bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–09–07
forty-five papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis.
  2. Outcomes and Patterns of Relapse of NPM1 Mutated Acute Myeloid Leukemia Treated With Venetoclax Based Therapies.
  3. TP53 mutations drive therapy resistance via post-mitochondrial caspase blockade.
  4. Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia.
  5. Measurable residual disease-guided therapy in acute myeloid leukaemia: Practical insights.
  6. C-C motif chemokine receptor-like 2 promotes the interferon-γ signaling response in myeloid neoplasms with erythroid differentiation and mutated TP53.
  7. Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML.
  8. Impact of discordant revised versus molecular international prognostic scoring system risk in myelodysplastic syndrome.
  9. MDS-associated SF3B1 mutations promote aberrant fate choice of hematopoietic stem cell via mis-splicing of mediator kinase module component CDK8.
  10. Outcomes of patients treated with venetoclax plus azacitidine versus azacitidine alone stratified by advanced age and acute myeloid leukemia composite model.
  11. Loss of SETD8 Impairs Mitochondrial Homeostasis to Suppress Leukemia Stem Cell Function in t(8;21) Acute Myeloid Leukemia.
  12. Genetic risk classification in acute myeloid leukemia patients treated with hematopoietic cell transplantation and post-transplant cyclophosphamide.
  13. Cytomolecular Mechanisms of Relapse and Post-Relapse Outcomes After Frontline FLT3 Inhibitor-Based Therapy in FLT3-Mutated AML.
  14. Resolving leukemic stem cell heterogeneity and plasticity with single-cell multiomics.
  15. Monitoring of measurable residual disease by next-generation sequencing in patients with acute myeloid leukaemia.
  16. Computational measurable residual disease assessment in acute myeloid leukemia: a retrospective validation in the HOVON-SAKK-132 trial.
  17. A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML.
  18. Sequential occurrence of BCR::ABL1-negative MPN and CML and vice versa: results from a real world cohort.
  19. Triple A Plus (AAA+) Survival Prediction Model for Essential Thrombocythemia: Analysis Involving 7308 Patients.
  20. Reporting blast percentage for response assessment in acute leukemias: recommendations from an EHA/ELN expert panel.
  21. Conditioning intensity in myelodysplastic patients aged ≥ 50 years undergoing allogeneic hematopoietic cell transplantation (allo-HCT): a study on behalf of the chronic malignancies working party of the EBMT.
  22. Combination Strategies with Menin Inhibitors for Acute Leukemia.
  23. Impact of Donor Type on Outcomes After Allogeneic Hematopoietic Cell Transplantation in Myelofibrosis: A Study on Behalf of the Chronic Malignancies Working Party of the EBMT.
  24. SLC25A1 reprograms mitochondrial and fatty acid metabolism to promote the progression of acute myeloid leukemia.
  25. Impact of ASXL1 at diagnosis in patients with CML receiving frontline potent TKIs: high risk of kinase domain mutations.
  26. Treatment-relevant misdiagnosis of autoimmune myelofibrosis.
  27. Long-term benefits of autologous stem cell transplantation versus intensive chemotherapy consolidation for acute myeloid leukemia patients: A propensity score matching analysis from the PETHEMA AML registry.
  28. The impact of donor and recipient age on post-transplantation clonality in murine haematopoiesis.
  29. Innate lymphoid cells prevent graft-versus-host disease via IL-9-driven T-cell senescence.
  30. Identifying Drug Combination Strategies for ZMYM2: FGFR1 Fusion Positive Leukemia.
  31. Id1 promotes clonal hematopoiesis in mice with Tet2 loss of function.
  32. CHIP ahoy: charting a decade of discovery in clonal hematopoiesis.
  33. The deacetylases HDAC1/HDAC2 control JAK2V617F-STAT signaling through the ubiquitin ligase SIAH2.
  34. Nanobioreactor detection of space-associated hematopoietic stem and progenitor cell aging.
  35. Hypomethylating agents increase L1 retroelement expression without inducing novel insertions in myeloid malignancies.
  36. UBA1-depleted neutrophils disrupt immune homeostasis and induce VEXAS-like autoinflammatory disease in mice.
  37. A single-cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis.
  38. Transcript isoform diversity defines molecular subtypes and prognosis in acute myeloid leukemia through long-read sequencing.
  39. What's hidden in plain sight? Impact of clonal hematopoiesis on the risk and progression of non-hematologic cancers.
  40. Distinct roles for NF-κB in hematopoietic stem cells and the bone marrow milieu in promoting hematopoietic aging.
  41. B12 promotes gut dysbiosis and an inflammatory microenvironment that potentiates Tet2 -deficient hematopoiesis.
  42. Clinical and molecular characterization of patients with juvenile myelomonocytic leukaemia.
  43. Off-the-shelf dual CAR-iNKT cell immunotherapy eradicates medullary and leptomeningeal high-risk KMT2A-rearranged leukemia.
  44. Analysis of chromatin accessibility associated with azacitidine response in higher-risk myelodysplastic neoplasms.
  45. Management of Chronic Myeloid Leukemia During Pregnancy: Review of Evidence and Treatment Algorithm.
  1. Nat Genet. 2025 Aug 28.
    Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis.
    Matthew A McLoughlin, Sruthi Cheloor Kovilakam, William G Dunn, Muxin Gu, Jake Tobin, Yash Pershad, Nicholas Williams, Daniel Leongamornlert, Kevin Dawson, Laura Bond, Ludovica Marando, Sean Wen, Rachael Wilson, Giampiero Valenzano, Vasiliki Symeonidou, Justyna Rak, Aristi Damaskou, Malgorzata Gozdecka, Xiaoxuan Liu, Clea Barcena, Josep Nomdedeu, Paul Costeas, Ioannis D Dimitriou, Edoardo Fiorillo, Valeria Orrù, Jose Guilherme de Almeida, Thomas McKerrell, Matthew Cullen, Irina Mohorianu, Theodora Foukaneli, Alan J Warren, Chi Wong, George Follows, Anna L Godfrey, Emma Gudgin, Francesco Cucca, Eoin McKinney, E Joanna Baxter, Moritz Gerstung, Jonathan Mitchell, Daniel Wiseman, Alexander G Bick, Margarete Fabre, Pedro M Quiros, Jyoti Nangalia, Siddhartha Kar, George S Vassiliou.
      The mechanisms through which mutations in splicing factor genes drive clonal hematopoiesis (CH) and myeloid malignancies, and their close association with advanced age, remain poorly understood. Here we show that telomere maintenance plays an important role in this phenomenon. First, by studying 454,098 UK Biobank participants, we find that, unlike most CH subtypes, splicing-factor-mutant CH is more common in those with shorter genetically predicted telomeres, as is CH with mutations in PPM1D and the TERT gene promoter. We go on to show that telomere attrition becomes an instrument for clonal selection in advanced age, with splicing factor mutations 'rescuing' HSCs from critical telomere shortening. Our findings expose the lifelong influence of telomere maintenance on hematopoiesis and identify a potential shared mechanism through which different splicing factor mutations drive leukemogenesis. Understanding the mechanistic basis of these observations can open new therapeutic avenues against splicing-factor-mutant CH and hematological or other cancers.
    DOI:  https://doi.org/10.1038/s41588-025-02296-x
  2. Am J Hematol. 2025 Aug 28.
    Outcomes and Patterns of Relapse of NPM1 Mutated Acute Myeloid Leukemia Treated With Venetoclax Based Therapies.
    Wei-Ying Jen, Sanam Loghavi, Alexandre Bazinet, Alex Bataller, Ian Bouligny, Naval G Daver, Ghayas C Issa, Naszrin Arani, Emmanuel Almanza Huante, Abhishek Maiti, Guillermo Montalban-Bravo, Gautam Borthakur, Nicholas J Short, Sherry Pierce, Elias Jabbour, Guillermo Garcia-Manero, Farhad Ravandi, Hagop M Kantarjian, Courtney D DiNardo, Tapan M Kadia.
      
    Keywords:  AML; CLAD LDAC VEN; CLIA VEN; FLAG IDA VEN; hypomethylating agents; intensity; intensive chemotherapy; low intensity therapy
    DOI:  https://doi.org/10.1002/ajh.70046
  3. bioRxiv. 2025 Aug 31. pii: 2025.08.28.672283. [Epub ahead of print]
    TP53 mutations drive therapy resistance via post-mitochondrial caspase blockade.
    Ahmed M Mamdouh, Elyse A Olesinski, Fang Qi Lim, Shaista Jasdanwala, Yang Mi, Nicole Si En Lin, Daniel Tan En Liang, Nishtha Chitkara, Leah Hogdal, R Coleman Lindsley, Anthony Letai, Koji Itahana, Shruti Bhatt.
      Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a broad spectrum of molecular alterations that influence clinical outcomes. TP53 mutations define one of the most lethal subtypes of acute myeloid leukemia (AML), driving resistance to nearly all available treatment modalities, including venetoclax plus azacitidine (VenAza). Yet, the molecular basis of this resistance, beyond affecting transactivation of BCL-2 family genes, has remained elusive. Here, we demonstrate that VenAza treatment leads to reduced transcriptional upregulation of the p53 signaling pathway in TP53 mutant/deficient AML compared to wild-type AML. Functionally, TP53 mutant/deficient AML exhibits selective failure in apoptosis induction rather than impaired G1 arrest or senescence. Despite inhibition of pro-apoptotic BAX and selective enrichment for MCL-1 in TP53 mutant isogenic AML cells, compensatory upregulation of BIM preserved functional mitochondrial outer membrane permeabilization (MOMP). TP53 mutant primary AML tumors at baseline also had retained capacity for MOMP. Instead, TP53 mutant AML exhibited disruption in caspase-3/7 activation to evade apoptosis after VenAza therapy, decoupling the mitochondrial and executioner phases of apoptosis. Importantly, this (post-MOMP brake) is not a bystander effect but itself a driver of VenAza and chemotherapy resistance in TP53 mutant/deficient AML. This previously unrecognized mechanistic insight shifts the focus from mitochondrial priming to terminal caspase blockade in TP53 mutant AML and opens the door for urgently needed therapeutic strategies that reignite apoptosis at its execution point.
    DOI:  https://doi.org/10.1101/2025.08.28.672283
  4. Nat Rev Clin Oncol. 2025 Sep 01.
    Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia.
    Antonino Glaviano, Ellen Weisberg, Hiu Y Lam, Donavan J J Tan, Andrew J Innes, Yubin Ge, Catherine E Lai, Wendy Stock, Christina Glytsou, Linda Smit, Tatsushi Yoshida, Tian Y Zhang, Vanessa E Kennedy, B Douglas Smith, Thomas Mercher, Stéphane de Botton, Patrizia Diana, Marina Konopleva, Michael J Mauro, James D Griffin, Courtney D DiNardo, Alan P Kumar.
