bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–08–31
thirty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. The role of menin inhibitors in acute myeloid leukemia.
  2. TLR2 Agonism Suppresses Myeloid Leukemogenesis by Reprogramming Leukemia Stem Cells.
  3. Reconsidering 'primary myelofibrosis with increased haemoglobin' within the myeloproliferative neoplasms biological continuum.
  4. SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms.
  5. Germline Jak2-R1063H mutation interferes with normal hematopoietic development and increases risk of thrombosis and leukemic transformation.
  6. Curing the Incurable: TP53 Mutated Myeloid Neoplasms.
  7. Plasma lipid levels predict chemotherapy response and survival in acute myeloid leukemia.
  8. Retinoic acid disrupts an NPM1c/ROS/SENP3/ARF oncogenic axis in acute myeloid leukemia.
  9. Predicting antigen-specific T-cell immunity against Wilms tumor 1 in hematologic cancer.
  10. Acute leukemia of ambiguous lineage with KMT2A-alterations in adults.
  11. Quality of life and life satisfaction in long-term survivors of acute myeloid leukemia.
  12. Who truly benefits from gilteritinib combinations in FLT3-mutated relapsed-refractory(R/R) AML: a Canadian single center analysis.
  13. Novel Strategies Targeting Mutant Calreticulin in Essential Thrombocythemia and Myelofibrosis.
  14. Mesenchymal stromal cells from JAK2 V617F myeloproliferative neoplasms support healthy and malignant hematopoiesis in a humanized scaffold model in vivo.
  15. Pemigatinib for Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement.
  16. The bispecific innate cell engager AFM28 eliminates CD123+ leukemic stem and progenitor cells in AML and MDS.
  17. Contemporary Outcomes of Adults With Acute Lymphoblastic Leukemia With KMT2A Rearrangements Treated With Immunotherapy-Based Regimens.
  18. Transcriptional profiling directs the classification of acute leukemias of ambiguous lineage into AML, B-ALL, or T-ALL.
  19. Venetoclax in combination with ponatinib for the treatment of asciminib-resistant chronic myeloid leukemia.
  20. CD371-Targeted CAR T cells Secreting Interleukin-18 Exhibit Robust Expansion and Clear Refractory Acute Myeloid Leukemia.
  21. Multi-omics analysis identifies an M-MDSC-like immunosuppressive phenotype in lineage-switched AML with KMT2A rearrangement.
  22. Targeting the roots of myeloid malignancies with T cell receptors.
  23. BK virus kinetics and associated cystitis/urethritis symptoms after PTCy-based allogeneic hematopoietic cell transplant.
  24. A decade of experience using ATG and PTCy for graft-versus-host disease prophylaxis in matched unrelated donor allogeneic haematopoietic cell transplantation.
  25. Gilteritinib in FLT3-mutated acute myeloid leukemia: A real-world Italian experience.
  26. The evolving nosology of myeloid neoplasms: the semi-centennial of the 1976 French-American-British classification.
  27. Clonal Hematopoiesis and Outcomes After High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with AML, Myeloma, and Lymphoma.
  28. Real-world generalizability of clinical trial cytomolecular risk in pediatric acute myeloid leukemia: a report from the REAL-AML cohort.
  29. Targeting p16INK4a-mediated cellular senescence as a therapeutic strategy for FLT3-ITD-driven acute myeloid leukemia.
  30. Haematopoietic stem cell number is not solely defined by niche availability.
  31. A stem cell differentiation model reveals two alternative fates in CBFA2T3::GLIS2-driven acute megakaryoblastic leukemia initiation.
  32. Mapping early human blood cell differentiation using single-cell proteomics and transcriptomics.
  1. Curr Opin Oncol. 2025 Aug 08.
    The role of menin inhibitors in acute myeloid leukemia.
    Alessandro Isidori, Giovanni Marconi.
       PURPOSE OF REVIEW: Acute myeloid leukemia (AML) characterized by NPM1 mutations or KMT2A rearrangements depends on abnormal epigenetic programs mediated by menin, a critical scaffold protein for sustaining the expression of oncogenic HOX/MEIS1 genes. Therefore, menin inhibitors have become a promising class of AML treatments.
    RECENT FINDINGS: Early-phase trials have shown that agents such as revumenib, ziftomenib, bleximenib, and enzomenib are active, particularly in relapsed/refractory disease, with 23-48% of patients achieving composite complete remission. However, the durability of single-agent treatment remains limited, and resistance mechanisms, such as MEN1 mutations or transcriptional reprogramming, have been identified. Consequently, combination approaches involving venetoclax, hypomethylating agents, or chemotherapy are being investigated to improve response depth and duration. Recent SAVE, KOMET-007, and cAMeLot-2 trials have demonstrated high overall response rates (68%-100%) and encouraging MRD-negative complete remissions when combining menin inhibitors with venetoclax-based regimens. This has been observed even in patients who have previously received venetoclax. Combinations with intensive chemotherapy (e.g., 7 + 3) in the frontline setting have also yielded high CRc rates (up to 94% in NPM1-mutated AML) without exacerbating toxicity.
    SUMMARY: These findings justify the integration of menin inhibitors into the AML therapeutic landscape, and support ongoing randomized trials to confirm their benefit in both frontline and relapse or refractory settings.
    Keywords:  KMT2A rearrangement; NPM1 mutation; acute leukemias; menin inhibitors; refractory disease; relapsed disease
    DOI:  https://doi.org/10.1097/CCO.0000000000001185
  2. Blood Adv. 2025 Aug 20. pii: bloodadvances.2025017018. [Epub ahead of print]
    TLR2 Agonism Suppresses Myeloid Leukemogenesis by Reprogramming Leukemia Stem Cells.
    Michael E Lawler, Jennifer S Romer-Seibert, Michael S Bowman, Ramkrishna Mitra, Christine M Eischen, Robert L Bowman, Sara E Meyer.
      The consequences of activated innate immune signaling in acute myeloid leukemia (AML) is not well understood. Using ligands directed at the Toll-like family receptors (TLR) in models of high-risk AML, we uncover that TLR2 ligands exert unique anti-leukemic effects that are distinct from other TLRs. While TLR2 signaling broadly induces inflammatory gene expression in AML cells, at the single cell level, cell-type-dependent, divergent transcriptional responses coordinate cellular outputs of proliferation, differentiation, cell death, and activation of immune cell function. TLR2 ligands were the only TLR agonists capable of extending survival of AML-bearing mice through leukemia stem cell (LSC) reprogramming that elevated MHC class II surface expression and ultimately impaired self-renewal. We find that the co-expression of TLR2 and MHCII genes is associated with better overall survival in AML patients, which is consistent with our observations of activated TLR2 signaling in mice. These data reveal functional TLR2 signaling critically antagonizes leukemogenesis and emphasizes a role for TLR2 agonism in AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017018
  3. Br J Haematol. 2025 Aug 26.
    Reconsidering 'primary myelofibrosis with increased haemoglobin' within the myeloproliferative neoplasms biological continuum.
    Hans Carl Hasselbalch.
      
    DOI:  https://doi.org/10.1111/bjh.70103
  4. Leukemia. 2025 Aug 26.
    SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms.
