targeted, resulted in impaired zinc uptake and decreased malignant cell growth. These findings suggest that therapeutic approaches that target the zinc influx transporter ZIP10 may offer novel means of treatment for patients suffering from AML.

Keywords:  AML; acute myeloid leukaemia; leukaemia; trace elements; zinc

DOI:  https://doi.org/10.1111/bjh.20229
Br J Haematol. 2025 Jul 02.

Efficacy and safety of luspatercept with or without erythropoiesis-stimulating agent in patients with myelodysplastic neoplasms with ring sideroblasts: A multicentre real-life study by the GFM.

Maud D'Aveni, Laurence Schenone, Jose Miguel Torregrosa, Jean Pardo, Aspasia Stamatoullas, Colombe Saillard, Sylvain Thépot, Sophie Dimicoli, Clemence Santana, Etienne Daguindau, Francianne Paul, Lenaig Le Clech, Sophie Park, Thomas Cluzeau, Etienne Paubelle, Anne-Laure Taksin-Bressot, Fatiha Chermat, Lionel Adès, Pierre Fenaux, Thibault Comont.



Keywords:  luspatercept; myelodysplastic neoplasm; real‐life

DOI:  https://doi.org/10.1111/bjh.20247
Leukemia. 2025 Jul 03.

Induction chemotherapy with CPX-351 in acute myeloid leukemia: revisiting the role of early bone marrow assessment.

Julian Ronnacker, Leo Ruhnke, Christoph Röllig, Jan Moritz Middeke, Regina Herbst, Anke Morgner, Julia M Unglaub, Tim Sauer, Karin Huber, David Baden, Lars Fransecky, Melanie Nogueira Gezer, Martina Crysandt, Edgar Jost, Madlen Jentzsch, Klaus H Metzeler, Andrew F Berdel, Marc-André Urbahn, Lina Kolloch, Matthias Stelljes, Uwe Platzbecker, Tim H Brümmendorf, Claudia Baldus, Carsten Müller-Tidow, Mathias Hänel, Martin Bornhäuser, Klaus Wethmar, Utz Krug, Georg Lenz, Jan-Henrik Mikesch, Christoph Schliemann.

DOI: https://doi.org/10.1038/s41375-025-02675-7
Stem Cell Reports. 2025 Jun 25. pii: S2213-6711(25)00175-4. [Epub ahead of print] 102571

Disruption of normal stem cell function and transmission of myelodysplastic syndrome by self-renewal of committed myeloid lineage cells.

Yang Jo Chung, Ryan Bertoli, Dengchao Cao, Robert L Walker, Yuelin Jack Zhu, Paul Meltzer, Peter D Aplan.

  The ineffective hematopoiesis of myelodysplastic syndrome (MDS) suggests that hematopoietic stem and progenitor cells (HSPCs) are defective. Here, we demonstrate that NUP98::HOXD13 (NHD13) MDS mice have significantly decreased functional HSPCs. Moreover, in contrast to wild-type (WT) bone marrow (BM), lineage-positive (Lin+) BM cells from NHD13 mice have self-renewal potential. Specific subsets of NHD13 Lin+ cells that express B220 and Kit antigens were able to self-renew and generate MDS in WT recipients. Although this unique B220+Kit+ phenotype could be found in WT as well as NHD13 BM, the population was markedly increased in NHD13 BM. Further characterization using Mac1 and Gr1 markers revealed that both Mac1+Gr1+B220+Kit+ and Mac1-Gr1- B220+Kit+ populations showed self-renewal and led to an MDS phenotype in WT recipients. Taken together, these findings demonstrate that as normal hematopoiesis derived from typical HSPCs decreases in NHD13 mice, committed hematopoietic progenitor cells proliferate, self-renew, and initiate MDS.

Keywords:  MDS-initiating cell; NHD13; hematopoiesis; kit; myelodysplastic syndrome; stem cells

DOI:  https://doi.org/10.1016/j.stemcr.2025.102571
Blood Adv. 2025 Jul 02. pii: bloodadvances.2025016665. [Epub ahead of print]

Asciminib for relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia.

Mathilde Chanut, Aurélie Cabannes-Hamy, Marie Balsat, Nassim Sahki, Emmanuel Raffoux, Yosr Hicheri, Bruno Lioure, Lucie Laemmel, Thibaut Tl Leguay, Victoria Cacheux, Maria Pilar Gallego-Hernanz, Andrea Pieragostini, Gabrielle Roth-Guepin, Ludovic Gabellier, Nathalie Denizon, Lise Willems, Quentin Cabrera, Sylvain P Chantepie, Valérie Coiteux, Claudie Capdupuy, Martin Carre, Antoine Machet, Juliette Lambert, Sandrine Roux, Franck-Emmanuel Emmanuel Nicolini, Nicolas Boissel, Emmanuelle Clappier, Rathana Kim, Philippe Rousselot.

Asciminib (ASC) is an allosteric inhibitor of BCR::ABL1 that binds the myristoylation site of the ABL1 protein. We report the use of ASC in relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and lymphoid blast crisis of chronic myeloid leukemia (LBC-CML) in 41 patients retrospectively collected in France. Median age was 56 years (range: 19-84). Most patients (78%) received ASC as a third-line or later treatment, with 93% previously treated with ponatinib. Twenty-seven out of 35 analyzed patients had BCR::ABL1 mutations, including T315I (n=18) or compound mutations (n=8). ASC was prescribed at 200 mg BID in 83% of the patients, alone (n=20) or in combination (n=21). Overall, 30/36 evaluable patients achieved a composite complete response (CR/CRi), including measurable residual disease negativity (defined by BCR::ABL1/ABL1 <0.01% in bone marrow) in 13/23 patients (57%). The median overall survival and event-free survival (EFS) were 9.8 and 4.9 months respectively. EFS was improved when ASC was administered in combination rather than as monotherapy (7.93 vs 4.23 months). Post-ASC mutations were analyzed in 7 relapsing patients, identifying a new Q252H mutation in 2 cases. In conclusion, our findings suggest that ASC is an effective salvage therapy for Ph+ ALL and LBC-CML.