      Acute myeloid leukaemia (AML) remains a challenging haematological malignancy, with most patients developing resistance to standard-of-care (SOC) treatments. This resistance is often attributed to the overexpression of anti-apoptotic BCL-2 family proteins, which regulate the intrinsic apoptotic pathway by inhibiting pro-apoptotic effector proteins such as BAX and BAK. AML cells exploit this imbalance to evade apoptosis and sustain survival, necessitating the development of novel therapeutic strategies. BH3 mimetics are small-molecule inhibitors targeting the pro-survival BCL-2 family proteins and have emerged as promising agents in patients with AML who are unable to receive high-intensity induction chemotherapy. Co-treatment with the BCL-2-specific inhibitor venetoclax and various SOC therapies has been proven effective, with several combinations now approved by the US Food and Drug Administration for adults with AML who are ≥75 years of age and/or are ineligible for intensive induction chemotherapy, on the basis of improved response rates and survival outcomes compared with the previous SOC. In this Review, we highlight the transformative potential of BH3 mimetics in AML therapy, including ongoing studies investigating novel combination regimens and efforts to further refine treatment strategies, with the ultimate goal of improving outcomes for patients with AML.
    DOI:  https://doi.org/10.1038/s41571-025-01068-0
  5. Br J Haematol. 2025 Aug 31.
    Measurable residual disease-guided therapy in acute myeloid leukaemia: Practical insights.
    Boaz Nachmias, Arnon Haran, Meira Yisraeli Salman, Eytan M Stein.
      Measurable residual disease (MRD) is a prognostic marker in patients with acute myeloid leukaemia (AML). This review examines the role of MRD assessment in guiding treatment strategies. We evaluate key questions, such as the prognostic power of MRD in specific genetic subgroups of AML, the optimal pre-emptive approach for MRD persistence or recurrence, the effect of MRD on allogeneic stem cell transplantation decisions and MRD-guided maintenance considerations. The absence of randomized trials comparing MRD-guided treatment strategies precludes definitive statements. However, by critically evaluating recent studies and emerging trends, we highlight the evolving role of MRD as a decision-making tool in AML, identify key gaps in evidence and suggest directions for future research to optimize personalized treatment approaches.
    Keywords:  AML; MRD‐guided therapy; measurable residual disease
    DOI:  https://doi.org/10.1111/bjh.70038
  6. Haematologica. 2025 Aug 28.
    C-C motif chemokine receptor-like 2 promotes the interferon-γ signaling response in myeloid neoplasms with erythroid differentiation and mutated TP53.
    Nour Sabiha Naji, Sergiu Pasca, Theodora Chatzilygeroudi, Pablo Toledano-Sanz, Joseph Rimando, Yuju An, Yashvi Hemani, Brandy Perkins, Xinghan Zeng, Conover Talbot, Bogdan Paun, Abdulmuez Abdulmalik, Chen Lossos, Tatianna R Boronina, Ilias Sinanidis, Panagiotis Tsakiroglou, Priyanka Fernandes, Christopher Esteb, Alexander J Ambinder, Robert N Cole, Rena Xian, Ivana Gojo, Suman Paul, Mark J Levis, Amy E DeZern, Leo Luznik, Styliani Karanika, Linda S Resar, Richard J Jones, Frederick Bunz, Lukasz Gondek, Marios Arvanitis, Theodoros Karantanos.
      Patients with myeloid neoplasms with loss-of-function TP53 mutations and erythroid differentiation have poor outcomes, and a better understanding of disease biology is required. Upregulation of interferon-γ (IFN-γ) signaling has been associated with acute myeloid leukemia (AML) progression, selection of TP53 mutated clones and chemotherapy resistance, but its drivers remain unclear. In this study, we found that the surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in AML with erythroid differentiation and TP53 mutations compared to other AML subtypes and healthy hematopoietic cells. CCRL2 knockout (KO) suppressed erythroleukemia growth in vitro and in vivo. Further proteomics and transcriptomics analysis revealed IFN-γ signaling response as the top CCRL2-regulated pathway in erythroleukemia. Our mechanistic studies support direct CCRL2-driven IFN-γ signaling upregulation without a clear effect of exogenous IFN-γ, through phosphorylation of STAT1, which is partially mediated by JAK2. CCRL2/IFN-γ signaling is upregulated in erythroid leukemias, and TP53 mutated AML and appears to be directly induced by TP53 KO. Finally, CCRL2/IFN-γ signaling is associated with the transformation of pre-leukemic single-hit TP53 clones to multi-hit TP53 mutated AML, increased resistance to venetoclax and worse survival in AML. Overall, our findings support that CCRL2 is an essential driver of cell-autonomous IFN-γ signaling response in myeloid neoplasms with erythroid differentiation and TP53 mutations and highlight CCRL2 as a relevant novel target for these neoplasms.
    DOI:  https://doi.org/10.3324/haematol.2025.287740
  7. EMBO Mol Med. 2025 Aug 29.
    Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML.
    Lise Brault, Edwige Voisset, Mathieu Desaunay, Antonia Boudet, Paraskevi Kousteridou, Sébastien Letard, Nadine Carbuccia, Armelle Goubard, Rémy Castellano, Yves Collette, Julien Vernerey, Isabelle Vigon, Jean-Max Pasquet, Patrice Dubreuil, Sophie Lopez, Paulo De Sepulveda.
      The heterogeneity of leukemic cells is the main cause of resistance to therapy in acute myeloid leukemia (AML). Consequently, innovative therapeutic approaches are critical to target a wide spectrum of leukemic clones, regardless of their genetic and non-genetic complexity. In this report, we leverage the vulnerability of AML cells to CDK6 to identify a combination therapy capable of targeting common biological processes shared by all leukemic cells, while sparing non-transformed cells. We demonstrate that the combined inhibition of CDK6 and LSD1 restores myeloid differentiation and depletes the leukemic progenitor compartment in AML samples. Mechanistically, this combination induces major changes in chromatin accessibility, leading to the transcription of differentiation genes and diminished LSC signatures. Remarkably, the combination is synergistic, induces durable changes in the cells, and is effective in PDX mouse models. While many AML samples exhibit only modest responses to LSD1 inhibition, co-targeting CDK6 restores the expected transcription response associated with LSD1 inhibition. Given the availability of clinical-grade CDK6 and LSD1 inhibitors, this combination holds significant potential for implementation in clinical settings through drug repositioning.
    Keywords:  Iadademstat; Inhibitor; Kinase; Leukemia; Palbociclib
    DOI:  https://doi.org/10.1038/s44321-025-00296-2
  8. Leukemia. 2025 Sep 05.
    Impact of discordant revised versus molecular international prognostic scoring system risk in myelodysplastic syndrome.
    Alexandre Bazinet, Guillermo Montalban-Bravo, Alex Bataller, Danielle Hammond, Sanam Loghavi, Kelly Chien, Koji Sasaki, Ian Bouligny, Mahesh Swaminathan, Wei Ying Jen, Uday Popat, Tapan Kadia, Courtney DiNardo, Elias Jabbour, Nicholas Short, Naval Daver, Farhad Ravandi, Guillermo Garcia-Manero.
      
    DOI:  https://doi.org/10.1038/s41375-025-02760-x
  9. bioRxiv. 2025 Aug 19. pii: 2025.08.14.670174. [Epub ahead of print]
    MDS-associated SF3B1 mutations promote aberrant fate choice of hematopoietic stem cell via mis-splicing of mediator kinase module component CDK8.
    Elizabeth A Bonner, Tun-Yun Hsueh, Axia Song, Erica A Arriaga-Gomez, Rasika Venkataraman, Sayantani Sinha, Evan Nguyen, P Brent Ferrell, Robert S Welner, Rui Lu, Derek L Stirewalt, Sergei Doulatov, Stanley C Lee.
      Mutations in the RNA splicing factor SF3B1 are among the most common in MDS and are strongly associated with MDS with ring sideroblasts (MDS-RS). While aberrant splicing of terminal erythroid regulators has been implicated in MDS pathogenesis, the impact of SF3B1 mutations on early hematopoietic progenitor function remains unclear. Here, we identify CDK8, a key kinase of the mediator complex involved in transcriptional regulation, as a recurrent mis-spliced target in SF3B1 -mutant MDS. Mutant SF3B1 induces cryptic 3' splice site selection in CDK8, leading to loss of CDK8 mRNA and protein. Using primary human HSPCs, our study identifies CDK8 as an important regulator of HSPC homeostasis and cell fate determination. CDK8 depletion results in expanded primitive HSPCs and shifts differentiation toward the and erythroid lineages, mirroring phenotypes observed in SF3B1 -mutant MDS, and functional rescue of CDK8 rescues early erythroid phenotypes in SF3B1 -mutant cells. These findings implicate CDK8 mis-splicing as a mechanistic driver of altered progenitor fate and dysplasia in SF3B1-mutant MDS, linking aberrant splicing to transcriptional dysregulation and hematopoietic lineage commitment.
    DOI:  https://doi.org/10.1101/2025.08.14.670174
  10. Leukemia. 2025 Sep 05.
    Outcomes of patients treated with venetoclax plus azacitidine versus azacitidine alone stratified by advanced age and acute myeloid leukemia composite model.
    Adriano Venditti, Jing-Zhou Hou, Pierre Fenaux, Brian A Jonas, Radovan Vrhovac, Pau Montesinos, Jacqueline S Garcia, David Rizzieri, Michael J Thirman, Meng Zhang, Jalaja Potluri, Catherine Miller, Mazaher Dhalla, Vinod Pullarkat.
      Venetoclax plus azacitidine is recognized as standard of care for patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC). However, some patients may still not be treated with venetoclax combinations due to frailty concerns. We evaluated efficacy and safety of venetoclax plus azacitidine vs. placebo plus azacitidine in patients with newly diagnosed AML ineligible for IC from the phase 3 VIALE-A study (NCT02993523) and the phase 1b M14-358 study (NCT02203773), stratified by two methods to potentially assess frailty. The first method was age-based (75-79, 80-84, ≥85 years; n = 303 pooled from both studies) and the second was fitness-based using the AML composite model (AML-CM), a comorbidity-based model to estimate mortality risk (Group A, B, C; n = 380, from VIALE-A). Efficacy, including composite complete remission and overall survival, were improved with venetoclax plus azacitidine vs. placebo plus azacitidine across age and AML-CM groups. Safety was generally similar between age and AML-CM groups and no new safety signals were identified. Taken together, these data suggest that patients benefit from venetoclax plus azacitidine regardless of age or degree of frailty and the combination may be considered for patients with AML who may be deemed frail. Clinical trial information NCT02993523; NCT02203773.