    Jonas Thier, Sophia Hofmann, Katharina M Kirchhof, Gabriele Todisco, Teresa Mortera-Blanco, Ingrid Lilienthal, Dimitris C Kanellis, Indira Barbosa, Ann-Charlotte Björklund, André G Deslauriers, Jiri Bartek, Nikolas Herold, Elli Papaemmanuil, Eirini P Papapetrou, Eva Hellström-Lindberg, Pedro L Moura, Vanessa Lundin.
      Myelodysplastic syndromes with somatic mutations in the splicing factor SF3B1 gene (MDS-SF3B1) result in RNA mis-splicing, erythroid dysplasia and ultimately refractory anemia. Precision medicine approaches for MDS-SF3B1 remain challenging due to both the complexity of the mis-splicing landscape and its evaluation in disease-accurate models. To uncover novel RNA mis-splicing events, isogenic SF3B1K700E and SF3B1WT iPSC lines from an MDS-SF3B1 patient were differentiated into hematopoietic cells and analyzed via unsupervised splicing event profiling using full-length RNA sequencing. This identified SF3B1K700E-specific mis-splicing of ubiquitin-like modifier activating enzyme 1 (UBA1), which encodes a key E1 protein at the apex of the ubiquitination cascade. UBA1 mis-splicing (UBA1ms) introduced protein instability and decreased total UBA1 levels, rendering mutated cells susceptible to the small-molecule UBA1 inhibitor TAK-243. Analysis of CD34+ RNA sequencing data from an MDS patient cohort confirmed unique and ubiquitous UBA1ms in MDS-SF3B1 patients, absent in other splicing factor-mutated MDS cases or healthy controls. TAK-243 selectively targeted MDS-SF3B1 primary CD34+ cells and reduced mutant cell numbers in colony-forming assays. In contrast, normal hematopoietic progenitor cells were unaffected. Altogether, we here define UBA1ms as a novel therapeutic vulnerability in SF3B1-mutant cells, introducing UBA1 inhibition as a potential avenue for future MDS-SF3B1 treatments.
    DOI:  https://doi.org/10.1038/s41375-025-02740-1
  5. Leukemia. 2025 Aug 21.
    Germline Jak2-R1063H mutation interferes with normal hematopoietic development and increases risk of thrombosis and leukemic transformation.
    Veronika Zimolova, Monika Burocziova, Linda Berkova, Srdjan Grusanovic, Jan Gursky, Lubos Janotka, Petr Kasparek, Alena Pecinova, David Kundrat, Dusan Hrckulak, Jakub Onhajzer, Ivana Jeziskova, Lucie Nekvindova, Barbora Weinbergerova, Sarka Pospisilova, Michael Doubek, Meritxell Alberich-Jorda, Vladimir Korinek, Vladimir Divoky, Lucie Lanikova.
      The acquired JAK2-V617F mutation plays a causal role in myeloproliferative neoplasms (MPN). Weakly activating JAK2 germline variants have been associated with MPN risk, but the underlying mechanisms remain unclear. We previously identified the JAK2-R1063H germline variant, which contributes to hereditary MPN and increased disease severity in essential thrombocythemia. Here, we studied alterations in hematopoiesis in Jak2-R1063H knock-in mice. The Jak2-R1063H mouse cohort exhibited increased mortality, stimulated thrombopoiesis and elevated D-dimers levels, indicative of thrombotic complications. Bone marrow analysis revealed myeloid bias, enhanced megakaryopoiesis and activation of inflammatory signaling. Transcriptional and functional assays of hematopoietic stem cells suggested their accelerated aging and functional decline. The Egr1 transcriptional network, including the Thbs1 gene, progressively increased in aging mice, reinforcing alterations initiated by Jak2/Stat signaling. In murine acute myelogenous leukemia models, the Jak2-R1063H cooperated with a driver oncogene in promoting leukemogenesis. Germline JAK2-R1063H was found in 10 of 200 MPN patients from local hematology centers, with a higher minor allele frequency compared to healthy controls. Patients harboring JAK2-R1063H variant exhibited an increased incidence of thrombotic complications and disease progression with shortened survival. In conclusion, our findings identify the JAK2-R1063H germline variant as a risk factor for MPN development, thrombotic complications, and leukemic transformation. Our study, which involves a mouse model and a cohort of 200 MPN patients, characterizes the JAK2-R1063H germline mutation as a risk factor for MPN development, thrombotic complications, and leukemic transformation. These findings may have important clinical implications for managing MPN patients carrying the JAK2-R1063H germline variant.
    DOI:  https://doi.org/10.1038/s41375-025-02737-w
  6. Clin Lymphoma Myeloma Leuk. 2025 Jul 27. pii: S2152-2650(25)00256-3. [Epub ahead of print]
    Curing the Incurable: TP53 Mutated Myeloid Neoplasms.
    Nathan Punwani, Saurabh Chhabra.
      The TP53 gene ensures genetic fidelity by regulating cell cycle kinetics and apoptosis. In myeloid neoplasms, TP53 mutation is witnessed in 13% of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Alterations in TP53 or its respective protein is associated with a near-universal dismal prognosis, especially if there is TP53 protein hyper-expression or multi-hit genetic disease as defined by: biallelic loss, 17p chromosomal deletion, complex karyotypic features, loss of heterozygosity, or variant allele frequency (VAF) of 50% or more. TP53 mutations or protein hyper-expression instill an immunosuppressive bone marrow microenvironment, exacerbating an already poor prognosis. We will survey the pathobiology of TP53 mutated/hyper-expressed myeloid disease, its classification schema, and its immunologic ramifications to the bone marrow milieu. The differential prognosis of the mutation in various chromosomal and VAF settings will be explored. Lastly, we will outline therapeutic options, promising treatments on the horizon, and whether allogeneic stem cell transplant is curative.
    Keywords:  AML; Allogeneic stem cell transplant; Bone marrow; Flotetuzumab; Iadademstat; MDS
    DOI:  https://doi.org/10.1016/j.clml.2025.07.013
  7. Blood. 2025 Aug 26. pii: blood.2025029132. [Epub ahead of print]
    Plasma lipid levels predict chemotherapy response and survival in acute myeloid leukemia.
    Cristiana O'Brien, Nirvana Nursimulu, Anit Tyagi, Rachel Culp-Hill, Andrea Arruda, Tracy Murphy, Mark D Minden, Andrew Kent, Brett M Stevens, Daniel A Pollyea, Kristin Hope, Sushant Kumar, Julie A Reisz, Angelo D'Alessandro, Courtney L Jones.
      Acute myeloid leukemia (AML) is characterized by a low five-year survival rate. Despite having many clinical metrics to assess patient prognosis, there remain opportunities to improve risk stratification. We hypothesized that an underexplored resource to examine AML patient prognosis is the plasma metabolome. Circulating metabolites are influenced by patients' clinical status and can serve as accessible cancer biomarkers. To establish a resource of circulating metabolites in genetically diverse AML patients, we performed an unbiased metabolomic and lipidomic analysis of 231 diagnostic AML plasma samples prior to treatment with intensive chemotherapy. Intriguingly, circulating metabolites were highly associated with the mutation status within the AML cells. Further, lipids were associated with refractory status. We established a machine learning algorithm trained on chemo-refractory associated lipids to predict patient survival. Cox regression and Kaplan-Meier analysis demonstrated that the high-risk lipid signature predicted overall survival in this patient cohort. Impressively, the top lipid in the high-risk lipid signature, sphingomyelin (d44:1), was sufficient to predict overall survival in the original and an independent validation dataset. Overall, this research underscores the potential of circulating metabolites to capture AML heterogeneity and lipids to be used as potential AML biomarkers.