DOI: https://doi.org/10.1182/bloodadvances.2025016665
Leukemia. 2025 Jul 03.

Autophagosome-lysosome mediated secretion of the thrombopoietin receptor is modulated by distinct driver mutations of myeloproliferative neoplasm.

Shayeri Chowdhury, Saurabh Shrivastva, Aditi Singh, Farmaanullah Ansari, Saadia Naseer, Anita Roy.

The maintenance of the haematopoietic stem cells and the production of platelets thereof is acutely dependent upon the thrombopoietin receptor (TpoR). TpoR dimerizes in the presence of its ligand thrombopoietin leading to the activation of downstream JAK2-STAT signalling. Alternatively, the receptor dimerizes in the presence of activating mutations of JAK2 (JAK2 V617F), calreticulin or TpoR leading to myeloproliferation. These effects are dependent upon the surface expression of the receptor. TpoR is secreted through the Golgi-dependent pathway. Although, an unconventional autophagosome-lysosome mediated traffic has been postulated; questions remained whether the observed lysosomal localization was indicative of degradation or secretion. We fused the pH-sensitive FRET pair of TOLLES-YPet with TpoR (SRAI-TpoR) that showed FRET quenching at low pH environment of lysosomes. Using this construct, we demonstrated the presence of quenched SRAI-TpoR on the cell surface indicating that TpoR could indeed be secreted through low pH compartments. We further demonstrated that the lysosome-autophagosome-mediated secretion of TpoR was promoted by JAK2 V617F mutation, partially utilized by TpoR W515L but abrogated by calreticulin mutations. Finally, we showed that the lysosome-autophagosome mediated secretion was dependent upon Rab1A. Our study conclusively showed the unconventional traffic of TpoR and its modulation by the driver mutations causing myeloproliferation.

DOI: https://doi.org/10.1038/s41375-025-02676-6
Leukemia. 2025 Jun 30.

SIRT5 inhibition impairs mitochondrial metabolism and enhances venetoclax-induced elimination of acute myeloid leukemia cells.

Moran Wang, Ruiqi Zhu, Donald Small, Lan Lin, Li Li, Shengling Ma, Linghui Xia, Shanshan Luo, Wenjuan He, Jianming Yu, Junying Li, Ruowen Wei, Ao Zhang, Wei Shi, Yu Hu.

Metabolic reprogramming is a key focus of targeted therapies in acute myeloid leukemia (AML). The mitochondrial sirtuin SIRT5 removes succinyl groups from specific lysines and impacts cell metabolism, but its role in AML tumorigenesis has not been extensively explored. A recent study highlighted that SIRT5 regulates AML cell activity by modulating glutamine metabolism, but its molecular targets in AML remain unclear. This study aims to identify the substrates of SIRT5 in AML. It was found that a total of 83 proteins with 121 lysine (K) residues showed increased succinylation after SIRT5 knockdown, as determined by succinylome analysis of MOLM-13 cells. SIRT5 was validated to interact with HADHA, a key molecule in the fatty acid oxidation pathway. Knockdown of SIRT5 resulted in hypersuccinylation and reduced enzymatic activity of HADHA. Mimetic mutations of lysine indicated that SIRT5 desuccinylates HADHA at K644. Inhibiting SIRT5 or HADHA increased sensitivity to venetoclax (VEN) in both VEN-sensitive and VEN-resistant cell lines. SIRT5 knockdown enhanced VEN-mediated suppression of mitochondrial metabolism and improved the survival of AML-transplanted NSG mice when combined with VEN. This study reveals the role of SIRT5 in AML metabolic regulation and provides valuable insights for developing SIRT5-targeted drugs and combination therapies with metabolic inhibitors.

DOI: https://doi.org/10.1038/s41375-025-02673-9
Nat Commun. 2025 Jul 01. 16(1): 5489

A heterozygous CEBPA mutation disrupting the bZIP domain in a RUNX1 and SRSF2 mutational background causes MDS disease progression.

Ruba Almaghrabi, Yara Alyahyawi, Peter Keane, Syed A Mian, Khadidja Habel, Amelia Atkinson, Carl Ward, Rachel Bayley, Claudia Sargas, Pablo Menendez, George J Murphy, Turki Sobahy, Mohammed A Baghdadi, Arwa F Flemban, Saeed M Kabrah, Raul Torres-Ruiz, Eirini P Papapetrou, Ildem Akerman, Manoj Raghavan, Eva Barragan, Dominique Bonnet, Constanze Bonifer, Paloma Garcia.