    DOI:  https://doi.org/10.1038/s41375-025-02730-3
  11. Cancer Res. 2025 Aug 29.
    Loss of SETD8 Impairs Mitochondrial Homeostasis to Suppress Leukemia Stem Cell Function in t(8;21) Acute Myeloid Leukemia.
    Yongwei Su, Shuyi Li, Lei Wang, Yiran Wang, Shujiao He, Xiaotong Li, Jingqiao Qiao, Jingfeng Zhou, Li Yu.
      Leukemic stem cells (LSCs) contribute to relapse and resistance in patients with t(8;21) acute myeloid leukemia (AML). Chromatin accessibility remodeled by epigenetic alterations represents a defining hallmark of LSCs that endows them with enhanced survival and self-renewal capacities, which may offer potential therapeutic opportunities for intervention. Here, we showed that SETD8, a lysine methyltransferase that monomethylates lysine 20 of histone H4 (H4K20me1), is essential for the maintenance of stemness in t(8;21) AML LSCs. Genetic deletion or pharmacological inhibition of SETD8 impaired the survival and self-renewal of LSCs in retroviral AML1-ETO9a-driven t(8;21) AML mice and primary t(8;21) AML CD34+ cells. Mechanistically, SETD8 promoted the expression of the mitochondrial outer membrane protein RHOT1 by increasing chromatin accessibility at the enhancer region, thereby reprogramming mitochondrial homeostasis. These findings improve our understanding of gene regulation through chromatin accessibility remodeling and establish a link between histone lysine methylation and mitochondrial homeostasis, suggesting a potential strategy for eliminating LSCs in t(8;21) AML.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3659
  12. Haematologica. 2025 Sep 04.
    Genetic risk classification in acute myeloid leukemia patients treated with hematopoietic cell transplantation and post-transplant cyclophosphamide.
    Marta Villalba, Juan Montoro, Aitana Balaguer-Roselló, Pedro Chorão, Pedro Asensi Cantó, Pablo Granados, Inés Gómez-Seguí, Pilar Solves, Esperanza Such, José Cervera, Eva Barrragán, Marta Santiago, José V Gil-Ortí, Brais Lamas, Ana Bataller, Alberto Louro, Javier De la Rubia, Miguel Á Sanz, Jaime Sanz.
      We analyzed outcomes of 217 AML patients in complete remission who underwent allogeneic HCT with myeloablative conditioning and post-transplant cyclophosphamide-based GVHD prophylaxis, aiming to assess the prognostic significance of genetic risk categories. In the overall cohort, the 2-year overall survival (OS) and event-free survival (EFS) were 77% (95% CI, 71-83) and 72% (95% CI, 66- 78), respectively. ELN2022 risk stratification lacked prognostic value in HCT. Instead, we identified four risk categories with distinct impact on OS: standard risk (ELN2022 favorable/intermediate and adverse-risk without high-risk genetic under the defined subcategories), intermediate risk (≥2 myelodysplasia-related gene mutations) (HR 2.23, 95% CI 1.14-4.92), adverse risk (complex karyotype, monosomal karyotype, inv(3)/t(3;3), KMT2A rearrangement) (hazard ratio (HR) 4.24, 95% CI 2.00 - 9.02), and very adverse risk (TP53 mutations) (HR 6.81, 95% CI 3.00 - 15.5). These categories demonstrated similar predictive power for EFS and cumulative incidence of relapse. Moreover, integrating pre-transplant MRD refined risk stratification, identified MRDnegative patients with ≥2 myelodysplasia-related gene mutations whose OS and EFS were comparable to standard-risk patients. This refined classification improves the prognostic value of ELN2022 for AML patients undergoing allogeneic HCT with modern platform by integrating genetic features and MRD status to better guide post-transplant management.
    DOI:  https://doi.org/10.3324/haematol.2025.287860
  13. Am J Hematol. 2025 Sep 02.
    Cytomolecular Mechanisms of Relapse and Post-Relapse Outcomes After Frontline FLT3 Inhibitor-Based Therapy in FLT3-Mutated AML.
    Sankalp Arora, Sanam Loghavi, Naval Daver, Farhad Ravandi, Courtney D DiNardo, Tapan M Kadia, Gautam Borthakur, Elias Jabbour, Musa Yilmaz, Ghayas C Issa, Justin McCormack, Omer Karrar, Sherry Pierce, Hagop Kantarjian, Nicholas J Short.
      
    DOI:  https://doi.org/10.1002/ajh.70053
  14. Semin Hematol. 2025 Aug 05. pii: S0037-1963(25)00033-2. [Epub ahead of print]
    Resolving leukemic stem cell heterogeneity and plasticity with single-cell multiomics.
    Frank Y Huang, Andreas Trumpp, Patrick Stelmach.
      Acute myeloid leukemia (AML) is an aggressive blood cancer in which disease initiation and relapse are driven by leukemic cells with stem-like properties, known as leukemic stem cells (LSCs). The LSC compartment is highly heterogenous and this contributes to differences in therapy response. This heterogeneity is determined by genetic and nongenetic factors including somatic mutations, the cell of origin, transcriptional and epigenetic states as well as phenotypic plasticity. While this complicates the identification and eradication of LSCs, it also presents an opportunity to tailor therapeutic strategies to the phenotypic and functional states of LSCs present in a patient, exploiting their specific vulnerabilities. The emergence of single-cell multiomics technologies has transformed our ability to dissect cellular heterogeneity in AML, enabling simultaneous interrogation of genomic, transcriptomic, epigenomic and proteomic layers and providing high-resolution molecular snapshots of individual cells. In this review, we discuss causes and consequences of LSC heterogeneity, highlight advances in single-cell multiomics technologies to resolve it and outline how they can address shortcomings in our understanding of LSC heterogeneity and plasticity to revolutionize diagnostics and disease monitoring of AML.
    Keywords:  Acute myeloid leukemia (AML); Leukemic stem cells (LSCs); Plasticity; Therapy response and resistance; Venetoclax
    DOI:  https://doi.org/10.1053/j.seminhematol.2025.07.001
  15. Br J Haematol. 2025 Sep 03.
    Monitoring of measurable residual disease by next-generation sequencing in patients with acute myeloid leukaemia.
    Augustin Boudry, Laure Goursaud, Delphine Lebon, Florent Dumezy, Véronique Harrivel, Alexandre Boue-Raguet, Romane Joudinaud, Alice Marceau-Renaut, Sandrine Geffroy, Carine Hauspie, Jan Brijs, Laurène Fenwarth, Céline Berthon, Jean-Pierre Marolleau, Martin Figeac, Claude Preudhomme, Nicolas Duployez.
      Measurable residual disease (MRD) is a strong prognostic factor in acute myeloid leukaemia (AML). Next-generation sequencing (NGS) offers promise but must distinguish true signal from background. We assessed MRD in 98 adult AML patients in first complete remission after intensive chemotherapy using a duplex unique molecular identifier (UMI)-based NGS capture panel. Error reduction analysis showed up to a 20-fold decrease in artefactual calls versus conventional sequencing. Linearity studies with serial dilutions confirmed accurate quantification down to 0.01% variant allele frequency. In this cohort, NGS-MRD positivity did not significantly affect overall survival (OS) or relapse-free survival (RFS) after one course of chemotherapy. However, NGS-MRD positivity >0.1%, excluding DNMT3A, TET2, ASXL1, IDH1 and IDH2 mutations, was significantly associated with inferior outcomes after two courses (OS: hazard ratio [HR] = 3.04, p = 0.0173; RFS: HR = 2.83, p = 0.0097). Combining multiparameter flow cytometry (MFC-MRD) with NGS-MRD identified a double-positive subgroup with particularly poor outcomes after the first course (OS: HR = 7.98, p < 0.001; RFS: HR = 7.87, p < 0.001). These findings underscore that duplex UMI-based NGS is a sensitive, quantitative approach for MRD assessment in AML, offering prognostic information complementary to MFC-MRD.
    Keywords:  AML; MRD; NGS
    DOI:  https://doi.org/10.1111/bjh.70135
  16. Leukemia. 2025 Sep 03.
    Computational measurable residual disease assessment in acute myeloid leukemia: a retrospective validation in the HOVON-SAKK-132 trial.
    Tim R Mocking, Lukas H Haaksma, Tom Reuvekamp, Angèle Kelder, Willemijn J Scholten, Lok Lam Ngai, Dimitri A Breems, Thomas Fischer, Bjørn T Gjertsen, Laimonas Griškevičius, Gunnar Juliusson, Johan A Maertens, Markus G Manz, Thomas Pabst, Jakob R Passweg, Kimmo Porkka, Peter J M Valk, Patrycja Gradowska, Bob Löwenberg, David C de Leeuw, Jeroen J W M Janssen, Gert J Ossenkoppele, Arjan A van de Loosdrecht, Jacqueline Cloos, Costa Bachas.
      
    DOI:  https://doi.org/10.1038/s41375-025-02747-8
  17. bioRxiv. 2025 Aug 21. pii: 2025.08.17.670714. [Epub ahead of print]
    A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML.
    Nour Sabiha Naji, Taha Ahmedna, J David Peske, Xinghan Zeng, Brandy Perkins, Zanshe Thompson, Tushar D Nichakawade, Bum Seok Lee, Evangeline Watson, Theodora Chatzilygeroudi, Li Luo, Bogdan Paun, Melanie Klausner, Yuju An, Teodora Supeanu, Ivana Gojo, Gabriel Ghiaur, Amy E DeZern, Mark J Levis, Linda Resar, Richard J Jones, Styliani Karanika, Suman Paul, Theodoros Karantanos.
      Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with high-risk features including TP53 mutations and deletions have poor outcomes due to lack of effective therapies. The atypical chemokine surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in MDS and secondary AML (sAML) compared to healthy hematopoietic cells and we recently found that TP53 -mutated MDS/AML and AML with erythroid features express the highest levels of this receptor across MDS/AML subtypes. To illustrate the therapeutic potential of CCRL2 as a therapeutic target, we developed an anti-CCRL2 antibody-drug conjugate (ADC) by conjugating an anti-CCRL2 antibody with the cytotoxic drug pyrrolobenzodiazepine (PBD), which causes DNA double-strand breaks leading to cancer cell death. The anti-CCRL2 ADC demonstrated strong CCRL2-selective cytotoxicity against cell lines derived from MDS/AML patients with TP53 mutations and erythroid features, surpassing the cytotoxic effects observed with gemtuzumab and PBD-conjugated anti-CD33 and anti-CD123 ADCs. It also induced apoptosis and suppressed the clonogenicity of primary MDS/AML bone marrow samples without affecting the survival, differentiation and clonogenicity of healthy hematopoietic stem and progenitor cells. This agent also suppressed the leukemic growth of TP53- mutated MDS/AML cell line xenografts, improving mice survival and decreasing the leukemic burden in patient-derived TP53 -mutated MDS/AML xenografts. In conclusion, our study introduces CCRL2 as a potential new therapeutic target in high-risk MDS/AML.