    DOI:  https://doi.org/10.1182/blood.2025029132
  8. Leukemia. 2025 Aug 26.
    Retinoic acid disrupts an NPM1c/ROS/SENP3/ARF oncogenic axis in acute myeloid leukemia.
    Rita Hleihel, Hala Skayneh, Hsin-Chieh Wu, Maguy Hamie, Abdallah Kurdi, Jana Dakour, Charbel Machaalani, Marwan El-Sabban, Hugues de Thé, Ali Bazarbachi, Hiba El Hajj.
      Nucleophosmin-1 (NPM1) is a nucleolar chaperone protein frequently mutated in acute myeloid leukemia (AML). ARF and Sentrin/SUMO Specific Peptidase 3 (SENP3) control NPM1 functions through dynamic SUMOylation/de-SUMOylation. Mutated NPM1 is an oncoprotein that exhibits an aberrant cytoplasmic localization (NPM1c) and disrupts PML/P53 signaling. Studies reported increased survival of patients with NPM1c AML when retinoic acid (RA) was added to chemotherapy or hypomethylating agents. Ex vivo, RA initiates NPM1c degradation, P53 activation and cell death. Yet, the molecular mechanisms involved remain elusive. Here we show that in NPM1c AML cell lines or patients' blasts, NPM1c-triggered mitochondrial dysfunction and oxidative stress drive NPM1c stabilization through SENP3 upregulation. RA decreases mitochondrial ROS production, driving degradation of SENP3, ARF stabilization, PML-dependent NPM1c hyperSUMOylation followed by RNF4-dependent ubiquitination and degradation. Thus, the feedback loop stabilizing NPM1c protein can be interrupted by RA-triggered enhanced mitochondrial fitness, mechanistically explaining the benefit of RA in chemotherapy or hypomethylating agents-treated AMLs.
    DOI:  https://doi.org/10.1038/s41375-025-02731-2
  9. Leukemia. 2025 Aug 22.
    Predicting antigen-specific T-cell immunity against Wilms tumor 1 in hematologic cancer.
    iCAN
      Wilms tumor 1 (WT1) is a tumor-associated antigen expressed in solid tumors and hematological malignancies. T-cell immunotherapies targeting WT1 are currently under development. To analyze endogenous T-cell responses against WT1, we trained computational models capable of detecting WT1-specific T-cell responses from T-cell receptor (TCR) sequencing data. We peptide-pulsed healthy donor and acute myeloid leukemia (AML) patient samples with VLDFAPPGA (VLD, WT137-45) and RMFPNAPYL (RMF, WT1126-134) peptides, then sequenced the WT1 dextramer-positive CD8 + T-cells with single-cell RNA + TCRαβ sequencing. The TCRGP machine-learning TCR-classification method was trained with epitope-specific and control TCR repertoires, and we obtained AUROC values of 0.74 (VLD) and 0.75 (RMF), allowing reliable identification of WT1-specific T-cells. In bulk TCRβ sequenced patient samples (AML n = 21, chronic myeloid leukemia (CML) n = 26, and myelodysplastic syndrome n = 25), the median WT1-specific T-cell abundance was similar to healthy controls, but their VLD and RMF-specific TCR repertoires exhibited higher clonality with two patients presenting up to 13% of WT1-specific T-cells. ScRNA+TCRαβ sequencing of AML bone marrow T-cells revealed that WT1-specific T-cells predominantly exhibit an effector or terminal effector memory phenotype. In conclusion, our novel computational models enable large-scale WT1-specific T-cell identification from TCR sequencing datasets and leukemia-antigen-specific immune response monitoring.
    DOI:  https://doi.org/10.1038/s41375-025-02727-y
  10. Leuk Lymphoma. 2025 Aug 25. 1-6
    Acute leukemia of ambiguous lineage with KMT2A-alterations in adults.
    Steven Tessier, Patricia T Greipp, Dragan Jevremovic, Hassan B Alkhateeb, Aref Al-Kali, Mithun V Shah, William J Hogan, Mrinal M Patnaik, Antoine N Saliba, Naseema Gangat, James M Foran, Cecilia Y Arana Yi, Ayalew Tefferi, Kebede H Begna.
      
    DOI:  https://doi.org/10.1080/10428194.2025.2547988
  11. Leukemia. 2025 Aug 22.
    Quality of life and life satisfaction in long-term survivors of acute myeloid leukemia.
    Eva Telzerow, Dennis Görlich, Cristina Sauerland, Maja Rothenberg-Thurley, Anna Sophia Moret, Simon M Krauß, Friederike H A Mumm, Susanne Amler, Wolfgang E Berdel, Bernhard J Wörmann, Utz Krug, Jan Braess, Pia Heußner, Wolfgang Hiddemann, Karsten Spiekermann, Klaus H Metzeler.
      We performed a questionnaire-based cross-sectional study to analyze Acute Myeloid Leukemia (AML) long-term survivor (LTS) outcomes, including psychosocial well-being and somatic health status. Four-hundred-twenty-seven former AML patients participated (response rate, 63%) ≥5 years[y] and up to 18.6 y past their leukemia diagnosis (median, 11.3 y). Median age at study participation was 61 y (range 28y-93y), 23% had experienced disease relapse, and 63% had received allogeneic hematopoietic stem cell transplantation (alloHSCT). Overall, quality of life (QoL) and general life satisfaction (gLS) summary scores were higher in AML LTS (p < 0.001) compared to age-/sex-matched reference cohorts, although differences were small and likely not clinically relevant. However, we identified subgroups of survivors reporting impaired QoL (27%), gLS (13%) and health-related life satisfaction (hrLS; 17%). Using multivariable regression models, we identified predisposing and protective factors for each of these outcomes. Treatment with alloHSCT did not adversely impact QoL, gLS, or hrLS. In summary, global QoL and LS in AML LTS are comparable to the general population, irrespective of treatment modality, although some survivors report clinically significant impairment of global QoL and/or in specific domains. We identified factors associated with impaired outcomes (e.g., comorbidity and fatigue), delineating a subgroup of survivors with unmet needs ≥5 y after their AML diagnosis.
    DOI:  https://doi.org/10.1038/s41375-025-02735-y
  12. Blood Cancer J. 2025 Aug 26. 15(1): 143
    Who truly benefits from gilteritinib combinations in FLT3-mutated relapsed-refractory(R/R) AML: a Canadian single center analysis.
    Akhil Rajendra, Elliot Smith, Maria Agustina Perusini, Kenny Tang, Eshetu G Atenafu, Aniket Bankar, Steven Chan, Marta B Davidson, Vikas Gupta, Dawn Maze, Mark D Minden, Guillaume Richard-Carpentier, Aaron D Schimmer, Andre C Schuh, Karen Yee, Hassan Sibai.
      
    DOI:  https://doi.org/10.1038/s41408-025-01353-2
  13. Blood. 2025 Aug 26. pii: blood.2025028642. [Epub ahead of print]
    Novel Strategies Targeting Mutant Calreticulin in Essential Thrombocythemia and Myelofibrosis.
    Gabriel S Salzman, Ann Mullally.
