bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–09–14
28 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Similar Outcome With Haploidentical, Matched Sibling, or Matched Unrelated Donor Hematopoietic Cell Transplantation for Adult Patients With Adverse-Risk TP53-Mutated Acute Myeloid Leukemia in First Remission: A Comparative Study From the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
  2. CUX1 restrains latent hematopoietic stem cell plasticity by suppressing stem cell-intrinsic inflammatory pathways.
  3. Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging.
  4. Tagraxofusp, a CD123-targeted therapy, for chronic myelomonocytic leukemia: final results of a phase 1/2 study.
  5. The lncRNA ELDR suppresses tumorigenicity of AML by interfering with DNA replication and chromatin accessibility.
  6. Critical role of niche S100A8 for acute myeloid leukemia progression and hematopoiesis regeneration.
  7. Menin inhibition for the treatment of acute leukemia.
  8. A phase 1 study of IO-202, an anti-LILRB4 antibody, in chronic myelomonocytic leukemia and acute myeloid leukemia.
  9. Outcome of patients with accelerated and blast-phase myeloproliferative neoplasms not eligible for intensive chemotherapy or allogeneic hematopoietic cell transplantation treated by azacitidine alone or in combination-A FIM study.
  10. Acute myeloid leukaemia cells express high levels of androgen receptor but do not depend on androgen signaling for survival.
  11. Allogeneic hematopoietic stem cell transplantation in germline DDX41 mutated patients with myeloid malignancies.
  12. PML::RARα+ myeloid cells display metabolic alterations that can be targeted to treat resistant/relapse acute promyelocytic leukemias.
  13. Myeloablative and Reduced Intensity Allogeneic Transplant in Patients with Myeloproliferative Neoplasms.
  14. V-FAST: a phase 1b master trial to investigate CPX-351 combined with targeted agents in adults with newly diagnosed AML.
  15. Impact of Measurable Residual Disease Status on Outcomes After HLA-Matched Donor Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia.
  16. CHEK2 Germline Variants in Early-Onset and Familial Myeloproliferative Neoplasms.
  17. UK recommendations for chimerism testing and monitoring following allogeneic haematopoietic stem cell transplantation (HSCT): Best practice consensus guidelines from the British Society for Blood and Marrow Transplant and Cellular Therapies (BSBMTCT), NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group, UK Cancer Genetics Group (UKCGG) and the UK National External Quality Assessment Service for Leucocyte Immunophenotyping (UK NEQAS LI).
  18. Improved GVHD-free relapse-free survival when rATG/ATLG is used in allo-HCT from matched sibling donors - an EBMT registry study by the Transplant Complications Working Party.
  19. Targeting O-GlcNAcylated METTL3 impedes MDS/AML progression via diminishing SRSF1 m6A modification.
  20. Dissecting infant leukemia developmental origins with a hemogenic gastruloid model.
  21. KMT2A-rearranged leukemia: from mechanism to drug development.
  22. An inhibitor of UHM splicing factors exerts anti-leukemic activity by altering cell cycle progression and reducing lysosome acidification.
  23. Targeting scavenger receptor class B type 1 with a bioinspired ligand induces apoptosis or ferroptosis in AML.
  24. Longitudinal single-cell analysis reveals treatment-resistant stem and mast cells with potential treatments for pediatric AML.
  25. Induction of Moderate DNA Damage Enhances Megakaryopoiesis and Platelet Production.
  26. An unconquered challenge in MDS: review of pathophysiology, clinical manifestations, and management options of MDS with thrombocytopenia.
  27. Somatic mtDNA mutations at intermediate levels of heteroplasmy are a source of functional heterogeneity among primary leukemic cells.
  28. Fluctuating DNA methylation tracks cancer evolution at clinical scale.
  1. Am J Hematol. 2025 Sep 10.
    Similar Outcome With Haploidentical, Matched Sibling, or Matched Unrelated Donor Hematopoietic Cell Transplantation for Adult Patients With Adverse-Risk TP53-Mutated Acute Myeloid Leukemia in First Remission: A Comparative Study From the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
    Yuhua Ru, Jia Chen, Allain-Thibeault Ferhat, Hélène Labussière-Wallet, Tobias Gedde-Dahl, Nicolaus Kröger, Gérard Socié, Ibrahim Yakoub-Agha, Matthias Eder, Stephan Mielke, Depei Wu, Mohamad Mohty, Fabio Ciceri, Norbert-Claude Gorin.