    Statement of significance: Pyrrolobenzodiazepine(PBD)-conjugated anti-CCRL2 ADC shows anti-leukemic effect in MDS/AML models including TP53 -mutated disease without affecting healthy hematopoietic cells supporting that it is a promising candidate for single-agent or combination therapies in high-risk MDS/AML.
    DOI:  https://doi.org/10.1101/2025.08.17.670714
  18. Int J Hematol. 2025 Sep 04.
    Sequential occurrence of BCR::ABL1-negative MPN and CML and vice versa: results from a real world cohort.
    Katrin Schweneker, Miriam Lenk, Wolfgang Kern, Claudia Haferlach, Manja Meggendorfer, Christian Pohlkamp, Torsten Haferlach.
      Chronic myeloid leukemia (CML) and BCR::ABL1-negative MPN were thought to be mutually exclusive, but synchronous and sequential cases have been reported. We screened 35,001 patients for BCR::ABL1 fusion or JAK2, CALR, or MPL mutations to investigate the sequential development of CML and BCR::ABL1 negative-MPNs. We discovered that 5.6% had primary CML followed by BCR::ABL1-negative MPN, and 5.8% had the reverse sequence. Notably, we identified higher JAK2 variant allele frequencies (VAFs) in patients developing secondary CML. Previous MPN did not compromise the effectiveness of tyrosine kinase inhibitors (TKI) in treating secondary CML. The emergence of secondary MPN appeared to be unrelated to JAK2 VAF progression or BCR::ABL1 transcript levels. Our research indicates that newly detected leukocytosis or thrombocytosis should prompt consideration of secondary MPN. It also showed that secondary CML had no negative impact on response to therapy when patients were treated according to CML guidelines.
    Keywords:   BCR::ABL1 negative-MPN; JAK2 ; CML; Myeloid malignancies; Sequential myeloproliferative disorders
    DOI:  https://doi.org/10.1007/s12185-025-04046-5
  19. Am J Hematol. 2025 Sep 03.
    Triple A Plus (AAA+) Survival Prediction Model for Essential Thrombocythemia: Analysis Involving 7308 Patients.
    Ayalew Tefferi, Giuseppe G Loscocco, Lior Rokach, Tamar Tadmor, Priyansh Faldu, Guy Melamed, Hilel Alapi, Maymona Abdelmagid, Rania M Abdelaziz, Muhammad Yousuf, Merry Nakhleh, Animesh Pardanani, Kebede H Begna, Mirnal M Patnaik, Natasha Szuber, Alessandra Carobbio, Tiziano Barbui, Kaaren K Reichard, Rong He, Paola Guglielmelli, Naseema Gangat, Alessandro M Vannucchi.
      Survival prediction models in essential thrombocythemia (ET) include the International Prognostic Scoring System (IPSET) and the more recently introduced triple-A (AAA) prognostic score. The latter enlists age and absolute neutrophil (ANC) and lymphocyte (ALC) counts as risk variables. In the current study, a Mayo Clinic discovery cohort of 658 patients with ET was used to identify AAA-independent risk variables. Accordingly, multivariable analysis-derived HRs (95% CI) were 15.7 (8.4-29.5) for age > 70 years (8 points); 4.2 (2.3-7.5) for age 50 to 70 years (2 points); 1.8 (1.2-2.5) for ANC ≥ 8 × 109/L (1 point); 1.4 (1.03-1.9) for ALC < 1.7 × 109/L (1 point); 1.8 (1.2-2.6) for absolute monocyte count (AMC) ≥ 0.5 × 109/L (1 point); 1.8 (1.2-2.3) for male sex (1 point); 1.8 (1.3-2.4) for arterial hypertension (1 point); and 1.6 (1.2-2.3) for arterial thrombosis (1 point). HR-weighted scoring enabled a 4-tiered risk classification: ultra-low (0-1 points; N = 94; median survival 42.7 years), low (2-4 points; N = 297; 23 years), intermediate (5 points; N = 66; 17.3 years), and high (6-14 points; N = 201; 10.8 years). Time-dependent predictive performance at 20/25 years favored AAA+ (AUC 0.92/0.91) vs. AAA (0.86/0.86) vs. IPSET (0.81/0.84). The AAA+ risk model was subsequently validated by two external cohorts from Israel (N = 5968) and Italy (N = 682). In the cohort from Israel, disease-specific mortality was assessed by comparing observed survival to an age- and sex-matched reference population, which suggested near-normal life expectancy in ultra-low risk patients. The current study highlights host-related factors as the primary determinants of longevity in ET and provides a composite risk score (AAA+) that is based on complete blood count-derived parameters and host-related factors. Predictive performance of the new model was shown to be superior to that of IPSET and AAA.
    Keywords:  leukemia; life‐expectancy; myelofibrosis; myeloproliferative; polycythemia
    DOI:  https://doi.org/10.1002/ajh.70065
  20. Haematologica. 2025 Sep 04.
    Reporting blast percentage for response assessment in acute leukemias: recommendations from an EHA/ELN expert panel.
    Sa A Wang, Leonor Arenillas, Francesco Buccisano, Monika Bruggemann, Wolfgang Kern, Manuel Menes, Adriana Plesa, Louisa Stone, Dominique Wellnitz, David A Westerman, Brent L Wood, Sylvie D Freeman.
      Evaluation of bone marrow blast percentage is paramount to response criteria in acute leukemias. There is an identified need within the framework of updated laboratory practices to reduce inconsistencies in methodologies used by clinical laboratories to report blast values and clarify aspects of reporting. Representatives from international specialised working groups including the European Hematology Association (EHA) Diagnosis in Hematological Diseases Specialised Working Group and the European LeukemiaNet (ELN) produced consensus guidance for harmonised blast assessment to define response categories in acute leukemic patients. These address sampling best practice, key considerations for generating the most accurate blast enumeration and the limitations across the methodologies in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and acute leukemia of ambiguous lineage. An integrated reporting scheme for deriving blast percentage is provided for ALL and AML. This incorporates results from appropriate measurable residual disease assays with morphological crosscheck. The practical guide and approach presented herein should facilitate uniform reporting standards both within clinical trials and in broader clinical practice.
    DOI:  https://doi.org/10.3324/haematol.2025.288228
  21. Bone Marrow Transplant. 2025 Aug 29.
    Conditioning intensity in myelodysplastic patients aged ≥ 50 years undergoing allogeneic hematopoietic cell transplantation (allo-HCT): a study on behalf of the chronic malignancies working party of the EBMT.
    Noureddine Henoun Loukili, Luuk Gras, Linda Koster, Didier Blaise, Tobias Gedde-Dahl, Johan Maertens, Lone Smidstrup Friis, Stephan Mielke, Patrice Chevallier, Jakob R Passweg, Jennifer Louise Byrne, Urpu Salmenniemi, Patrice Ceballos, Jérôme Cornillon, Simona Sica, Francesco Onida, Christof Scheid, Carmelo Gurnari, Joanna Drozd-Sokolowska, Kavita Raj, Marie Robin, Donal P McLornan, Ibrahim Yakoub-Agha.
      Reduced intensity conditioning (RIC) is usually used for patients with myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (allo-HCT), particularly in the elderly or those with comorbidities. The impact of conditioning intensity on patients' outcome remains controversial with clinicians' subjective opinion/ experience remaining a major guide in choosing the intensity. Here, we compare RIC versus MAC in a large EBMT retrospective study in MDS patients aged ≥50 years undergoing allo-HCT between 2014 and 2018. Among the 1393 included patients, 922 (66%) were males, and the median age at transplant was 62.8 (50.0-77.9) years. The majority of patients (n = 884; 64.3%) had MDS with excess blasts. IPSS-R recorded was very low/low (n = 598, 43%), intermediate (n = 352, 25%), and high/very high (n = 443, 32%). Karnofsky index was ≥90 in 916 (69.3%) patients, and HCT-CI ≥ 3 in 292(27.3%) patients. A RIC regimen was used in 1053 (75.5%) patients. Median follow-up was 27.9 months (IQR: 26.4-30.6). Both uni- and multi-variable analyses did not show any significant association between conditioning intensity and outcomes. This study highlights a lack of association between RIC/MAC regimens and outcomes in allo-HCT MDS patients. Our results support the recently published systematic review and meta-analysis, where evidence for using one conditioning regimen over another remains weak.
    DOI:  https://doi.org/10.1038/s41409-025-02682-3
  22. Blood Cancer Discov. 2025 Sep 03.
    Combination Strategies with Menin Inhibitors for Acute Leukemia.
    Ghayas C Issa, Sheng F Cai, Alex Bataller, Hagop M Kantarjian, Eytan M Stein.
      Menin inhibitors are targeted therapies for the treatment of genetically defined subsets of acute leukemia. The menin inhibitor revumenib is currently approved for relapsed or refractory leukemia with rearrangement of lysine methyltransferase 2 A (KMT2A). However, multiple other menin inhibitors are currently in clinical development aimed at targeting additional subsets such as nucleophosmin 1 (NPM1) mutations which form up to 30% of acute myeloid leukemia. As observed with other targeted therapies for cancer, on-target resistance mutations emerged in advanced cases following monotherapy. Therefore, combination strategies incorporating menin inhibitors are needed to improve durability and depth of remission.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-24-0212
  23. Am J Hematol. 2025 Aug 29.
    Impact of Donor Type on Outcomes After Allogeneic Hematopoietic Cell Transplantation in Myelofibrosis: A Study on Behalf of the Chronic Malignancies Working Party of the EBMT.
    Juan Carlos Hernández-Boluda, Vipul Sheth, Simona Iacobelli, Linda Koster, Nicolaus Kröger, Patrizia Chiusolo, Thomas Schroeder, Marie Robin, Massimiliano Gambella, Didier Blaise, Henrik Sengeloev, Jakob Passweg, Mattias Stelljes, Robert Zeiser, Ibrahim Yakoub-Agha, Andrew Clark, Urpu Salmenniemi, Piero Galieni, Werner Rabisch, Kavita Raj, Joanna Drozd-Sokolowska, Giorgia Battipaglia, Nicola Polverelli, Tomasz Czerw, Donal P McLornan.