Myelodysplastic syndrome disease (MDS) is caused by the successive acquisition of mutations and thus displays a variable risk for progression to AML. Mutations in CEBPA are commonly associated with a high risk of disease progression, but whether they are causative for AML development is unclear. To analyse the molecular basis of disease progression we generated MDS patient-derived induced pluripotent stem cells from a low risk male patient harbouring RUNX1/SRSF2 mutations. This experimental model faithfully recapitulates the patient disease phenotypes upon hematopoietic differentiation. Introduction of a frameshift mutation affecting the C/EBPα bZIP domain in cells from low-risk stages mimicks disease progression by reducing clonogenicity of myeloid cells, blocking granulopoiesis and increasing erythroid progenitor self-renewal capacity. The acquisition of this mutation reshapes the chromatin landscape at distal cis-regulatory regions and promotes changes in cellular composition as observed by single cell RNAseq. Mutant C/EBPα is therefore causative for MDS disease progression. Our work identifies mutant CEBPA as causative for MDS disease progression, providing a new isogenic MDS experimental model for drug screening to improve diagnostic and therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-025-60192-8
Nat Aging. 2025 Jun 30.

Clusterin drives myeloid bias in aged hematopoietic stem cells by regulating mitochondrial function.

Ninghe Sun, Chun-Hsin Lin, Michelle Y Li, Yuting Wang, Danyang Chen, Xiangle Ren, Feng Zhang, Yi Zhang.

Aged hematopoietic stem cells (HSCs) exhibit diminished self-renewal and myeloid-biased differentiation with a decline in hematopoiesis and adaptive immune function. However, the molecular regulation of this impaired function remains largely unknown. Here, through an in vivo CRISPR-Cas9-based screen, we uncovered clusterin (Clu) as a driver of biased differentiation. Clu is upregulated in aged HSCs, and its knockout diminishes biased differentiation. Clu promotes mitochondrial hyperfusion by interacting with Mfn2 in aged HSCs, and its ablation attenuates oxidative phosphorylation, improves mitophagy, and reverses myeloid-biased differentiation via the OXPHOS-p38-Cebpb axis. Transplantation of Clu-depleted aged HSCs into middle-aged mice results in balanced hematopoiesis and improved physical functions. Together, our data identify Clu as a critical regulator of aging-associated myeloid bias and reveal an Mfn2-OXPHOS-p38-Cebpb axis as the mechanism underlying how Clu upregulation in aged HSCs leads to myeloid-biased differentiation, providing a target for rejuvenation of aged hematopoietic and immune systems.

DOI: https://doi.org/10.1038/s43587-025-00908-z
Cell Stem Cell. 2025 Jun 24. pii: S1934-5909(25)00228-0. [Epub ahead of print]

TET2-mutant myeloid cells mitigate Alzheimer's disease progression via CNS infiltration and enhanced phagocytosis in mice.

Katie A Matatall, Trisha K Wathan, Minh Nguyen, Hu Chen, Alexandra McDonald, Guantong Qi, Julia A Belk, Marcus A Florez, Duy T Le, Temitope Olarinde, Caitlyn Vlasschaert, Marco M Buttigieg, Chih-Wei Fan, Saul Carcamo, Ruoqiong Cao, Daniel E Kennedy, Arushana A Maknojia, Apoorva Thatavarty, Josaura V Fernandez Sanchez, Hind Bouzid, Surabi Veeraragavan, Susan Crocker, Margaret A Goodell, Antony Rodriguez, Siddhartha Jaiswal, Michael J Rauh, Eirini P Papapetrou, Samuele G Marro, Katherine Y King.

  Clonal hematopoiesis (CH) is associated with many age-related diseases, but its interaction with Alzheimer's disease (AD) remains unclear. Here, we show that TET2-mutant CH is associated with a 47% reduced risk of late-onset AD (LOAD) in the UK Biobank, whereas other drivers of CH do not confer protection. In a mouse model of AD, transplantation of Tet2-mutant bone marrow reduced cognitive decline and β-amyloid plaque formation, effects not observed with Dnmt3a-mutant marrow. Bone-marrow-derived microglia-like cells were detected at an increased rate in Tet2-mutant marrow recipients, and TET2-mutant human induced pluripotent stem cell (iPSC)-derived microglia were more phagocytic and hyperinflammatory than DNMT3A-mutant or wild-type microglia. Strikingly, single-cell RNA sequencing (scRNA-seq) revealed that macrophages and patrolling monocytes were increased in brains of mice transplanted with Tet2-mutant marrow in response to chemokine signaling. These studies reveal a TET2-specific protective effect of CH on AD pathogenesis mediated by peripheral myeloid cell infiltration.

Keywords:  Alzheimer’s disease; DNMT3A; TET2; clonal hematopoiesis; inflammation; microglia, peripheral immune cells; myeloid cell activation; phagocytosis

DOI:  https://doi.org/10.1016/j.stem.2025.06.006
Br J Haematol. 2025 Jul 01.

A phase 1, first-in-human, dose-escalation study of JNJ-74856665 (dihydroorotate dehydrogenase inhibitor) alone or in combination in patients with AML or MDS.

Emma Searle, Thomas Cluzeau, Jenny O'Nions, Christian Recher, Emmanuel Gyan, Daniel Morillo, Jordi Esteve, Austin Kulasekararaj, Emmanuel Raffoux, Harriet S Walter, Arnaud Pigneux, David Valcárcel, Nikki Daskalakis, Jacqueline Bussolari, E Christine Pietsch, Scott Kuduk, Tammy Bush, Xiaochun Zhang, Ulrike Philippar, Adetokunbo Oluwasanjo, Kathryn Bradford, Jonathan Miller, Charlotte Van Bogaert, Martin Curtis, Shih-Yu Chang, Christina Guttke, Stan Gaj, Rachel Pearson, Joseph Murphy, Wim van Dijck, Ana Alfonso Piérola.