      Given the dismal prognosis for patients with TP53-mutated acute myeloid leukemia (AML), the optimal donor for those undergoing allogeneic hematopoietic cell transplantation (allo-HCT) remains unclear. We retrospectively analyzed adult patients with TP53-mutated AML who underwent first allo-HCT in CR1 between 2010 and 2021. Outcomes were compared among using a haploidentical donor (Haplo), a matched sibling donor (MSD), and a 10/10 matched unrelated donor (MUD). The analysis comprised 451 patients, including 86 Haplo, 117 MSD, and 248 MUD. Patients in the three groups were transplanted during a similar period. Haplo, MSD, and MUD groups experienced similar incidences of Day 180 Grades II-IV aGVHD (30.9% vs. 23.6% vs. 28.3%), Grades III-IV aGVHD (13.6% vs. 10.1% vs. 9.1%), 2-year cGVHD (28.9.% vs. 30.9% vs. 25.6%) and extensive cGVHD (10.9% vs. 16.1% vs. 13.3%). By multivariate analysis, the outcomes were similar in the three groups. The MSD group was associated with a similar 2-year overall survival (OS: 33.9%; p = 0.799), leukemia-free survival (LFS: 30.5%; p = 0.956), relapse incidence (RI: 54.2%; p = 0.497), non-relapse mortality (NRM: 15.3%; p = 0.368), and GVHD-free, relapse-free survival (GRFS: 21.8%, p = 0.957) when compared with the Haplo group (2-year OS: 46.7%, LFS: 37.4%, RI: 40.8%, NRM: 21.7%, GRFS: 25.7%). The MUD group also experienced a similar 2-year OS (36.9%; p = 0.892), LFS (31%; p = 0.904), RI (50.8%; p = 0.521), NRM (18.2%; p = 0.368) and GRFS (21.9%; p = 0.383) when compared with the Haplo group. In conclusion, outcomes of patients with TP53-mutated AML undergoing allo-HCT from a haploidentical donor were comparable to those from an MSD or 10/10 MUD HCT.
    Keywords:  AML; Haplo‐HCT; MSD‐HCT; MUD‐HCT; TP53; transplant outcomes
    DOI:  https://doi.org/10.1002/ajh.70069
  2. Blood. 2025 Sep 08. pii: blood.2024026815. [Epub ahead of print]
    CUX1 restrains latent hematopoietic stem cell plasticity by suppressing stem cell-intrinsic inflammatory pathways.
    Tanner C Martinez, Matthew R M Jotte, Saira Khan, Angela Stoddart, Hunter Z Blaylock, Ankit Malik, Megan E McNerney.
      Long-term maintenance of somatic stem cells relies on precise regulation of self-renewal and differentiation. Understanding the molecular framework for these homeostatic processes is essential for improved cellular therapies and treatment of myeloid neoplasms. CUX1 is a widely expressed, dosage-sensitive transcription factor crucial in development and frequently deleted in myeloid neoplasia in the context of -7/(del7q). Here, using novel mouse models and single-cell approaches, we report that dynamic and distinct CUX1 levels are integral to hematopoietic stem cell (HSC) activity. Knockdown of CUX1 reverses HSC differentiation and strikingly re-endows progenitors with stem cell function, accompanied by restoration of the HSC transcriptome and DNA accessibility landscape. CUX1 mediates these activities, in part, via suppressing endogenous retroelements (EREs) and the ensuing interferon-stimulated gene expression program. Both EREs and the interferon response are upregulated in CUX1-deficient acute myeloid leukemia (AML), suggesting a conserved role of CUX1 in regulating these elements. These data establish an unexpected entwinement of stem cell-intrinsic innate immune activation and the transcriptional programs of stem cell identity. Further, we reveal the profound effects of transcription factor levels in cell fate.
    DOI:  https://doi.org/10.1182/blood.2024026815
  3. Blood. 2025 Sep 08. pii: blood.2024027432. [Epub ahead of print]
    Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging.
    Sen Zhang, Charles E Ayemoba, Anna M Di Staulo, Kenneth Joves, Chandani M Patel, Eva Hin Wa Leung, Maura Lima Pereira Bueno, Xiaoping Du, Mortimer Poncz, Sang-Ging Ong, Claus Nerlov, Maria Maryanovich, Constantinos Chronis, Sandra Pinho.
      Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.
    DOI:  https://doi.org/10.1182/blood.2024027432
  4. Blood Neoplasia. 2025 Nov;2(4): 100115
    Tagraxofusp, a CD123-targeted therapy, for chronic myelomonocytic leukemia: final results of a phase 1/2 study.