      Selecting the optimal donor is crucial for optimizing results of allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed outcomes based on donor type in 2809 myelofibrosis (MF) patients undergoing first allo-HCT between 2015 and 2021 at EBMT centers. Study outcomes included overall survival (OS), progression-free survival (PFS), relapse, non-relapse mortality (NRM), engraftment, and graft-versus-host disease (GvHD). Four groups were compared: matched sibling donor (MSD, n = 742), matched unrelated donor (MUD, n = 1401), mismatched unrelated donor (MMUD, n = 379) and haploidentical donor (HD, n = 287). After a median follow-up of 33.5 months, 3-year OS rates were 65.8%, 61.5%, 53.2%, and 57.7% for MSD, MUD, MMUD, and HD, respectively. Multivariable analyses (MSD as reference) showed that donor type significantly correlated with OS (HR: 1.63 for MMUD, HR: 1.42 for HD), PFS (HR: 1.38 for MMUD), NRM (HR: 1.73 for MMUD, HR: 1.47 for HD), engraftment (HR: 0.72 for MMUD, HR: 0.40 for HD), grade 2-4 acute GvHD (HR: 1.53 for MUD, HR: 1.69 for MMUD, HR: 1.49 for HD), and extensive chronic GvHD (HR: 0.77 for MUD, HR: 0.65 for HD). Donor type was not associated with relapse risk. In patients over 60 years, correlations between donor type and outcomes were consistent with those in the overall study population. In summary, with current practices, MF patients receiving MSD or MUD grafts achieve comparable outcomes. In contrast, MMUD and HD transplants have worse OS due to increased NRM. MMUD transplants have a higher risk of GvHD than HD transplants, but this difference seems to disappear with post-transplant cyclophosphamide.
    Keywords:  donor type; myelofibrosis; outcome; transplantation
    DOI:  https://doi.org/10.1002/ajh.70049
  24. Haematologica. 2025 Sep 04.
    SLC25A1 reprograms mitochondrial and fatty acid metabolism to promote the progression of acute myeloid leukemia.
    Miao Chen, Wenze Li, Yuan Tao, Chenglong Hu, Rui Ge, Sijing Kang, Pengjie Yue, Cheuk Him Man, Lan Wang, Xiaojing Yan.
      Abnormal metabolic reprogramming is a hallmark of acute myeloid leukemia (AML), contributing to leukemia initiation, progression and drug resistance. The key mitochondrial citrate transporter SLC25A1 plays an essential role in regulating cellular energy metabolism and shows to play an important role in lipid metabolism regulation. However, the role of SLC25A1 in the pathogenesis and aberrant lipid metabolism in AML remain unexplored. In this study, our analysis of public datasets and patient samples revealed that SLC25A1 expression was markedly elevated in AML and was associated with poor prognosis. Knockdown or pharmacological inhibition of SLC25A1 significantly suppressed AML cell proliferation by inducing apoptosis, without affecting cell cycle progression or differentiation. Moreover, SLC25A1 proved vital for AML tumorigenesis in vivo. Mechanistically, we demonstrated that SLC25A1 inhibition disrupted citrate homeostasis, leading to mitochondrial dysfunction and reduced fatty acid metabolism. Notably, we developed a novel SLC25A1 inhibitor, CTPI3, which effectively inhibits the progression of AML in vivo, and synergizes with venetoclax to kill AML cells by mitochondrial and fatty acid metabolism regulation. In summary, our findings highlight that SLC25A1 plays a vital role of in maintaining AML cell survival and regulating its drug sensitivity, and further developed a more effective novel drug targeting SLC25A1, providing additional therapeutic options for venetoclax-resistant patients and highlighting SLC25A1 as a promising biomarker and therapeutic target for AML.
    DOI:  https://doi.org/10.3324/haematol.2024.287269
  25. Blood. 2025 Sep 02. pii: blood.2025030259. [Epub ahead of print]
    Impact of ASXL1 at diagnosis in patients with CML receiving frontline potent TKIs: high risk of kinase domain mutations.
    Naranie Shanmuganathan, David T Yeung, Carol Wadham, Adelina Fernandes, Muneeza Maqsood, NurHezrin Shahrin, Verity A Saunders, Rosalie Kenyon, Ming Lin, John Toubia, Joe McConnell, Dominik Kaczorowski, David M Ross, Agnes Sm Yong, Lynette Chee, Jake Shortt, Nicholas Viiala, Jodi A Braley, Chung Hoow Kok, Timothy P Hughes, Susan Branford.
      Genomic profiling in chronic-phase chronic myeloid leukemia (CP-CML) patients demonstrated somatic variants in blood cancer-related genes (CGVs) and rearrangements associated with the formation of the Philadelphia-chromosome (Ph-associated rearrangements) at diagnosis, collectively termed additional genetic abnormalities (AGA). AGAs had a negative impact on failure-free survival and molecular response in imatinib-treated patients. We investigated whether treatment with more potent therapies could overcome the negative impact of AGAs at diagnosis. Targeted RNA-based next generation sequencing (NGS) was performed on diagnostic samples of 315 patients consecutively enrolled in four clinical trials of frontline potent tyrosine kinase inhibitors (TKIs) in CP-CML. AGAs were present in 34% of patients at diagnosis, including 20% with CGVs and 18% with Ph-associated rearrangements (4% had both). While the negative impact of Ph-associated rearrangements was overcome by more potent inhibitors, patients with CGVs continued to have inferior outcomes. This was largely attributable to patients with ASXL1 variants, observed in 7% overall. Comparing patients with ASXL1 variants to ASXL1 wildtype: 12-month major molecular response 55% versus 83% (P=0.001); 2-year failure-free survival 61% versus 91% (P<0.001); and notably, development of treatment emergent BCR::ABL1 kinase domain mutations at 2 years, 35% versus 1% (P<0.001). In multivariable models, CGVs and ASXL1 variants were predictors of each of these outcomes. Treatment with frontline potent TKIs overcame the negative impact of Ph-associated rearrangements observed with frontline imatinib. However, inferior outcomes were still associated with the presence of CGVs. The acquisition of TKI-resistant BCR::ABL1 mutations was almost exclusively associated with mutated ASXL1 at diagnosis.
    DOI:  https://doi.org/10.1182/blood.2025030259
  26. Haematologica. 2025 Aug 28.
    Treatment-relevant misdiagnosis of autoimmune myelofibrosis.
    Naseema Gangat, Kaaren K Reichard, Attilio Orazi, David S Viswanatha, Curtis A Hanson, Ayalew Tefferi.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.288638
  27. Leukemia. 2025 Sep 01.
    Long-term benefits of autologous stem cell transplantation versus intensive chemotherapy consolidation for acute myeloid leukemia patients: A propensity score matching analysis from the PETHEMA AML registry.
    PETHEMA Group
      While allogeneic stem cell transplantation (allo-SCT) is the preferred consolidation for high and most intermediate-risk acute myeloid leukemia (AML) patients in first remission, the role of autologous SCT (auto-SCT) vs. chemotherapy (CT) when allo-SCT is not feasible or indicated, remains controversial. We conducted a real-world, retrospective cohort study using the PETHEMA AML registry to compare auto-SCT and CT. Multivariate Cox regression and propensity score matching (PS-matching) were used to adjust for confounding factors. A total of 1272 patients in first remission and who received 2 consolidation courses were included (615 receiving additional CT cycles and 657 undergoing auto-SCT). Overall, 78.08% of auto-SCT patients were diagnosed before 2017, compared to 38.11% in the CT cohort (p < 0.001). In the overall cohort, auto-SCT was associated with significantly prolonged overall survival (OS) (HR: 0.73, p < 0.001) and relapse-free survival (RFS) (HR: 0.73, p < 0.001). This benefit was particularly evident in patients ≤65 years, those with normal karyotype, and FLT3-ITD negativity. In the PS-matched cohort, the RFS advantage persisted (HR: 0.80, p = 0.092), but OS differences were not statistically significant (HR: 0.91, p = 0.563). The role of auto-SCT in the genomic and targeted agent era should not be discarded.
    DOI:  https://doi.org/10.1038/s41375-025-02744-x
  28. Stem Cells. 2025 Sep 04. pii: sxaf059. [Epub ahead of print]
    The impact of donor and recipient age on post-transplantation clonality in murine haematopoiesis.
    Lars Thielecke, Kalpana Nattamai, Aishlin Hassan, Ingmar Glauche, Hartmut Geiger, Kerstin Cornils.
      The sustained production of blood and immune cells is driven by a pool of hematopoietic stem cells (HSCs) and their offspring. Due to the intrinsic heterogeneity of HSCs, the composition of emergent clones changes over time, leading to a reduced clonality in aging mice and humans. Theoretical analyses suggest that clonal conversion rates and clonal complexity depend not only on HSC heterogeneity, but also on additional stress conditions. These insights are particularly relevant in the context of stem cell transplantations, which still remain the only curative option for many hematologic diseases, increasingly considered viable for elderly individuals. However, age-related clonal changes post-transplantation are not well understood. To address this, we conducted a barcode-based assessment of clonality to investigate post-transplantation changes in both homo- and hetero-chronic settings, combined with low- and high-intensity pre-conditioned recipients. A robust and polyclonal engraftment was observed across all groups, but with distinct differences in barcode diversity. In particular, transplanted aged HSCs showed no changes in clonality, regardless of recipient age or pre-conditioning. Young HSCs transplanted into severely pre-conditioned old hosts as well as under reduced pre-conditioning, allowed for full lymphoid reconstitution, but showed substantial differences in clonality. Also, myeloid lineage bias, a hallmark of aged HSCs, was confirmed at a clonal level across all experimental groups. Overall, we found that aged HSCs generally maintain clonal diversity similar to young HSCs, but notable differences emerge under hetero-chronic conditions and varying pre-conditioning regimens. These findings challenge current paradigms and underscore the complex interactions between aging and transplantation conditions.
    Keywords:  aging; cellular barcodes; clonality; hematopoiesis; stem cell transplantation
    DOI:  https://doi.org/10.1093/stmcls/sxaf059
  29. Blood. 2025 Sep 04. pii: blood.2025028504. [Epub ahead of print]
    Innate lymphoid cells prevent graft-versus-host disease via IL-9-driven T-cell senescence.
    Dejene Milkessa Tufa, Eric Hoffmeyer, Kristin L Schaller, Ben Kooiman, Elena Woods, Dong Wang, Dallas Clinton Jones, Spencer C Hall, Joselyn Cruz Cruz, Michael Vernaris.