Keywords:  JNJ‐74856665; acute myeloid leukaemia; dihydroorotate dehydrogenase; myelodysplastic syndromes; phase 1

DOI:  https://doi.org/10.1111/bjh.20224
Nat Genet. 2025 Jul 01.

The long-term effects of chemotherapy on normal blood cells.

Emily Mitchell, My H Pham, Anna Clay, Rashesh Sanghvi, Nicholas Williams, Sandra Pietsch, Joanne I Hsu, Hyunchul Jung, Aditi Vedi, Sarah Moody, Jingwei Wang, Daniel Leonganmornlert, Michael Spencer Chapman, Ellie Dunstone, Anna Santarsieri, Alex Cagan, Heather E Machado, E Joanna Baxter, George Follows, Daniel J Hodson, Ultan McDermott, Gary J Doherty, Inigo Martincorena, Laura Humphreys, Krishnaa Mahbubani, Kourosh Saeb Parsy, Koichi Takahashi, Margaret A Goodell, David Kent, Elisa Laurenti, Peter J Campbell, Raheleh Rahbari, Jyoti Nangalia, Michael R Stratton.

Several chemotherapeutic agents act by increasing DNA damage in cancer cells, triggering cell death. However, there is limited understanding of the extent and long-term consequences of collateral DNA damage in normal tissues. To investigate the impact of chemotherapy on mutation burdens and the cell population structure of normal tissue, we sequenced blood cell genomes from 23 individuals aged 3-80 years who were treated with a range of chemotherapy regimens. Substantial additional somatic mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but the effects were dependent on the drug and blood cell types. Chemotherapy induced premature changes in the cell population structure of normal blood, similar to those caused by normal aging. The results show the long-term biological consequences of cytotoxic agents to which a substantial fraction of the population is exposed as part of disease management, raising mechanistic questions and highlighting opportunities for the mitigation of adverse effects.

DOI: https://doi.org/10.1038/s41588-025-02234-x
Ther Adv Hematol. 2025 ;16 20406207251351086

Histamine dihydrochloride and low-dose interleukin-2 in an emerging landscape of relapse prevention in acute myeloid leukemia.

Malin S Nilsson, Anna Martner, Lovisa Wennström, Markus Hansson, Fredrik B Thorén, Kristoffer Hellstrand.

  Effective strategies to maintain complete remission in adults with acute myeloid leukemia (AML) are critically needed. Early clinical trials aimed at preventing relapse in the postconsolidation phase explored prolonged chemotherapy, single-agent immunotherapy, and hybrid chemo-immunotherapy, but none of these approaches produced practice-changing results. More recent trials have identified efficacious remission maintenance strategies, including (1) midostaurin or quizartinib for patients with FLT3-mutated AML, (2) oral azacitidine for older AML patients, and (3) immunotherapy with histamine dihydrochloride and low-dose interleukin-2 (HDC/IL-2) for younger patients. In this review, we examine key phase III trial and follow-up study results for approved remission maintenance therapies, with a particular focus on HDC/IL-2. We discuss clinical efficacy in relation to patient age and anti-leukemic immunity as well as leukemic cell chemosensitivity, chromosomal integrity, and mutational profiles. Finally, we propose a role for HDC/IL-2 within an evolving landscape of strategies to achieve durable remission in a broader population of AML patients.

Keywords:  acute myeloid leukemia; histamine dihydrochloride; immunotherapy; relapse prevention; remission maintenance

DOI:  https://doi.org/10.1177/20406207251351086
Ann Rheum Dis. 2025 Jun 27. pii: S0003-4967(25)01039-8. [Epub ahead of print]

Disease Trajectories and Glucocorticoid Exposure in VEXAS Syndrome Treated with Cytokine-Directed Therapies.

Benjamin A Turturice, Alice Fike, Bhavisha A Patel, Emma M Groarke, Fernanda Gutierrez-Rodriguez, Karyssa Stonick, Hannah Berrett, Shanni Liu, Ivana Darden, Kaitlin A Quinn, Neal S Young, Peter C Grayson.

OBJECTIVES: To establish the long-term impact of cytokine-directed therapies on glucocorticoid use and clinical outcomes in Vacuoles, E1-enzyme, X-linked, Autoinflammatory, Somatic (VEXAS).
METHODS: Patients with VEXAS were prospectively followed for events of transfusion dependence, haematopoietic stem cell transplantation or death. Laboratory results, glucocorticoid exposure and clinical measures were retrospectively assessed in relationship to treatment initiation with interleukin-6-directed therapies (anti-IL6R) or Janus kinase inhibitors (JAKi). Patients were stratified by UBA1 variants and presence of typical clonal haematopoiesis with variant allele fraction ≥ 10% (CHVAF≥10%).
RESULTS: In 71 VEXAS patients (81.7% with anti-IL6R or JAKi exposure), event-free survival differed by genotype and presence of concomitant CHVAF≥10%: p.M41V (HR [95% confidence interval (CI)]: 5.7 [1.5-20.4]) or p.M41L/T with CHVAF≥10% (hazard ratio [HR]: 5.7 [1.6-20.8]) compared to p.M41L. No association between event rates and exposure to anti-IL6R or JAKi was observed. The p.M41V genotype had the highest risk of anaemia, elevated C-reactive protein (CRP) levels, and monocytopenia. Over a median follow-up of 4.8 (interquartile range [IQR] 3.0, 8.1) years, the patients' mean glucocorticoid dose was >15 mg/day prednisone regardless of variant or disease duration. At prospective visits, clinical remission on ≤10 mg/day prednisone was observed in only 2.7% of visits. Treatment with anti-IL6R or JAKi showed no clinically meaningful reduction (<5 mg/day difference) in steroid exposure at 1 year post-treatment. No attenuation in the progression of anaemia was observed in response to anti-IL6R and JAKi.
CONCLUSIONS: Cytokine-directed therapies alone do not alter the risk of haematologic disease progression or significantly reduce glucocorticoid exposure in VEXAS. These data provide benchmarks for future interventional studies.