      The discovery of calreticulin (CALR) mutations in patients with myeloproliferative neoplasms (MPN) has paved the way for the elucidation of a unique disease mechanism that is particularly well-suited to targeting by biologics. All MPN-associated pathogenic CALR mutations are characterized by a frameshift, resulting in translation of the same neoantigen peptide. This neoantigen directly activates the thrombopoietin receptor, leading to uncontrolled neoplastic cell proliferation. Current therapeutic approaches for MPN are focused primarily on blood count control. Furthermore, current approaches are neither disease-modifying nor clonally selective. However, as the mutant CALR neoantigen peptide is functional and not expressed in normal physiology, it is an ideal drug target. Here, we review the structure and function of mutant CALR, including the subtle yet clinically and therapeutically relevant differences between the two most commonly occurring types of mutation. We also review the current therapeutic landscape for CALR-mutated MPN, highlighting the areas in which current approaches are inadequate. Finally, we review ongoing clinical and preclinical experimental approaches for targeting mutant CALR in MPN in a clonally selective manner using monoclonal antibodies, bispecific antibodies, cancer vaccination, chimeric antigen receptor T cells, and antibody-drug conjugates. Taken together, we expect that ongoing developments in mutant CALR-targeted therapeutics will lead to promising novel strategies for long-term disease control.
    DOI:  https://doi.org/10.1182/blood.2025028642
  14. Hemasphere. 2025 Aug;9(8): e70185
    Mesenchymal stromal cells from JAK2 V617F myeloproliferative neoplasms support healthy and malignant hematopoiesis in a humanized scaffold model in vivo.
    Alessandra Ferrelli, Syed Mian, Marion Piganeau, Hector Huerga Encabo, Despoina Papazoglou, Giuseppe D'Agostino, Fatihah Mohamad Nor, Manuel Garcia-Albornoz, Steven Ngo, Linda Ariza-McNaughton, Erika Morsia, Matteo Giovanni Della Porta, Claire Harrison, Shahram Kordasti, Dominique Bonnet.
      Myeloproliferative Neoplasms (MPN) are malignancies of hematopoietic stem and progenitor cells (HSPCs) that lead to the overproduction of mature blood cells. These disorders include Essential Thrombocythemia (ET), Polycythemia Vera (PV), and Primary Myelofibrosis (PMF), primarily driven by somatic mutations such as JAK2 V617F . Research indicates that mesenchymal stromal cells (MSCs) support fibrosis in PMF, though their role in ET and PV remains less clear. Furthermore, in vivo studies of ET/PV HSPCs remain a challenge due to low engraftment levels in xenograft models. We employed a 3D scaffold model to create an MPN humanized xenograft mouse model, enabling in vivo functional studies of primary MPN progenitor cells and the supportive role of human MSCs. Using this model, we first demonstrated robust hematopoietic support of healthy (HD) HSPCs by PV and ET MSCs. We then investigated the role of MSCs in sustaining JAK2 V617F mutant cells by using a CRISPR-Cas9 editing model, along with primary PV and ET HSPCs. Our results showed consistent engraftment of CRISPR-edited JAK2 V617F mutant HSPCs and PV and ET patient-derived HSPCs in scaffolds seeded with HD, PV, and ET stroma, providing the first in vivo evidence that PV and ET MSCs can sustain both healthy and MPN-associated hematopoiesis. Furthermore, HD MSCs were also capable of sustaining PV and ET HSPCs in vivo. Overall, we present the first humanized MPN xenograft model that offers valuable insights into how human BM MSCs interact with JAK2 V617F mutant clones.
    DOI:  https://doi.org/10.1002/hem3.70185
  15. NEJM Evid. 2025 Sep;4(9): EVIDoa2500017
    Pemigatinib for Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement.
    Srdan Verstovsek, Jean-Jacques Kiladjian, Alessandro M Vannucchi, Jay L Patel, Alessandro Rambaldi, William E Shomali, Stephen T Oh, Kensuke Usuki, Claire N Harrison, Ellen K Ritchie, Luke P Akard, Juan Carlos Hernández-Boluda, Françoise Huguet, Philomena Colucci, Huiling Zhen, Natalia Oliveira, Aidan Gilmartin, Cheryl Langford, Tracy I George, Andreas Reiter, Jason Gotlib.
       BACKGROUND: Myeloid/lymphoid neoplasms with fibroblast growth factor receptor 1 rearrangements (MLN-FGFR1) are associated with poor prognosis. They are caused by chromosome 8p11 rearrangements that result in FGFR1 fusion genes and constitutive FGFR1 activation. We report on a phase 2 study, in which there were no concurrent control patients, termed FIGHT-203, in which we evaluated the FGFR1-3 inhibitor, pemigatinib, for the treatment of MLN-FGFR1.
    METHODS: We assigned eligible patients to receive oral pemigatinib 13.5 mg once daily (2 weeks on followed by 1 week off or continuously). End points included complete response rate (primary) and complete cytogenetic response rate. Responses were assessed locally by investigators per protocol-defined criteria and were retrospectively adjudicated by a central review committee using criteria defined by the committee.
    RESULTS: Of 47 treated patients (safety population), 45 had confirmed FGFR1 rearrangement and were analyzed for efficacy; of these patients, 24 (53%) were in the chronic phase of illness; 18 (40%) were in blast phase; and three previously treated patients (7%) exhibited the rearrangement without morphologic bone marrow or extramedullary involvement. The overall complete response rate, as determined by central review, was 74% (31 out of 42); this occurred in 96% (23 out of 24) of patients in chronic phase and 44% (8 out of 18) of patients in blast phase. A complete cytogenetic response was observed in 73% (33 out of 45) of patients overall, consisting of 88% (21 out of 24) of patients in chronic phase, 50% (9 out of 18) of patients in blast phase, and all three patients who had a rearrangement only. The median duration of complete response was not reached (95% confidence interval, 27.9 months to not reached). The most common any-grade treatment-emergent adverse event was hyperphosphatemia (76%); the most common grade-3-and-over event was stomatitis (19%). Pemigatinib discontinuation, interruption, and dose reduction occurred in 5 (11%), 30 (64%), and 28 (60%) patients, respectively.
    CONCLUSIONS: In our study, pemigatinib manifested near complete efficacy in chronic-phase patients with MLN-FGFR1, while the complete response rate was close to 50% in blast-phase patients. Toxicities were manageable with dose modifications. (Funded by Incyte Corporation; FIGHT-203 ClinicalTrials.gov number, NCT03011372.).
    DOI:  https://doi.org/10.1056/EVIDoa2500017
  16. Nat Commun. 2025 Aug 21. 16(1): 7793
    The bispecific innate cell engager AFM28 eliminates CD123+ leukemic stem and progenitor cells in AML and MDS.
    Nanni Schmitt, Jana-Julia Siegler, Alexandra Beck, Thomas Müller, Izabela Kozlowska, Séverine Sarlang, Uwe Reusch, Stefan Knackmuss, José Medina-Echeverz, Joachim Koch, Thorsten Ross, Ali Darwich, Lea Hoppe, Mohammed Abba, Alexander Streuer, Stefan Klein, Wolf-Karsten Hofmann, Anna Lisa Gündner, Christian Merz, Jan Endell, Jens Pahl, Daniel Nowak.