      ABSTRACTInnate lymphoid cells (ILCs) are tissue-resident lymphocytes that regulate tissue homeostasis and immune responses. How ILCs modulate T cells remains incompletely understood. To investigate the interaction between ILCs and T cells, we differentiated ILC2s and ILC3s from hematopoietic stem cells (HSCs). Both suppressed T cell proliferation, enhanced cytokine production, and upregulated T cell senescence-associated surface receptors (CD57, KLRG1, TIGIT, and TIM3). T cells exposed to ILCs also increased expression of senescence-related proteins, including p16, p21, p53, GATA4, and NF-κB. Mechanistically, ILCs produced IL-9, and IL-9 blockade prevented ILC-driven T cell senescence. Conversely, addition of exogenous IL-9 to T cells recapitulated the effects of ILC co-culture. Finally, in both human xenogeneic and murine allogeneic hematopoietic cell transplantation (HCT) models, we observed ILC-mediated T cell modulation in vivo, with evidence of T cell senescence. In conclusion, HSC-derived ILCs from both humans and mice mitigate graft-versus-host disease (GVHD) by inducing T cell senescence.
    DOI:  https://doi.org/10.1182/blood.2025028504
  30. Precis Oncogenom. 2025 Jul 16.
    Identifying Drug Combination Strategies for ZMYM2: FGFR1 Fusion Positive Leukemia.
    Ariane Huang, Sofia R Beer, Christopher A Eide, Brian J Druker, Jeffrey W Tyner, Jessica Leonard, Cristina E Tognon.
      Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) are a class of fusion protein-driven, poor prognosis leukemias. Leukemias harboring FGFR1 fusions have previously been referred to as 8p11.2 myeloproliferative syndrome (EMS) or stem cell leukemia/lymphoma (SCLL) and are currently referred to as Myeloid/lymphoid neoplasms with FGFR1 rearrangement based on the most recent WHO classification system. To identify new therapeutic options for MLN-TK patients, we evaluated clinical and ex vivo drug response data from a ZMYM2:FGFR1-positive patient who was successfully treated with FGFR kinase-targeting inhibitors. After initially responding to ponatinib, the patient was switched to pemigatinib which eventually transitioned them to a successful transplant. Leukemia cells isolated from the patient exhibited ex vivo sensitivity to ponatinib, bortezomib and axitinib. ZMYM2:FGFR1-transformed Ba/F3 cells were exquisitely sensitive to next generation FGFR inhibitors, and combinations of FGFRi plus trametinib or midostaurin were found to be synergistic, suggesting novel therapeutic options for FGFR1-fusion positive patients.
    DOI:  https://doi.org/10.1080/28354311.2025.2530229
  31. Sci Adv. 2025 Aug 29. 11(35): eadr5867
    Id1 promotes clonal hematopoiesis in mice with Tet2 loss of function.
    Shweta Singh, Kristbjorn O Gudmundsson, Tanmoy Sarkar, Brad L Jakubison, Holly M Morris, Sandra Burkett, Karim Baktiar, Gary T Pauly, Dina M Sigano, Joel P Schneider, Lino Tessarollo, Jonathan R Keller.
      Hematopoietic malignancies emerge through the acquisition of genetic mutations within hematopoietic stem and progenitor cells (HSPCs). Some mutations impart a selective growth advantage to HSPCs, which expand and contribute to mature blood cells. This expansion is termed clonal hematopoiesis (CH). Inhibitor of DNA binding 1 (ID1) protein is a transcriptional regulator of proliferation/differentiation of hematopoietic cells. HSPCs express low levels of Id1 that is induced by growth factors and other mediators of inflammatory during stress to promote HSPC expansion. Since chronic inflammation is associated with the progression of hematopoietic malignancies, reducing Id1 expression may reduce CH. Genetic ablation of Id1 in Tet2-/- HSPCs reduces HSPC expansion/CH, extramedullary hematopoiesis, myeloid skewing, and genetic instability and delays the onset of disease. Mechanistically, p16 expression, senescence, and apoptosis were increased, and proliferation decreased in Tet2-/-;Id1-/- HSPCs. Thus, ID1 may represent a therapeutic target to reduce CH and delay the onset of disease.
    DOI:  https://doi.org/10.1126/sciadv.adr5867
  32. Haematologica. 2025 Sep 04.
    CHIP ahoy: charting a decade of discovery in clonal hematopoiesis.
    Casey K Wong, Alexandra McDonald, Marco M Buttigieg, Michael J Rauh.
      Clonal hematopoiesis (CH) involves the expansion of hematopoietic stem cells with ageacquired mutations linked to myeloid malignancy. Advances in next-generation and single-cell sequencing, along with computational modeling, have expanded our ability to detect both common and rare CH drivers, including single-nucleotide variants and mosaic chromosomal alterations, with increasing sensitivity. While sequencing methods differ in accuracy, cost, and ability to detect low-frequency variants, they have deepened our understanding of CH biology. A growing body of evidence has identified both somatic drivers, such as variants in DNMT3A, TET2, and ASXL1, and germline genetic variants that modify CH risk, highlighting the complex interplay between inherited and acquired factors. These collective discoveries are guiding the development of targeted therapies and interventions, particularly for individuals at risk of progression to myeloid neoplasms or cardiovascular disease. Additionally, CH is emerging as a clinically relevant factor in the treatment of solid tumors, where it may influence the tumour microenvironment, treatment response and the risk of therapy-related complications. Risk stratification models are facilitating earlier identification and monitoring of high-risk individuals, enabling personalized treatment decisions. The scope of CH management continues to expand, from surveillance to intervention, with ongoing trials testing preventive strategies in high-risk populations. Emerging trial frameworks emphasize risk stratification, age-appropriateness, inclusive recruitment, decentralized trial models, and the use of traditional clinical and novel endpoints. Together, these advances reflect a shift from passive observation to proactive intervention, charting a course for early detection, precision treatment, and prevention in CH care.
    DOI:  https://doi.org/10.3324/haematol.2023.283896
  33. Signal Transduct Target Ther. 2025 Aug 29. 10(1): 275
    The deacetylases HDAC1/HDAC2 control JAK2V617F-STAT signaling through the ubiquitin ligase SIAH2.
    Al-Hassan M Mustafa, Giuseppe Petrosino, Marten A Fischer, Tina M Schnöder, Désirée Gül, Yanira Zeyn, Christoph Hieber, Johanna Lossa, Sabine Muth, Markus P Radsak, Walburgis Brenner, Markus Christmann, Matthias Bros, Florian H Heidel, Oliver H Krämer.
      Epigenetic modulators of the histone deacetylase (HDAC) family control key biological processes and are frequently dysregulated in cancer. There is superior activity of HDAC inhibitors (HDACi) in patients with myeloproliferative neoplasms (MPNs) that carry the Janus kinase-2 point mutant JAK2V617F. This constitutively active tyrosine kinase activates signal-transducer-and-activator-of-transcription (STAT) transcription factors to promote cell proliferation and inflammatory processes. We reveal that the inhibition of HDAC1/HDAC2 with the clinically advanced HDACi romidepsin, the experimental HDACi entinostat and MERCK60, and genetic depletion of HDAC1/HDAC2 induce apoptosis and long-term growth arrest of primary and permanent MPN cells in vitro and in vivo. This treatment spares normal hematopoietic stem cells and does not compromise blood cell differentiation. At the molecular level, HDAC1 and HDAC2 control the protein stability of SIAH2 through acetylation. Genetic knockout experiments show that SIAH2 accelerates the proteasomal degradation of JAK2V617F in conjunction with the E2 ubiquitin-conjugating enzyme UBCH8. SIAH2 binds to the surface-exposed SIAH degron motif VLP1002 in the catalytic domain of JAK2V617F. At the functional level, SIAH2 knockout MPN cells are significantly less sensitive to HDACi. Global RNA sequencing verifies that JAK-STAT signaling is a prime target of SIAH2. Moreover, HDAC1 is an adverse prognostic factor in patients with acute myeloid leukemia (n = 150, p = 0.02), being a possible complication of MPNs. These insights reveal a previously unappreciated link between HDAC1/HDAC2 as key molecular targets, the still undefined regulation of cytoplasmic-to-nuclear signaling by HDACs, and how HDACi kill JAK2V617F-positive cells from MPN patients and mice with JAK2V617F in vitro and in vivo.
    DOI:  https://doi.org/10.1038/s41392-025-02369-7
  34. Cell Stem Cell. 2025 Sep 04. pii: S1934-5909(25)00270-X. [Epub ahead of print]32(9): 1403-1420.e8
    Nanobioreactor detection of space-associated hematopoietic stem and progenitor cell aging.
    Jessica Pham, Jane Isquith, Larisa Balaian, Shuvro P Nandi, Claire Engstrom, Karla Mack, Inge van der Werf, Patrick Chang, Jana Stoudemire, Luisa Ladel, Emma Klacking, Antonio Ruiz, Daisy Chilin-Fuentes, Jenna Sneifer, David Mays, Paul Gamble, Shelby Giza, Jiya Janowitz, Trevor Nienaber, Tejaswini Mishra, Anna A Khachatrian, Elsa Molina, Michael P Snyder, Sheldon R Morris, Twyman Clements, Alysson R Muotri, Thomas Whisenant, Ludmil B Alexandrov, Catriona H M Jamieson.
      Human hematopoietic stem and progenitor cell (HSPC) fitness declines following exposure to stressors that reduce survival, dormancy, telomere maintenance, and self-renewal, thereby accelerating aging. While previous National Aeronautics and Space Administration (NASA) research revealed immune dysfunction in low-earth orbit (LEO), the impact of spaceflight on human HSPC aging had not been studied. To study HSPC aging, our NASA-supported Integrated Space Stem Cell Orbital Research (ISSCOR) team developed bone marrow niche nanobioreactors with lentiviral bicistronic fluorescent, ubiquitination-based cell-cycle indicator (FUCCI2BL) reporter for real-time HSPC tracking in artificial intelligence (AI)-driven CubeLabs. In month-long International Space Station (ISS) missions (SpX-24, SpX-25, SpX-26, and SpX-27) compared with ground controls, FUCCI2BL reporter, whole-genome and transcriptome sequencing, and cytokine arrays demonstrated cell-cycle, inflammatory cytokine, mitochondrial gene, human repetitive element, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) deregulation together with clonal hematopoietic mutations. Furthermore, HSPC functionally organized multi-omics aging (HSPC-FOMA) analyses revealed reduced telomere maintenance, adenosine deaminase acting on RNA1 (ADAR1) p150 self-renewal gene expression, and replating capacity indicative of space-associated HSPC aging that may limit long-duration spaceflight.