DOI: https://doi.org/10.1016/j.ard.2025.05.021
Sci Rep. 2025 Jul 02. 15(1): 23603

Modeling mesenchymal stromal cell support to hematopoiesis within a novel 3D artificial marrow organoid system.

Bérénice Schell, Lin-Pierre Zhao, Inés M'Sibih, Maria Kalogeraki, Camille Kergaravat, Emilie Lereclus, Pierre Fenaux, Lionel Adès, Antoine Toubert, Marion Espéli, Karl Balabanian, Emmanuel Clave, Nicolas Dulphy, Valeria Bisio.

The human bone marrow (BM) microenvironment involves hematopoietic and non-hematopoietic cell subsets organized in a complex architecture. Tremendous efforts have been made to model it in order to analyze normal or pathological hematopoiesis and its stromal counterpart. Herein, we report an original, fully-human in vitro 3D model of the BM microenvironment dedicated to study interactions taking place between mesenchymal stromal cells (MSC) and hematopoietic stem and progenitor cells (HSPC) during the hematopoietic differentiation. This fully-human Artificial Marrow Organoid (AMO) model is highly efficient to recapitulate MSC support to myeloid differentiation and NK cell development from the immature CD34 + HSPCs to the most terminally differentiated CD15 + polymorphonuclear neutrophils, CD64 + monocytes or NKG2A-KIR2D + CD57 + NK subset. Lastly, our model is suitable for evaluating anti-leukemic NK cell function in presence of therapeutic agents. Overall, the AMO is a versatile, low cost and simple model able to recapitulate normal hematopoiesis and allowing more physiological drug testing by taking into account both immune and non-immune BM microenvironment interactions.

DOI: https://doi.org/10.1038/s41598-025-07717-9
Stem Cells. 2025 Jul 03. pii: sxaf047. [Epub ahead of print]

15-PGDH inhibition enhances hematopoietic regeneration during aging.

Rahul Chaudhary, Brittany A Cordova, Marcus Hong, Bailey R Klein, Lyannah A Contreras, Ritisha Rashmil, Filip Goshevski, Julianne N P Smith, Derek J Taylor, Andrew A Pieper, Sanford Markowitz, Amar B Desai.

  Hematopoietic aging is characterized by diminished stem cell regenerative capacity and an increased risk of hematologic dysfunction. We previously identified that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) regulates hematopoietic stem cell activity. Here, we expand on this work and demonstrate that in aged mice, (1) 15-PGDH expression and activity remain conserved in the bone marrow and spleen, suggesting it remains a viable therapeutic target in aging, (2) prolonged PGDH inhibition (PGDHi) significantly increases the frequency and number of phenotypic hematopoietic stem and progenitor cells across multiple compartments, with transcriptional changes indicative of enhanced function, (3) PGDHi-treated bone marrow enhances short-term hematopoietic recovery following transplantation, leading to improved peripheral blood output and accelerated multilineage reconstitution, and (4) PGDHi confers a competitive advantage in primary hematopoietic transplantation while mitigating age-associated myeloid bias in secondary transplants. Notably, these effects occur without perturbing steady-state blood production, suggesting that PGDHi enhances hematopoiesis under regenerative conditions while maintaining homeostasis. Our work identifies PGDHi as a translatable intervention to rejuvenate aged HSCs and mitigate hematopoietic decline.

Keywords:  aging; drug target; hematopoietic stem cell transplantation; hematopoietic stem cells; stem cells

DOI:  https://doi.org/10.1093/stmcls/sxaf047
Nat Genet. 2025 Jul 03.

Detecting and quantifying clonal selection in somatic stem cells.

Verena Körber, Niels Asger Jakobsen, Naser Ansari-Pour, Rachel Moore, Nina Claudino, Marlen Metzner, Eva Thielecke, Franziska Esau, Batchimeg Usukhbayar, Mirian Angulo Salazar, Simon Newman, Benjamin J L Kendrick, Adrian H Taylor, Rasheed Afinowi-Luitz, Roger Gundle, Bridget Watkins, Kim Wheway, Debra Beazley, Stephanie G Dakin, Antony Palmer, Andrew J Carr, Paresh Vyas, Thomas Höfer.

As DNA variants accumulate in somatic stem cells, become selected or evolve neutrally, they may ultimately alter tissue function. When, and how, selection occurs in homeostatic tissues is incompletely understood. Here, we introduce SCIFER, a scalable method that identifies selection in an individual tissue, without requiring knowledge of the driver event. SCIFER also infers self-renewal and mutation dynamics of the tissue's stem cells, and the size and age of selected clones. Probing bulk whole-genome sequencing data of nonmalignant human bone marrow and brain, we detected pervasive selection in both tissues. Selected clones in hematopoiesis, with or without known drivers, were initiated uniformly across life. In the brain, we found pre-malignant clones with glioma-initiating mutations and clones without known drivers. In contrast to hematopoiesis, selected clones in the brain originated preferentially from childhood to young adulthood. SCIFER is broadly applicable to renewing somatic tissues to detect and quantify selection.