      Strategies targeting leukemic stem and progenitor cells (LSPCs) are needed for durable remissions in acute myeloid leukemia (AML) and high-risk myelodysplastic neoplasms (MDS). While CD123 constitutes a promising target on LSPCs and leukemic blasts, previous CD123-targeting approaches showed limited efficacy and challenging safety profiles. Here, we describe the preclinical efficacy and safety of the bispecific CD123/CD16A innate cell engager "AFM28", demonstrating superior activity against AML and MDS patient-derived LSPCs and blasts in vitro compared to an Fc-enhanced CD123-targeting antibody, especially towards CD123low and/or CD64+ leukemic cells. AFM28 induces autologous anti-leukemic activity in fresh AML whole blood cultures, demonstrating its potential to enhance NK cell function from AML patients. Responsiveness can be further enhanced by allogeneic NK cell addition. Anti-leukemic activity of AFM28 is confirmed in xenograft mouse models. In addition, AFM28 is well tolerated and demonstrates pharmacodynamic activity in cynomolgus monkeys. Altogether, our results indicate that AFM28 has the potential to reduce relapse-inducing residual disease and promote long-term remissions for patients with AML and MDS with a favorable safety profile.
    DOI:  https://doi.org/10.1038/s41467-025-63069-y
  17. Am J Hematol. 2025 Aug 27.
    Contemporary Outcomes of Adults With Acute Lymphoblastic Leukemia With KMT2A Rearrangements Treated With Immunotherapy-Based Regimens.
    Hannah Goulart, Elias Jabbour, Nicholas Short, Nitin Jain, Ghayas Issa, Himachandana Atluri, Alex Bataller, Tapan Kadia, Naval Daver, Courtney DiNardo, Rebecca Garris, Jayastu Senapati, Farhad Ravandi, Hagop Kantarjian.
      
    Keywords:  ALL—molecular diagnosis and therapy; immunotherapy; leukemia; stem cell transplantation
    DOI:  https://doi.org/10.1002/ajh.70048
  18. Hemasphere. 2025 Aug;9(8): e70195
    Transcriptional profiling directs the classification of acute leukemias of ambiguous lineage into AML, B-ALL, or T-ALL.
    Roger Mulet-Lazaro, Anikó Sijs-Szabó, Remco M Hoogenboezem, Stanley van Herk, Carla Exalto, Jasper E Koenders, Patricia G Hoogeveen, François G Kavelaars, Anita M Schelen, Willemijn van den Ancker, Arjan A van de Loosdrecht, Charles G Mullighan, H Berna Beverloo, Vincent van der Velden, Jan J Cornelissen, Peter J M Valk, Anita W Rijneveld, Mathijs A Sanders.
      Acute leukemia of ambiguous lineage (ALAL) is a rare, poor-prognosis acute leukemia subtype that cannot be assigned to a single hematopoietic lineage. Although ALAL patients are typically treated with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) regimens, optimal treatment choice is hindered by their lineage ambiguity. Therefore, we investigated the added value of transcriptomics for improving lineage assignment, currently based mainly on surface markers. First, we used an in-house pipeline to detect genetic lesions in RNA sequencing data (n = 30) with a sensitivity > 90% for small variants. Second, we compared ALAL gene expression profiles (GEPs) with representative AML (n = 145), B-ALL (n = 223), and T-ALL (n = 85) cases. In a principal component analysis (PCA), ALALs did not form a clear separate group, as most clustered with AML, B-ALL, or T-ALL. Accordingly, a machine learning classifier trained with GEPs of acute leukemias segregated 27/30 ALALs into myeloid-, B-, or T-lymphoid. These 27 cases harbored genetic abnormalities consistent with the classifier-assigned leukemia. Furthermore, deconvolution of ALAL GEPs revealed enrichment for signatures of normal hematopoietic cells corresponding to the leukemic type predicted by our algorithm. The classifier was also applied on an external ALAL cohort (n = 24), assigning 75% of the patients to a lineage matching their immunophenotypic and methylation profiles. In conclusion, integrative analysis of RNA sequencing data can accurately classify most ALAL cases as lineage-defined, while others show true transcriptional and epigenetic ambiguity driven by lesions like BCL11B. The pipeline and classifier developed here are valuable tools to improve ALAL diagnosis and guide therapeutic decisions.
    DOI:  https://doi.org/10.1002/hem3.70195
  19. Leukemia. 2025 Aug 26.
    Venetoclax in combination with ponatinib for the treatment of asciminib-resistant chronic myeloid leukemia.
    Nikola Curik, Adam Laznicka, Jitka Krizkova, Pavla Suchankova, Adela Vavrova, Vaclava Polivkova, Eva Pokorna, Pavel Semerak, Pavel Burda, Daniela Kuzilkova, Tomas Kalina, Andreas Hochhaus, Katerina Machova Polakova.
      
    DOI:  https://doi.org/10.1038/s41375-025-02732-1
  20. Blood. 2025 Aug 27. pii: blood.2025029532. [Epub ahead of print]
    CD371-Targeted CAR T cells Secreting Interleukin-18 Exhibit Robust Expansion and Clear Refractory Acute Myeloid Leukemia.
    Mark B Geyer, Susan DeWolf, Xiaoli Mi, Kenyon Weis, Brian C Shaffer, Briana Cadzin, Devin McAvoy, Zoe A Katsamakis, Rachel Lorenc, Alexander M Lewis, Brianna Gipson, M Adriana Cuibus, Narina N Girotra, Kenton Wu, Natalie Smith, Erin R Burns, Jasmine S Um, Sarah Yoo, Behzad Kharabi Masouleh, Pallavi K Galera, Kinga Hosszu, Jagrutiben Chaudhari, Xiuyan Wang, Qianqian Lin, Kevin J Curran, Jae H Park, David A Scheinberg, Marcel R M van den Brink, Omar Abdel-Wahab, Renier J Brentjens, Anthony F Daniyan.
      Success of chimeric antigen receptor (CAR) T-cell therapy in lymphoid malignancies has not yet been recapitulated in acute myeloid leukemia (AML). We developed CAR T-cells targeting CD371 with a mutated CD28 costimulatory domain to limit T-cell exhaustion, and constitutive interleukin-18 secretion to enhance immune function (CD371/SAVVY/IL-18 CAR). We initiated a phase I trial (NCT06017258), successfully manufactured and administered CD371/SAVVY/IL-18 CAR T-cells in 5 patients with relapsed/refractory AML and observed expansion following a single infusion of 3x104 or 3x105 CAR T-cells/kg; three patients refractory to ≥5 lines of therapy and post-allogeneic transplant exhibited AML clearance and no evidence of graft-versus-host disease. Dose-limiting toxicity in the two patients treated with 3x105 CAR T-cells/kg dose (prolonged cytopenias with marrow hypoplasia; severe cytokine release syndrome) led to dose reduction to 3x104 CAR T-cells/kg in the following three patients. Single-cell analyses revealed that circulating CAR T-cells in responders included predominantly cytotoxic CD8+ effector T-cells 2 weeks post-infusion while co-existing NK-cells expressed markers of activation. This pilot study highlights the activity of low-dose IL-18 "armored" CAR T-cells against refractory AML and their potential to promote CAR T-cell cytotoxicity and innate endogenous anti-tumor immunity. NCT06017258.