    Keywords:  ADAR1; APOBEC3; aging; cell cycle; clonal hematopoiesis; dark genome; hematopoietic stem and progenitor cells; low-earth orbit; nanobioreactor; repetitive elements
    DOI:  https://doi.org/10.1016/j.stem.2025.07.013
  35. Mol Oncol. 2025 Sep 04.
    Hypomethylating agents increase L1 retroelement expression without inducing novel insertions in myeloid malignancies.
    Šárka Pavlová, Hana Svozilová, Marcela Krzyžánková, Radim Sonnek, Anastasiya Volakhava, Anastasia Smirnova, Tatiana Grigoreva, Zuzana Jašková, Hana Synáčková, Dennis Wahl, Michaela Bilčíková, Libor Červinek, Šárka Pospíšilová, Ilgar Mamedov, Karla Plevová.
      Retroelements in the human genome are silenced via multiple mechanisms, including DNA methylation, to prevent their potential mutagenic effect. Retroelement activity, demonstrated by their expression and somatic retrotransposition events, was shown to be deregulated in multiple tumors but not yet in leukemia. We hypothesized that treatment with hypomethylating agents, commonly used in myelodysplastic syndromes and acute myeloid leukemia, could lead to increased retroelement activity and somatic retrotranspositions, thus contributing to disease progression. To address this hypothesis, we induced the expression of ORF1p protein with hypomethylating agents in DAMI and HL-60 myeloid cell lines. To study whether long-term hypomethylating agent therapy induces somatic retrotranspositions, we analyzed (i) both cell lines treated for 4 weeks, and (ii) sequential samples from 17 patients with myelodysplastic syndrome treated with hypomethylating agents. Using a sensitive next-generation sequencing (NGS)-based method, no retroelement events were identified. To conclude, we show that although hypomethylating agents induce the expression of LINE-1-encoded proteins in myeloid cell lines, de novo somatic retrotransposition events do not arise during the long-term exposure to these agents.
    Keywords:  5′‐azacytidine; L1; LINE‐1; ORF1p; ORF2p; hypomethylation agent; myelodysplastic syndrome; retrotransposition; transposable elements
    DOI:  https://doi.org/10.1002/1878-0261.70111
  36. J Clin Invest. 2025 Sep 04. pii: e193011. [Epub ahead of print]
    UBA1-depleted neutrophils disrupt immune homeostasis and induce VEXAS-like autoinflammatory disease in mice.
    Ge Dong, Jingjing Liu, Wenyan Jin, Hongxi Zhou, Yuchen Wen, Zhiqin Wang, Keyao Xia, Jianlin Zhang, Linxiang Ma, Yunxi Ma, Lorie Chen Cai, Qiufan Zhou, Huaquan Wang, Wei Wei, Ying Fu, Zhigang Cai.
      VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a haemato-rheumatoid disease caused by somatic UBA1 mutations in hematopoietic stem cells (HSCs). The pathogenic cell type(s) responsible for the syndrome are unknown and murine models recapitulating the disease are lacking. We report that loss of Uba1 in various mouse hematopoietic cell types resulted in pleiotropic consequences and demonstrate that murine mutants with about 70% loss of Uba1 in neutrophils induced non-lethal VEXAS-like symptoms. Depletion of Uba1 in HSCs induced extensive hematopoietic cell loss while depletion of Uba1 in B or T cells, or in megakaryocytes induced corresponsive cell death but these mutants appeared normal. Depletion of Uba1 in monocytes and neutrophils failed to induce cell death and the mutants were viable. Among the tested models, only depletion of Uba1 in neutrophils induced autoinflammatory symptoms including increased counts and percentage of neutrophils, increased proinflammatory cytokines, occurrence of vacuoles in myeloid cells, splenomegaly and dermatitis. Residual Uba1 was about 30% in the mutant neutrophils, which disrupted cellular hemostasis. Finally, genetic loss of the myeloid pro-survival regulator Morrbid partially mitigated the VEXAS-like symptoms. The established VEXAS-like murine model will assist understanding and treatment of the newly identified autoinflammatory syndrome prevalent among aged men.
    Keywords:  Hematology; Hematopoietic stem cells; Inflammation; Neutrophils; Ubiquitin-proteosome system
    DOI:  https://doi.org/10.1172/JCI193011
  37. Cell Rep. 2025 Sep 03. pii: S2211-1247(25)01007-1. [Epub ahead of print]44(9): 116236
    A single-cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis.
    Asiri Ediriwickrema, Yusuke Nakauchi, Amy C Fan, Thomas Köhnke, Xiaoyi Hu, Bogdan A Luca, YeEun Kim, Sreejith Ramakrishnan, Margaret Nakamoto, Daiki Karigane, Miles H Linde, Armon Azizi, Aaron M Newman, Andrew J Gentles, Ravindra Majeti.
      Hematopoietic multipotent progenitors (MPPs) regulate blood cell production to meet the evolving demands of an organism. Adult human MPPs remain ill defined, whereas mouse MPPs are well characterized, with distinct immunophenotypes and lineage potencies. Using multi-omic single-cell analyses and functional assays, we identified distinct human MPPs within Lin-CD34+CD38dim/lo adult bone marrow with unique biomolecular and functional properties. These populations were prospectively isolated based on expression of CD69, CLL1, and CD2 in addition to classical markers like CD90 and CD45RA. We identified a CD69+ MPP with long-term engraftment and multilineage differentiation potential, a CLL1+ myeloid-biased MPP, and a CLL1-CD69- erythroid-biased MPP. We used this updated hematopoietic stem and progenitor cell (HSPC) profile to study human and mouse bone marrow cells and observe unique cell-type-specific homology between species and cell-type-specific changes associated with human aging. By identifying and functionally characterizing adult MPP sub-populations, we provide a framework for future studies in hematopoiesis.
    Keywords:  CP: Stem cell research; aging; bone marrow; differentiation; hematopoiesis; hematopoietic stem and progenitor cells; hematopoietic stem cells; multipotent progenitors; oligopotent progenitors; single-cell RNA sequencing and single-cell multi-omics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116236
  38. Cell Rep. 2025 Sep 02. pii: S2211-1247(25)00987-8. [Epub ahead of print]44(9): 116216
    Transcript isoform diversity defines molecular subtypes and prognosis in acute myeloid leukemia through long-read sequencing.
    Xiaoguang Shi, Shuai Wang, Shuting Yu, Fangying Jiang, Jinzeng Wang, Yao Dai, Jincan Li, Ruihong Zhang, Tong Yin, Yuting Dai, Hai Fang, Junmin Li, Hongming Zhu, Shengyue Wang.
      Acute myeloid leukemia (AML) is a genetically complex and clinically heterogeneous hematopoietic malignancy. This study employs long-read transcriptome analysis using oxford nanopore technologies sequencing on 60 primary AML bone marrow samples. This approach delivers comprehensive isoform-level resolution of splicing abnormalities and overcomes limitations of short-read sequencing. We detect extensive AML-specific splicing anomalies and identify 119,278 previously unannotated transcript isoforms. Of these, 80,294 (67.31%) contain complete open reading frames, with 9,812 (12.22%) validated using liquid chromatography-tandem mass spectrometry. Quantitative analysis in 175 RNA sequencing samples enables non-negative matrix factorization clustering, defining distinct molecular subtypes. These isoform-defined subtypes exhibit strong correlations with patient prognosis, indicating their potential as biomarkers for clinical classification. The findings highlight alternative splicing as a major contributor to AML molecular heterogeneity and provide a valuable foundation for advancing precision medicine and developing innovative therapeutic strategies targeting splicing abnormalities in AML.
    Keywords:  CP: Cancer; CP: Genomics; acute myeloid leukemia; alternative splicing; long-read RNA sequencing; molecular subtypes; non-negative matrix factorization; transcript isoform
    DOI:  https://doi.org/10.1016/j.celrep.2025.116216
  39. Haematologica. 2025 Sep 04.
    What's hidden in plain sight? Impact of clonal hematopoiesis on the risk and progression of non-hematologic cancers.
    José C Martínez, Catherine C Coombs.
      Clonal hematopoiesis (CH) is a frequently observed phenomenon in aging individuals without apparent illness and exhibits an increased prevalence in cancer patients. Mechanistic studies indicate that mutant immune cells alter the tumor microenvironment, leading to increased inflammation, blood vessel formation, and immune cell exhaustion. Paradoxically, these changes also preserve stem-like T-cell pools that can be utilized by immunotherapy. CH may be incidentally detected in patients whose solid tumors are profiled by next-generation sequencing. Clinically, CH confers higher risks of therapy-related myeloid neoplasms, cardiovascular and inflammatory toxicities, and context-specific changes in treatment efficacy. Moreover, tumorinfiltrating CH independently shortens survival. Two validated risk scores can inform the risk for myeloid malignancy, yet surveillance, cardiometabolic management, and regimen selection still primarily rely on expert consensus. Because CH may be discovered incidentally, rigorous confirmation of variant origin when CH is suspected is essential to avoid misdirected therapy. We propose a pragmatic approach: confirm CH with paired blood sequencing when feasible; integrate high-risk features into risk stratification, counseling, and monitoring for cytopenias and cardiovascular events; and prefer less genotoxic regimens when the oncologic benefit is comparable. Early trials blocking interleukin-1β suggest that targeting inflammation driven by CH may improve outcomes in patients with solid tumors. Prospective studies informed by mutation analysis and tracking clonal changes and inflammatory markers are needed to determine if routine CH assessment can be integrated into precision oncology to improve outcomes for patients with solid tumors and CH.
    DOI:  https://doi.org/10.3324/haematol.2025.287424
  40. Cell Rep. 2025 Aug 26. pii: S2211-1247(25)00964-7. [Epub ahead of print]44(9): 116193
    Distinct roles for NF-κB in hematopoietic stem cells and the bone marrow milieu in promoting hematopoietic aging.
    Jennifer J Chia, Apeksha Singh, Yu-Sheng Lin, Noa Popko, David Mastro, Yi Liu, Tiffany Tran, Jennifer K King, Dinesh S Rao, Alexander Hoffmann.