DOI: https://doi.org/10.1038/s41588-025-02217-y
Ann Hematol. 2025 Jul 04.

SGK1 repression by WT1 may confer a survival advantage to leukemic cells under stress conditions.

Miguel A Rubio, Sabina Cisa-Wieczorek, Ana Mozos, Helena Castellet, Elena Bussaglia, Maite Carricondo, María Isabel Hernández-Alvarez, Jorge Sierra, Josep F Nomdedéu.

  Increased WT1 mRNA levels are pervasive in acute myeloid leukemia (AML), and this marker has been used to assess the leukemic compartment size after chemotherapy or hematopoietic cell transplants. Little is known about the effects of WT1 on the leukemic cells and their targets. This work used data obtained from gene expression arrays performed on AML samples with high and low WT1 mRNA levels to pinpoint genes that WT1 can regulate. We singled out SGK1, which showed an inverse correlation between its mRNA levels and WT1 in leukemic cell lines and AML samples. In cellular models, forced expression of WT1 reduced mRNA and protein levels of SGK1. Furthermore, WT1 repressed the SGK1 promoter activity, and accordingly, WT1 knockdown showed an increased expression of SGK1. We also detected an inverse correlation between WT1 and SGK1 during leukemic cell-line differentiation. WT1 genetic knockdown displayed decreased cell viability under nutrient deprivation. By contrast, SGK1 knockdown or pharmacologic inhibition increased resistance to apoptosis in response to serum starvation, acting on cell cycle progression. The effects of SGK1 targeting in hematologic conditions merit further investigation.

Keywords:  Cell viability; Leukemia; SGK1; WT1

DOI:  https://doi.org/10.1007/s00277-025-06458-z
Eur J Haematol. 2025 Jun 30.

Treatment Free Remission (TFR) in Chronic Phase-Chronic Myeloid Leukemia (CP-CML): Analysis of Predictive Factors and Novel Baseline Scoring System to Predict Molecular Relapse.

Alessandro Laganà, Emilia Scalzulli, Ida Carmosino, Maria Laura Bisegna, Claudia Ielo, Daniela Diverio, Maurizio Martelli, Massimo Breccia.

   BACKGROUND: Treatment free remission (TFR) is a key treatment goal in chronic-phase chronic myeloid leukemia (CP-CML) patients with sustained deep molecular response (DMR). While clinical trials report that approximately 40%-50% of such patients can discontinue tyrosine kinase inhibitors (TKIs) without presenting a molecular relapse (MRec), real-world data remain limited. Optimizing patient selection before TKI discontinuation is crucial for CML management and resource allocation.
METHODS: We conducted a single-center retrospective study on CP-CML patients who discontinued TKIs to evaluate the rate and duration of successful TFR and to identify factors predictive of MRec. Eligibility required prior TKI treatment ≥ 3 years, a minimum molecular response (MR) of MR4.0 before discontinuation, and subsequent serial MR monitoring. MRec was defined as the loss of major MR (MMR).
RESULTS: Of the 118 consecutive CP-CML patients, 60.2% were on imatinib and 39.8% on 2G-TKIs before attempting TFR. Median TKI treatment duration was 10.6 years, and median stable DMR duration was 6.1 years. After a median follow-up of 72.5 months, 34 patients (28.8%) had an MRec, and estimated MRec-free survival was 79.7% at 6 months and 69.9% overall. Multivariate analysis identified three factors associated with shorter TFR: High-risk Sokal score (HR 2.93, p = 0.018), stable DMR duration before TKI suspension < 5 years (HR 3.63, p = 0.002), and prior unstable DMR (HR 2.47, p = 0.019). The BASE-TFR score, assigning one point per factor, stratified patients into low-risk, intermediate-risk (HR 4.19, p = 0.009) and high-risk (HR 14.06, p < 0.001) for MRec.
CONCLUSIONS: TFR is feasible in real-world settings. BASE-TFR score may help to better identify candidates for TKI discontinuation in real-life settings.

Keywords:  BASE‐TFR; chronic myeloid leukemia (CML); deep molecular response (DMR); molecular recurrence (MRec); treatment‐free remission (TFR); tyrosine kinase inhibitors (TKIs)

DOI:  https://doi.org/10.1111/ejh.70006
RSC Med Chem. 2025 Jun 19.

Structure-guided design of a methyltransferase-like 3 (METTL3) proteolysis targeting chimera (PROTAC) incorporating an indole-nicotinamide chemotype.

Annabelle C Weldert, Ariane F Frey, Mackenzie W Krone, Franziska Krähe, Hannah Kuhn, Christian Kersten, Fabian Barthels.

Methyltransferase-like 3 (METTL3) is the main catalytic subunit of the m6A methyltransferase complex (MTC) and plays an essential role in various disease indications, including acute myeloid leukemia (AML). Here, we describe the structure-guided design and evaluation of METTL3 proteolysis-targeting chimeras (PROTACs), starting from the potent small-molecule inhibitor STM2457. Across four design generations, we highlight key considerations, particularly regarding the exit vector, linker mechanics, and METTL3-binding chemotype composition. Our most effective PROTAC, AF151, forms a stable complex between the E3 ligase von Hippel-Lindau (VHL) and the target-of-interest METTL3, demonstrating efficient METTL3 degradation (DC50 = 430 nM) in the AML cell line MOLM-13. This molecule candidate exhibits more pronounced effects on viability inhibition (IC50 = 0.45 μM) and more significant m6A level reduction in cancer cells than its non-PRTOAC parent compounds. By incorporating the indole-nicotinamide chemotype as the METTL3-binding recruiter, this PROTAC is structurally distinct from recently published METTL3 PROTACs, expanding the design options for future METTL3 degrader development.