    DOI:  https://doi.org/10.1182/blood.2025029532
  21. Nat Commun. 2025 Aug 26. 16(1): 7955
    Multi-omics analysis identifies an M-MDSC-like immunosuppressive phenotype in lineage-switched AML with KMT2A rearrangement.
    Takashi Mikami, Itaru Kato, Akira Nishimura, Minenori Eguchi-Ishimae, Tatsuya Kamitori, Keiji Tasaka, Hirohito Kubota, Tomoya Isobe, Yoshinori Uchihara, Yui Namikawa, Satoru Hamada, Shinichi Tsujimoto, Shotaro Inoue, Takayuki Hamabata, Kazushi Izawa, Takako Miyamura, Daisuke Tomizawa, Toshihiko Imamura, Hidemi Toyoda, Mariko Eguchi, Hiroaki Goto, Seishi Ogawa, Masatoshi Takagi, James Badger Wing, Junko Takita.
      Lineage switching (LS) is the conversion of cancer cell lineage during the course of a disease. LS in leukemia cell lineage facilitates cancer cells escaping targeting strategy like CD19 targeted immunotherapy. However, the genetic and biological mechanisms underlying immune evasion by LS leukemia cells are not well understood. Here, we conduct a multi-omics analysis of patient samples and find that lineage-switched acute myeloid leukemia (LS AML) cells with KMT2A rearrangement (KMT2A-r) possess monocytic myeloid derived suppressor cell (M-MDSC)-like characteristics. Single-cell mass cytometry analysis reveals an increase in the M-MDSC like LS AML as compared to those of lineage-consistent KMT2A-r AML, and single-cell transcriptomics identify distinct expression patterns of immunoregulatory genes within this population. Furthermore, in vitro assays confirm the immunosuppressive capacity of LS AML cells against T cells, which is analogous to that of MDSCs. These data provide insight into the immunological aspects of the complex pathogenesis of LS AML, as well as development of future treatments.
    DOI:  https://doi.org/10.1038/s41467-025-63271-y
  22. Nat Rev Cancer. 2025 Aug 21.
    Targeting the roots of myeloid malignancies with T cell receptors.
    Zsofia Foldvari, Margs S Brennan, Aleksei Titov, Sten Eirik W Jacobsen, Johanna Olweus.
      Myeloid malignancies are clonal diseases of haematopoietic stem cell or haematopoietic progenitor cell origin, for which allogeneic haematopoietic stem cell transplantation remains the only curative treatment for most patients. However, the severe side effects and high relapse rates underscore the need for novel therapies. The success of adoptive transfer of chimeric antigen receptor (CAR) T cells targeting B cell-specific cell surface molecules in B cell cancers has not been replicated in myeloid malignancies. T cells engineered to express cancer-directed T cell receptors (TCRs) could provide an alternative, enabling targeting also of the intracellular proteome. In this Perspective, we have collated and reviewed available data from clinical trials exploiting TCR-engineered T cells for the treatment of haematological malignancies and discuss specific characteristics that make myeloid malignancies attractive candidates for TCR-based therapies. We also highlight the need to efficiently target the rare and notoriously therapy-resistant leukaemic stem cells, which represent the roots of myeloid malignancies, to achieve cures. This will require identification of novel targets and TCRs, and we discuss different target categories and strategies that can be applied towards this goal. We also highlight the importance of standardized preclinical testing and publicly available data to enable rapid identification and clinical advancement of promising TCRs towards clinical application.
    DOI:  https://doi.org/10.1038/s41568-025-00857-0
  23. Blood Adv. 2025 Aug 27. pii: bloodadvances.2025016589. [Epub ahead of print]
    BK virus kinetics and associated cystitis/urethritis symptoms after PTCy-based allogeneic hematopoietic cell transplant.
    Dimana Dimitrova, Elisabetta Xue, Mustafa A Hyder, Hyoyoung Choo-Wosoba, Kamil Rechache, Francis A Flomerfelt, Sanchita Das, Christi McKeown, Alison Cusmano, Ruby Sabina, Jennifer A Kanakry, Christopher G Kanakry.
      BK virus-associated cystitis/urethritis (BK-C) is a major cause of morbidity in allogeneic hematopoietic cell transplantation (HCT) recipients. We prospectively followed weekly plasma and urine BK viral loads and associated symptoms in 169 recipients of post-transplantation cyclophosphamide (PTCy)-based HCT. Patients with ≥2 positive BK specimens before day +100 were considered at-risk for developing BK-C. Many patients had detectable BK viruria already before the start of conditioning (40%) and HCT (51%), whereas baseline detectable BK viremia was less common (8% and 11%, respectively). Of 169 patients, 133 (79%) were at-risk for BK-C: of these 96 (72%) developed BK-C after a median 30 days post-HCT, which lasted a median 26 days; 79% had macroscopic hematuria. BK viral levels measured in the first post-HCT month had high prognostic value for subsequent occurrence of BK-C. At time of onset, 96% and 80% had BK viruria ≥7 and ≥9 log10 IU/mL, respectively. In univariate analyses, BK-C was associated with male sex, marrow grafts, sirolimus, and myeloablative conditioning (MAC); earlier BK-C onset was associated with high-dose (compared with intermediate- or low-dose) PTCy, BK positivity at HCT, reduced intensity conditioning (RIC), and underlying immune deficiency. Busulfan use, cyclophosphamide dosing, RIC, and underlying immune deficiency were associated with prolonged symptom duration. In MAC recipients, PTCy dosing also correlated with symptom duration. Our study confirms a very high rate of BK-C after PTCy-based HCT; lower PTCy dose may shorten BK-C duration in specific patient subsets. Early post-HCT monitoring of BK viruria may help identify patients who will subsequently develop BK-C.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016589
  24. Br J Haematol. 2025 Aug 27.
    A decade of experience using ATG and PTCy for graft-versus-host disease prophylaxis in matched unrelated donor allogeneic haematopoietic cell transplantation.
    Nihar Desai, Sergio Rodriguez-Rodriguez, Eshrak Al-Shaibani, Tommy Alfaro Moya, Arjun Datt Law, Igor Novitzky-Basso, Ivan Pasic, Fotios V Michelis, Rajat Kumar, Dennis Dong Hwan Kim, Jonas Mattsson, Auro Viswabandya.
      Anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) are both effective drugs for graft-versus-host disease (GvHD) prophylaxis, but their combined use remains underexplored. We conducted a retrospective analysis of 582 patients with haematological malignancies who underwent unrelated donor transplantation with Status GvHD prophylaxis consisting of low-dose ATG (2 mg/kg) and PTCy over a 10-year period. The median time to neutrophil and platelet engraftment was 18 days (95% CI, 17-19) and 20 days (95% CI, 19-21) respectively. The cumulative incidence of grade III-IV acute Status GvHD at D+100 was 7% (95% CI: 5-9), and the 24-month incidence of moderate-to-severe chronic GvHD was 15.7% (95% CI: 13-19). Clinically significant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation by D+180 occurred in 20.4% (95% CI: 17-24) and 22.7% (95% CI: 19-26) respectively. At 24 months, the cumulative incidence of NRM was 16.2% (95% CI: 13-19), and relapse was 21.3% (95% CI: 18-25). Graft-versus-host disease-free, relapse-free survival (GRFS) at 24 months was 49% (95% CI: 44-53), and overall survival (OS) was 68.3% (95% CI: 64-72). Our decade-long experience supports the safety and efficacy of combining low-dose ATG with PTCy for GvHD prophylaxis in unrelated donor transplantation. These findings warrant further validation in prospective studies.