      Hematopoietic aging is characterized by chronic inflammation associated with myeloid bias, hematopoietic stem cell (HSC) accumulation, and functional HSC impairment. Yet it remains unclear how inflammation promotes aging phenotypes. Nuclear factor κB (NF-κB) both responds to and directs inflammation, and we present an experimental model of elevated NF-κB activity ("inhibitor of κB deficient" [IκB-]) to dissect its role in hematopoietic aging phenotypes. We find that while elevated NF-κB activity is not sufficient for HSC accumulation, HSC-autonomous NF-κB activity impairs their functionality, leading to reduced bone marrow reconstitution. In contrast, myeloid bias is driven by the IκB- proinflammatory bone marrow milieu, as observed functionally, epigenomically, and transcriptomically. A single-cell RNA sequencing (scRNA-seq) HSPC labeling framework enables comparisons with aged murine and human HSC datasets, documenting an association between HSC-intrinsic NF-κB activity and quiescence but not myeloid bias. These findings delineate separate regulatory mechanisms that underlie the three hallmarks of hematopoietic aging, suggesting that they are specifically and independently therapeutically targetable.
    Keywords:  C/EBP; CP: Immunology; CP: Stem cell research; NF-κB; bone marrow cytokine milieu; bone marrow niche; hematopoietic aging; hematopoietic stem cell impairment; inflammaging; microenvironment; myeloid bias; stem cell aging
    DOI:  https://doi.org/10.1016/j.celrep.2025.116193
  41. bioRxiv. 2025 Aug 27. pii: 2025.08.22.671600. [Epub ahead of print]
    B12 promotes gut dysbiosis and an inflammatory microenvironment that potentiates Tet2 -deficient hematopoiesis.
    P D Lyon, T E Leesang, J P Brabson, Ktt Do, M Dalzell, L A Nivelo, M Q Lam, A Peci, B Fang, V Strippoli, A A Armand, P K Singh, S Roy, F Beckedorff, A V Villarino, L Cimmino.
      Recent studies have linked elevated vitamin B12 serum levels with the presence of clonal hematopoiesis (CH) and an increased risk of developing myeloid malignancy. High B12 supplementation increases serum levels, alters gut microbial composition, and reduces the production of short-chain fatty acids (SCFAs), which help maintain gut barrier function and mucosal integrity. TET2 mutation is a frequent driver of CH that progresses in a positive feedback loop in response to microbial signals suggesting that B12 may influence CH via the gut microbiome. We evaluated the microenvironmental effects of B12 supplementation in a Tet2 -deficient model of CH and found that B12 enhances myelopoiesis, heightens the responses of myeloid cells to bacterial stimuli, and increases the levels of circulating inflammatory cytokines. B12 supplementation also induced gut dysbiosis and reduced the levels of SCFA-producing bacteria in both wild-type and Tet2 -deficient mice. Importantly, the effects of excess B12 were reversible upon oral supplementation with the SCFA butyrate. These findings suggest that B12 may promote CH progression by disrupting microbiome-derived SCFA metabolism, highlighting a potential therapeutic role for SCFA supplementation in mitigating CH.
    DOI:  https://doi.org/10.1101/2025.08.22.671600
  42. Br J Haematol. 2025 Aug 31.
    Clinical and molecular characterization of patients with juvenile myelomonocytic leukaemia.
    Julia A Meyer, Sherin Xirenayi, Juwita Werner, Rust Turakulov, Aaron Hechmer, Zied Abdullaev, Nayera Hamdy, Adam Olshen, Elliot Stieglitz, Mahmoud Hammad, Alaa Elhaddad.
      Juvenile myelomonocytic leukaemia (JMML) is a rare haematological malignancy caused by mutations in the Ras signalling pathway. Next-generation sequencing (NGS) and DNA methylation profiling used for diagnostic and risk stratification purposes are now standard of care in Europe and the United States for patients with JMML. To better understand how implementing these types of technologies would impact the treatment of JMML patients in different settings, molecular profiling was performed on 81 patients treated for JMML in Egypt from 2009 to 2022. NGS increased the number of patients with a molecular diagnosis compared to conventional Sanger sequencing. NGS and DNA methylation analysis also identified patients with a higher risk for relapse based on the presence of multiple mutations or intermediate/high methylation respectively. Mutational burden, cytogenetics and methylation subgrouping were combined to develop a risk stratification model that may help to prioritize patients for haematopoietic stem cell transplantation. In summary, advanced molecular testing is key to enabling an accurate diagnosis and predicting outcome in JMML.
    Keywords:  acute leukaemia; childhood haematological malignancies; childhood leukaemia; myeloid leukaemia; myeloproliferative disorder
    DOI:  https://doi.org/10.1111/bjh.70106
  43. Blood. 2025 Sep 03. pii: blood.2025029302. [Epub ahead of print]
    Off-the-shelf dual CAR-iNKT cell immunotherapy eradicates medullary and leptomeningeal high-risk KMT2A-rearranged leukemia.
    Hongwei Ren, Natalina Elliott, Bryan Lye, Mohammad Umer Sharif Shohan, Joe Wilson Cross, Lucy May Field, Kanagaraju Ponnusamy, Siobhan Rice, Thomas Jackson, Ilia Leontari, Nouhad El Ouazzani, Rebecca Thomas, Sarah Inglott, Jack Bartram, Owen Smith, Jonathan Bond, Irene Roberts, Christina Halsey, Rachael Bashford-Rogers, Thomas A Milne, Anindita Roy, Anastasios Karadimitris.
      Current therapies, including autologous CAR-T immunotherapy, fail to cure half of infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2Ar-ALL), a disease characterized by frequent central nervous system involvement, poor treatment response, early relapse and lineage switching. More effective treatment strategies, including the availability of 'off-the-shelf' immunotherapies is particularly relevant in infants. PROM1/CD133 is a direct target of KMT2A-fusion oncoproteins and is expressed on leukemic cells. Allogeneic iNKT cells, 'innately' more powerful effectors than T cells can be deployed 'off-the-shelf' without risk of acute graft-versus-host disease. Here, we equip iNKT with CD19- and/or CD133-targeting CARs and investigate their anti-leukaemia activity against KMT2Ar-ALL in relevant in vitro and in vivo models. Compared to mono-specific counterparts and dual, bi-specific CAR-T, bi-specific CD19-CD133 CAR-iNKT have a more potent anti-leukemia activity, effectively targeting both CAR antigen-high and -low leukemia. Bi-specific CAR-iNKT eradicate medullary and, notably, leptomeningeal leukemia and induce sustained remissions without discernible hematologic toxicity. Mechanistically, the more potent anti-leukemia effect of CAR-iNKT over CAR-T cells is mediated by a pronounced CAR- and CAR antigen-dependent upregulation of the innate activating receptor NKG2D on CAR-iNKT and its engagement by its corresponding ligands on KMT2Ar-ALL cells. This ensures effective leukemia targeting even with downregulation of CD133 or CD19. Thus, by engaging with two different types of leukemia-associated antigens i.e., CAR antigens and NKG2D ligands, CAR-iNKT provide a powerful platform for the treatment of KMT2Ar-ALL. This approach can be readily adapted for other high-risk malignancies, including those with otherwise difficult to target leptomeningeal involvement.
    DOI:  https://doi.org/10.1182/blood.2025029302
  44. iScience. 2025 Sep 19. 28(9): 113297
    Analysis of chromatin accessibility associated with azacitidine response in higher-risk myelodysplastic neoplasms.
    Dayoung Kim, Silvia Park, Yong-Rim Kwon, Heejei Yoon, Byung-Sik Cho, Inwha Baek, Joo H Kang, Tae-Eun Park, M Ryan Corces, Hee-Je Kim, Yoo-Jin Kim, Seung Woo Cho.
      Azacitidine, used in the treatment of higher-risk myelodysplastic neoplasms, is a DNA methyltransferase inhibitor that modifies epigenetic regulatory programs. The efficacy of azacitidine varies among patients, with approximately 50% of patients failing to respond. However, whether epigenomic factors affect responses to azacitidine has not been investigated. We examined chromatin accessibility in bone marrow cells from 23 treatment-naive patients with higher-risk myelodysplastic syndrome, suggesting azacitidine response is strongly associated with distinct hematopoietic cell states. Chromatin-accessible regions in non-responders were enriched for myeloid progenitor signatures, whereas those in responders were enriched for T cell signatures. Notably, CD8+ T cells from non-responders exhibited reduced chromatin accessibility at TBX/EOMES-binding sites, bridging T cell differentiation state and azacitidine response. These findings suggest that immune cell function contributes to the responses to hypomethylating agents in myelodysplastic neoplasms and that chromatin accessibility could be used to predict drug responses in high-risk myelodysplastic syndrome patients.
    Keywords:  Health sciences; Internal medicine; Medical specialty; Medicine; Oncology
    DOI:  https://doi.org/10.1016/j.isci.2025.113297
  45. Clin Lymphoma Myeloma Leuk. 2025 Aug 06. pii: S2152-2650(25)00261-7. [Epub ahead of print]
    Management of Chronic Myeloid Leukemia During Pregnancy: Review of Evidence and Treatment Algorithm.
    Fadi G Haddad, Jennifer Croden, Koji Sasaki, Ghayas C Issa, Naveen Pemmaraju, Hagop Kantarjian, Elias Jabbour.
      Philadelphia chromosome-positive chronic myeloid leukemia (CML) during pregnancy is rare, with an annual incidence of 1 per 100,000 pregnancies. Managing CML in pregnancy is challenging due to concerns about the teratogenicity of the BCR::ABL1 tyrosine kinase inhibitors (TKIs). While some pregnant patients with chronic-phase CML may be managed with close monitoring and no therapy, others, particularly those diagnosed in the first trimester, may require treatment to prevent disease progression and maternal complications. Imatinib has been associated with an increased risk of congenital malformations when used in the first trimester; however, growing evidence support its safety later in the second and third trimesters. Similar to imatinib, nilotinib has limited placental transfer with no congenital malformations reported to date in women who received it later in pregnancy. Dasatinib, however, is contraindicated due to its high association with congenital abnormalities and hydrops fetalis. Ponatinib exposure has been linked to a higher incidence of Hirschsprung's disease and should be avoided in pregnancy. Although no congenital malformations have been reported with bosutinib or asciminib, data remains limited, and their use is not recommended. Interferon-α is a safer alternative during pregnancy but is slower in achieving cytoreduction, and less effective compared to TKIs. Hydroxyurea, while not teratogenic, may increase the risk of miscarriage and low birth weight. If a male patient is receiving TKI therapy, the female partner can safely become pregnant without an increased risk for the fetus. Shared decision-making and thorough counseling on the risks and benefits of different treatment options are essential. This review examines the potential fetotoxicity of CML therapies, focusing on TKIs and alternative treatments for pregnant women.
    Keywords:  BCR::ABL1; CML-CP; Conceive; Fetus; Pregnant
    DOI:  https://doi.org/10.1016/j.clml.2025.07.017
This page is being maintained by Thomas Krichel. It was last updated on 2025‒09‒08 at 9:25.