DOI: https://doi.org/10.1039/d5md00359h
Blood Rev. 2025 Jun 23. pii: S0268-960X(25)00063-3. [Epub ahead of print] 101318

Evaluation of current mouse in vivo models and advanced in vitro models for leukaemia research.

Xenia Bubnova, Lauren Hope, Helen Wheadon.

  Leukaemia is caused by genetic mutations within haematopoietic stem and progenitor cells, leading to the production of immature blasts. While mouse models have been instrumental in studying disease mechanisms and testing therapies, their limitations contribute to 90 % failure rate of new therapies in clinical trials. This is often attributed to the choice of model utilised, and failure of mouse models to accurately replicate the complexity of the human disease. This review examines different leukaemia mouse models, including transgenic, syngeneic and xenografts, discussing their phenotype, advantages and limitations. Finally, we describe advanced technologies for in vitro modelling of haematopoiesis and leukaemia. These models provide a promising platform for tumour microenvironment research, and a robust human-relevant pipeline for drug screening, reducing our reliance on in vivo testing. The information in this review will enable researchers to make informed decisions on the most appropriate models to carry out pre-clinical testing in the future.

Keywords:  Haematopoiesis; In vitro models; Leukaemia; Leukaemic stem cell; Mouse models

DOI:  https://doi.org/10.1016/j.blre.2025.101318
Blood Rev. 2025 Jun 23. pii: S0268-960X(25)00064-5. [Epub ahead of print] 101319

Iron chelation therapy in myelodysplastic syndromes and allogeneic hematopoietic cell transplantation, a delicate balance.

Fieke W Hoff, Eduard Schulz, Steven Pavletic, Alain Mina.

  Anemia is a hallmark of myelodysplastic syndromes/neoplasms (MDS) and most patients with MDS chronically require red blood cell transfusions. Due to the body's inability to excrete excess iron, patients are at increased risk of iron overload, often defined by ferritin levels >1000 ng/mL. Iron overload can cause progressive organ damage from iron deposition in tissues and has been linked to increased mortality. In MDS patients undergoing allogeneic hematopoietic cell transplantation (HCT), iron overload has also been associated with increased non-relapse mortality, decreased overall survival, and a higher incidence of relapse. Prospective and retrospective studies have demonstrated the safety and clinical benefit of iron chelation therapy (ICT) in lower-risk MDS. Despite some common adverse effects associated with ICT, such as renal toxicity and gastro-intestinal symptoms, managing iron levels remains essential in transfusion-dependent MDS patients, and those who are undergoing HCT to optimize pre-transplant conditions, and enhance post-transplant outcomes.

Keywords:  Allogeneic hematopoietic cell transplantation; Ineffective erythropoiesis; Myelodysplastic syndromes/ neoplasms; iron chelation therapy; iron overload

DOI:  https://doi.org/10.1016/j.blre.2025.101319
Br J Haematol. 2025 Jun 30.

Efficacy and safety of HRS-5965 monotherapy in complement inhibitor-naïve patients with paroxysmal nocturnal haemoglobinuria.

Li Zhang, Ziwei Liu, Xin Zhao, Bin Hu, Rong Huang, Chang Shu, Fengkui Zhang, Bing Han.

  Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, life-threatening disorder characterized by complement-mediated haemolysis, leading to anaemia and thrombosis. HRS-5965 is a novel, oral, selective complement factor B inhibitor targeting the alternative pathway, potentially reducing both intra- and extravascular haemolysis. In this randomized, open-label phase II study, we evaluated the efficacy and safety of HRS-5965 monotherapy in complement inhibitor-naïve adult PNH patients. Twenty-six patients were randomized 1:1 to receive HRS-5965 50 mg orally twice daily (BID) (with potential up-titration to 100 mg BID) or 75 mg BID for 12 weeks. The primary end-point was the change in haemoglobin (Hb) from baseline to Week 12. Both groups showed marked Hb increases, with least squares mean increases of 37.6 and 37.7 g/L for the 50 and 75 mg BID groups respectively. Lactate dehydrogenase levels declined by 87% and 85% from baseline. The most common treatment-related adverse events were mild lab abnormalities, including increased alkaline phosphatase and alanine aminotransferase. In conclusion, HRS-5965 monotherapy at either 50 or 75 mg BID resulted in substantial Hb improvements and reduced haemolysis with an acceptable safety profile, suggesting its potential as a promising oral therapy for complement inhibitor-naïve PNH patients.

Keywords:  HRS‐5965; haemoglobin; lactate dehydrogenase; paroxysmal nocturnal haemoglobinuria

DOI:  https://doi.org/10.1111/bjh.20230
Nat Commun. 2025 Jul 01. 16(1): 5470

Single-cell transcriptomics reveals BMP4-BMPR2 signaling promotes radiation resistance in hematopoietic stem cells following injury.

Yanhua Li, Yunxing Li, Bowen Zhang, Jiahui Zhao, Jinhua Qin, Siao Jiang, Yunqiao Li, Yanzhou Chen, Jisheng Li, Keyi Chen, Yang Lv, Tao Fan, Zuyin Yu, Hao Lu, Cheng Quan, Yiming Lu, Xuetao Pei, Gangqiao Zhou.