    Keywords:  ATG‐PTCy; allogeneic; graft‐versus‐host disease; transplantation; unrelated donor
    DOI:  https://doi.org/10.1111/bjh.70124
  25. Cancer. 2025 Sep 01. 131(17): e70055
    Gilteritinib in FLT3-mutated acute myeloid leukemia: A real-world Italian experience.
    Roberto Cairoli, Lorenzo Del Castello, Silvia Imbergamo, Elisabetta Pierdomenico, Cristina Papayannidis, Erika Borlenghi, Calogero Vetro, Patrizia Chiusolo, Monica Fumagalli, Clara Minotti, Francesco Marchesi, Massimo Bernardi, Pellegrino Musto, Nicola Fracchiolla, Anna Candoni, Monia Lunghi, Maurizio Musso, Fabio Guolo, Donato Mannina, Albana Lico, Anna Maria Scattolin, Monica Crugnola, Sara Galimberti, Gianpaolo Nadali, Mauro Turrini, Patrizia Zappasodi, Elisabetta Todisco, Claudia Basilico, Giovanni Grillo, Valentina Mancini, Marta Riva, Davide Paolo Bernasconi, Rosa Greco.
       BACKGROUND AND METHODS: This real-world study evaluated the clinical effectiveness of gilteritinib in 205 patients with relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) enrolled in the Italian expanded access since January 2018.
    RESULTS: Of the 205 patients, 124 (60.5%) received gilteritinib as a bridging therapy to allogeneic stem cell transplantation (allo-SCT), achieving complete remission in 52.4% (n = 65). The median overall survival (OS) for the entire cohort was 11.0 months, with estimated OS rates of 46.8% at 1 year and 28.5% at 3 years. Sixty patients (48% of those bridged) underwent allo-SCT after a median of 3.7 months on gilteritinib, achieving posttransplant OS rates of 65.2% at 1 year and 56.1% at 3 years. The acquisition of FLT3 mutations at relapse and the presence of TP53 co-mutations were significantly associated with inferior outcomes. Among 46 patients (22.4%) who relapsed after allo-SCT, gilteritinib treatment yielded an overall response rate (ORR) of 54.3%, a median OS of 11.1 months, and 1- and 3-year OS rates of 49.5% and 15.5%, respectively. Additionally, 35 patients (17.1%) previously treated with nonintensive chemotherapy received gilteritinib until disease progression or intolerance, achieving an ORR of 11.4%, a median OS of 5.9 months, and a 1-year OS rate of 29.0%.
    CONCLUSIONS: These real-world data confirm that clinical outcomes achieved with gilteritinib in patients with R/R FLT3-mutated AML are consistent with those observed in pivotal clinical trials. Notably, approximately half of the transplant-eligible patients were successfully bridged to allo-SCT and demonstrated encouraging long-term survival.
    Keywords:  FLT3; acute myeloid leukemia; gilteritinib; real‐world; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1002/cncr.70055
  26. Leukemia. 2025 Aug 26.
    The evolving nosology of myeloid neoplasms: the semi-centennial of the 1976 French-American-British classification.
    Shyam A Patel, John M Bennett.
      The year 2026 marks the semi-centennial of the first iteration of the classification schema for myeloid neoplasms, namely the 1976 French-American-British (FAB) classification created by John M. Bennett and colleagues. The FAB classification of acute leukemia formed the biological framework of our current understanding of myeloid neoplasia. Reflecting from this historical lens, we have seen remarkable advances in diagnostics, prognostication, and therapeutics over the decades. Concerted efforts from various consensus groups have paved the way for these advances. Herein, we perform a historical analysis of the evolution of the nosology of myeloid neoplasms over the past 50 years, beginning with the landmark 1976 FAB classification. We discuss how the new nosology of myeloid neoplasms has been inspired by the widespread availability of next-generation sequencing technology as a critical adjunct to classical morphological assessment. We discuss evidence in support of a conceptual framework for categorizing myeloid neoplasms based on ontogeny, beginning from clonal hematopoiesis of indeterminate potential (CHIP). We review the foundational definitions of CHIP, including parallels with Darwinism at the cellular level, and the relevance of incorporation of precursor conditions into the most recent disease classification of myeloid neoplasms. We shed light onto patient-focused practical implications of classification schema, with emphasis on mutation-adapted therapeutic strategies. Finally, we discuss how emerging techniques such as single-cell sequencing and multi-omics may integrate into future revisions.
    DOI:  https://doi.org/10.1038/s41375-025-02746-9
  27. Int J Mol Sci. 2025 Aug 19. pii: 8021. [Epub ahead of print]26(16):
    Clonal Hematopoiesis and Outcomes After High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with AML, Myeloma, and Lymphoma.
    Corinne Natalie Schmid, Katharina Sponagel, Ulrike Bacher, Katja Seipel, Naomi Porret, Gertrud Wiedemann, Michèle Hoffmann, Michael Daskalakis, Thomas Pabst.
      Autologous stem cell transplantation (ASCT) after high-dose chemo-therapy (HDCT) is an option of consolidation therapy in patients with AML, lymphoma, or myeloma. Clonal hematopoiesis (CH) is a premalignant state, associated with an increased risk of hematological cancer. The incidence of CH in patients with AML, myeloma, and lymphoma and its effect on the outcome after HDCT/ASCT remain poorly studied. Here we screened 142 patients treated with HDCT/ASCT between 2002 and 2021 at Bern University Hospital for somatic gene mutations in ASXL1, DNMT3A, JAK2, TET2, and TP53. CH-associated somatic gene mutations were detected in 14/31 AML patients (45%), 13/64 myeloma patients (20%), and 9/47 lymphoma patients (19%). Clinical characteristics, treatment modalities, and responses to treatment were similar in patients with and without CH. Patients with CH-associated gene mutations had higher relapse rates and reduced progression free survival, most evident in lymphoma patients (p = 0.007). Overall survival tended to be shorter in lymphoma patients with CH-associated mutations (p = 0.078), whereas this was not observed in AML and myeloma patients. Survival in lymphoma patients with CH was inferior, which may have an impact on post-transplant surveillance strategies in the future. In contrast, survival outcomes were not associated significantly with CH in AML and myeloma patients in our study. Longer follow-ups and larger cohorts will be needed to validate our observations.
    Keywords:  acute myeloid leukemia (AML); autologous stem cell transplantation (ASCT); clonal hematopoiesis (CH); high-dose chemotherapy (HDCT); lymphoma; myeloma
    DOI:  https://doi.org/10.3390/ijms26168021
  28. J Natl Cancer Inst. 2025 Aug 20. pii: djaf234. [Epub ahead of print]
    Real-world generalizability of clinical trial cytomolecular risk in pediatric acute myeloid leukemia: a report from the REAL-AML cohort.
    Daniel J Zheng, Gary Hettinger, Catherine Aftandilian, Kira Bona, Emi H Caywood, Anderson B Collier, Caitlin W Elgarten, Cody Gathers, Taumoha Ghosh, M Monica Gramatges, Meret Henry, Yuan-Shung V Huang, Yimei Li, Craig Lotterman, Kelly Maloney, Amir Mian, Tamara P Miller, Arunkumar Modi, Rajen Mody, Elaine Morgan, Regina Myers, Haley Newman, Jose Ortiz, Alix E Seif, Caroline Smith, Jamie Stokke, Xin Wang, Naomi Winick, Jennifer J Wilkes, Victor Wong, Richard Aplenc, Kelly D Getz.
      Cytomolecular features critical for risk-stratified treatment determination in pediatric acute myeloid leukemia (AML) were expanded in Children's Oncology Group (COG) Phase III trial AAML1831 based on previous trials. It remains unknown whether the cytomolecular risk profiles are generalizable to the real-world. We addressed this knowledge gap using a nationally representative real-world cohort of 913 pediatric AML patients. Distributions of cytomolecular risk profiles and individual markers were comparable for trial-enrolled and non-enrolled patients, as well as across social drivers of trial enrollment (race/ethnicity, language, insurance, acuity). Compared to patients with only favorable cytomolecular markers (4-year OS 89.48%; 95% CI: 84.46%-92.95%), patients with both favorable and unfavorable (hazards ratio [HR] = 2.49, 95% CI : 1.18-5.23), neutral (HR = 4.33, 95% CI : 2.75-6.82), and only unfavorable (HR = 5.80, 95% CI: 3.70-9.11) markers all had increased hazards of death. Cytomolecular risk informed by trial data appears to be generalizable to the real-world setting in pediatric AML.
    DOI:  https://doi.org/10.1093/jnci/djaf234
  29. Leukemia. 2025 Aug 21.
    Targeting p16INK4a-mediated cellular senescence as a therapeutic strategy for FLT3-ITD-driven acute myeloid leukemia.
    Jiarui Zheng, Linlin Jin, Yunlong Chen, Yongjuan Duan, Suyu Zong, Peng Wu, Xiaofan Zhu, Wenyu Yang, Tianyuan Hu, Yingchi Zhang.
      Cellular senescence serves as a critical tumor-suppressive mechanism across various cancer types, yet its role in FLT3-ITD-positive acute myeloid leukemia (AML) remains poorly understood. Through the analysis of multiple sequencing datasets, we identified that FLT3-ITD-positive patients with low p16INK4a expression have significantly worse prognoses. Consistent with these clinical findings, knockout of p16INK4a in mice was shown to accelerate FLT3-ITD AML onset. Mechanistic investigations further revealed that the FLT3-ITD mutation suppresses p16INK4a expression via the STAT5A-E2F3-EZH2 signaling axis. This downregulation of p16INK4a allows cells to evade senescence, thereby promoting increased malignancy and establishing a positive feedback loop that exacerbates disease progression. This mechanism provides a molecular explanation for the poorer long-term survival observed in this patient subset. Furthermore, the FLT3-ITD-STAT5A/E2F3/EZH2-p16INK4a axis identified in this study represents a promising therapeutic target for addressing refractory FLT3-ITD AML with low p16INK4a expression.
    DOI:  https://doi.org/10.1038/s41375-025-02743-y
  30. Nature. 2025 Aug 27.
    Haematopoietic stem cell number is not solely defined by niche availability.
    Shoichiro Takeishi, Tony Marchand, Wade R Koba, Daniel K Borger, Chunliang Xu, Chandan Guha, Aviv Bergman, Paul S Frenette, Kira Gritsman, Ulrich Steidl.
      Haematopoietic stem cells (HSCs) reside in specialized microenvironments, referred to as niches, and the classical model suggests that HSC numbers are predominantly determined by the niche size1-5. However, the vast excess of niche cells relative to HSCs challenges this perspective. To rigorously define the role of niche size in regulating HSC numbers, we developed a femur-transplantation system, enabling us to increase available HSC niches. Notably, the addition of niches did not alter the total HSC numbers in the body, suggesting the presence of a systemic mechanism that limits HSC numbers. Additionally, HSC numbers in transplanted wild-type femurs did not exceed physiological levels when HSCs were mobilized from defective endogenous niches to the periphery, indicating that HSC numbers are constrained at the local level as well. The notion of dual restrictions at systemic and local levels was further supported by other experimental approaches, including parabiosis and non-conditioned transfer of HSCs after bone transplantation. Moreover, we found that thrombopoietin has a pivotal role in determining the total number of HSCs in the body, even in the context of increased niche availability. Our study redefines key principles underlying HSC number regulation, providing insights into this critical biological process.
    DOI:  https://doi.org/10.1038/s41586-025-09462-5
  31. Commun Biol. 2025 Aug 27. 8(1): 1289
    A stem cell differentiation model reveals two alternative fates in CBFA2T3::GLIS2-driven acute megakaryoblastic leukemia initiation.
    Mohamed R Shoeb, Dagmar Schinnerl, Lisa E Shaw, Matthias Farlik, Sabine Strehl, Florian Halbritter, Klaus Fortschegger.
      The CBFA2T3::GLIS2 (CG) fusion protein causes aggressive pediatric acute megakaryoblastic leukemia (AMKL). Although dysregulated molecular pathways in AMKL have been identified, their role in early pre-leukemic transformation remains poorly understood. We developed a disease model utilizing genetically modified human induced pluripotent stem cells (hiPSC) physiologically and conditionally expressing CG. Using in vitro differentiation and single-cell multi-omics, we captured the impact of oncogene activity on gene-regulatory networks during hematopoiesis. We discovered that CG interferes with myelopoiesis through two alternative routes: by locking aberrant megakaryocyte progenitors (aMKP) in a proliferative state, or by impeding differentiation of aberrant megakaryocytes (aMK). Transcriptionally and functionally, aMKPs mimic CG-AMKL cells and establish a self-renewal network with co-factors GATA2, ERG, and DLX3. In contrast, aMKs partially sustain regulators of MK maturation but fail to complete differentiation due to repression of factors like NFE2, SPI1, GATA1 and LYL1. These insights may inform new strategies for targeting AMKL cell states.
    DOI:  https://doi.org/10.1038/s42003-025-08730-4
  32. Science. 2025 Aug 21. eadr8785
    Mapping early human blood cell differentiation using single-cell proteomics and transcriptomics.
    Benjamin Furtwängler, Nil Üresin, Sabrina Richter, Mikkel Bruhn Schuster, Despoina Barmpouri, Henrietta Holze, Anne Wenzel, Kirsten Grønbæk, Kim Theilgaard-Mönch, Fabian J Theis, Erwin M Schoof, Bo T Porse.
      Single-cell transcriptomics (scRNA-seq) has facilitated the characterization of cell state heterogeneity and recapitulation of differentiation trajectories. However, the exclusive use of mRNA measurements comes at the risk of missing important biological information. Here we leveraged recent technological advances in single-cell proteomics by Mass Spectrometry (scp-MS) to generate an scp-MS dataset of an in vivo differentiation hierarchy encompassing over 2500 human CD34+ hematopoietic stem and progenitor cells. Through integration with scRNA-seq, we identified proteins that are important for stem cell function, which were not indicated by their mRNA transcripts. Further, we showed that modeling translation dynamics can infer cell progression during differentiation and explain substantially more protein variation from mRNA than linear correlation. Our work offers a framework for single-cell multi-omics studies across biological systems.
    DOI:  https://doi.org/10.1126/science.adr8785
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