High doses of ionizing radiation (IR) cause severe damage to the hematopoietic system. However, the heterogeneity of hematopoietic stem and progenitor cells (HSPCs) in response to IR stress remains largely uncharacterized. Here, we present a dynamic single cell transcriptomic landscape and elucidate the complex crosstalk between HSPCs and the bone marrow (BM) microenvironment during IR-induced regeneration process. We reveal that BMP4 signaling in HSPCs confers IR resistance, and a single administration of BMP4 or SB4 can rescue mice from the IR-induced mortality. Furthermore, we identify BMPR2+ HSCs as a radiation resistant subset, displaying distinct epigenetic landscapes from BMPR2- HSCs under radiation stress. BMPR2+ HSCs sustain a strong self-renewal capacity primarily by reducing the H3K27me3 modification on the Nrf2 gene in response to radiation stress. In Nrf2 knockout mice, we demonstrate that Nrf2 is a critical downstream functional gene for BMP4-BMPR2 signaling on HSCs to resist IR-induced damage. Collectively, we provide insights into the molecular intricacies underlying HSPC heterogeneity and BM niche after radiation exposure, and we uncover that BMP4-BMPR2 signaling may serve as a promising target for developing innovative and effective intervention strategies to mitigate IR-induced hematopoietic injury.

DOI: https://doi.org/10.1038/s41467-025-60557-z
Ann Hematol. 2025 Jul 03.

Second allogeneic transplantation in relapsed acute leukemia - a risk worth taking?

Patrycja Zielińska, Karolina Gruenpeter, Agata Wieczorkiewicz-Kabut, Krzysztof Białas, Anna Koclęga, Izabela Noster, Izabela Szewczyk, Kinga Boral, Katarzyna Wiśniewska-Piąty, Aleksandra Butrym, Jarosław Czyż, Ewa Lutwin, Grzegorz Helbig.

  Second allogeneic stem cell transplantation (SCT2) presents a potentially curative treatment approach in patients who relapsed after first allogeneic transplant procedure. Currently there is no consensus on second allografting. The aim of our study was to analyze the outcome and prognostic factors of SCT2 in relapsed acute leukemia setting. The study comprised 60 patients at a median age of 44.7 years (37 females, 23 males) who underwent SCT2 due to relapsed acute leukemia between 2000 and 2024 in our center. Median remission duration after SCT1 was 13.6 (IQR 30.1) months and median time from relapse to SCT2 was 4 (IQR 3) months. Disease-risk index at SCT2 was as follows: low - 2 (3.3%), intermediate - 29 (48,4%), high - 27 (45%) and very high - 2 (3.3%). The same donor was used in 52 procedures (86.7%). Six patients died before engraftment due to severe infectious complications. The 2-year probability of overall survival (OS) and leukemia free survival (LFS) were 26.6% and 26.2%, respectively. Median follow-up after SCT2 was 10.7 (IQR 35) months. At the last follow-up, 22 patients (37%) were alive. The 2-year cumulative relapse incidence (RI) was 47.4% and cumulative non-relapse mortality (NRM) was 55.3%. The factors that adversely influenced survival were as follows: early relapse after SCT1 (< 6 months after transplantation) (p = 0.018) and the use of reduced intensity conditioning before SCT2 (p = 0.0272). Presented data indicate that second allograft is a feasible option in selected patients with relapsed acute leukemia. There is still room for improvement in terms of non-relapse mortality.

Keywords:  Acute leukemia; Outcome; Relapse; Second allogenic stem cell transplantation; Survival

DOI:  https://doi.org/10.1007/s00277-025-06468-x
Blood Adv. 2025 Jul 03. pii: bloodadvances.2024015185. [Epub ahead of print]

PROM1/CD133 MARKS A PROLIFERATIVE STEM CELL LIKE POPULATION OF BLASTS IN KMT2A REARRANGED INFANT ALL.

Joe Wilson Cross, Lucy May Field, Alastair Smith, Emily Neil, Lucy Hamer, Thomas Jackson, Natalina Elliott, Siobhan Rice, Nicholas Crump, Joe Harman, Rebecca E Ling, Qingqing Wu, Nouhad El Ouazzani, Rebecca Thomas, Sarah Inglott, Jack Bartram, Owen Smith, Jonathan Bond, Irene Roberts, Thomas A Milne, Anindita Roy.

DOI: https://doi.org/10.1182/bloodadvances.2024015185
Nature. 2025 Jul;643(8070): 47-59

The Somatic Mosaicism across Human Tissues Network.

Somatic Mosaicism across Human Tissues Network

From fertilization onwards, the cells of the human body acquire variations in their DNA sequence, known as somatic mutations. These postzygotic mutations arise from intrinsic errors in DNA replication and repair, as well as from exposure to mutagens. Somatic mutations have been implicated in some diseases, but a fundamental understanding of the frequency, type and patterns of mutations across healthy human tissues has been limited. This is primarily due to the small proportion of cells harbouring specific somatic variants within an individual, making them more challenging to detect than inherited variants. Here we describe the Somatic Mosaicism across Human Tissues Network, which aims to create a reference catalogue of somatic mutations and their clonal patterns across 19 different tissue sites from 150 non-diseased donors and develop new technologies and computational tools to detect somatic mutations and assess their phenotypic consequences, including clonal expansions. This strategy enables a comprehensive examination of the mutational landscape across the human body, and provides a comparison baseline for somatic mutation in diseases. This will lead to a deep understanding of somatic mutations and clonal expansions across the lifespan, as well as their roles in health, in ageing and, by comparison, in diseases.

DOI: https://doi.org/10.1038/s41586-025-09096-7