    Mrinal M Patnaik, Haris Ali, Eunice S Wang, Abdulraheem Yacoub, James M Foran, Vikas Gupta, Gary J Schiller, Don Ambrose Stevens, Moshe Talpaz, Sarah Wall, Terra L Lasho, Abhishek A Mangaonkar, Talha Badar, Ross Lindsay, Antonio Galleu, Ira Gupta, Naveen Pemmaraju, Guillermo Garcia-Manero.
      Chronic myelomonocytic leukemia (CMML) is an aggressive hematologic neoplasm characterized by an expansion of CD123+ monocytes and plasmacytoid dendritic cells (pDCs). pDC bone marrow clusters in CMML have been associated with higher rates of acute myeloid leukemia transformation. We evaluated tagraxofusp, a CD123-targeted therapy, in a phase 1/2 trial for patients with CMML. There were no dose-limiting toxicities. At the recommended phase 2 dose of 12 μg/kg per day, 37 patients were treated: 15 were treatment naïve; 22 had relapsed/refractory disease (median number of previous therapies, 1 [range, 1-7]). Common nonhematologic treatment-emergent adverse events (AEs) included fatigue (49%), hypoalbuminemia (46%), nausea, hypokalemia, and decreased appetite (44% each). Capillary leak syndrome occurred in 9 patients (23%; grade 3-4, 13%), whereas tumor lysis syndrome was seen in 13%. Hematologic grade 3/4 treatment-related AEs included thrombocytopenia (28%), anemia (13%), leukocytosis (15%), and neutropenia (13%). No complete or partial responses were observed. One patient each in the treatment-naïve and relapsed/refractory groups achieved complete cytogenetic remission with marrow response. Stable disease and clinical benefit were achieved by 40% and 27% of treatment-naïve patients and by 59% and 23% of relapsed/refractory patients, respectively. After a median follow-up of 43.7 months, overall survival was 11.2 months in treatment-naïve and 15.6 months in relapsed/refractory patients. Exploratory analysis showed stable CD123+ blast frequency, mutational variant allele frequencies, and monocyte subsets with treatment. Tagraxofusp demonstrated a manageable safety profile with limited clinical efficacy in CMML. This trial was registered at www.ClinicalTrials.gov as #NCT02268253.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100115
  5. Blood Adv. 2025 Sep 08. pii: bloodadvances.2024015427. [Epub ahead of print]
    The lncRNA ELDR suppresses tumorigenicity of AML by interfering with DNA replication and chromatin accessibility.
    Kaifee Arman, Julie Ross, Eva-Maria Piskor, Luca Lazzari, Virginie Calderon, Gaspard Reulet, Maria Vera, Edlie St Hilaire, Hugo Wurtele, Brian T Wilhelm, Tarik Möröy.
      Acute myeloid leukemia (AML) with rearrangement of the mixed lineage leukemia gene express MLL-AF9 fusion protein, a transcription factor that impairs differentiation and drives expansion of leukemic cells. We report here that the zinc finger protein GFI1 together with the histone methyltransferase LSD1 occupies the promoter and regulates expression of the lncRNA ELDR in the MLL-r AML cell line THP-1. Forced ELDR overexpression enhanced the growth inhibition of an LSD1i/ATRA combination treatment and reduced the capacity of these cells to generate leukemia in xenografts, leading to a longer leukemia-free survival. We found that ELDR binds the clamp protein PCNA and the MCM5 helicases causing defects of DNA replication fork progression. Moreover, AML cells overexpressing ELDR showed reduced chromatin accessibility and transcription at α-satellite repeats in centromeres. In addition, ELDR RNA was detected close to MLL-AF9 at centromeres suggesting that it impedes leukemic progression preferentially of MLL-r AML by interfering with both DNA replication and centromeric transcription. Our findings reveal novel functions of the lncRNA ELDR in DNA replication and centromere biology when expressed at high levels in AML cells with MLL rearrangements. These discoveries could provide rationale for future strategies to treat MLL-r AML, which has a poor prognosis in children and adults. Delivery of the ELDR RNA could potentially be utilized as an adjunct to LSD1i/ATRA treatment or other currently used chemotherapeutic drugs to develop novel therapies for these AML subtypes.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015427
  6. Blood Adv. 2025 Sep 08. pii: bloodadvances.2024015762. [Epub ahead of print]
    Critical role of niche S100A8 for acute myeloid leukemia progression and hematopoiesis regeneration.
    Xiaoyan Liu, Jinxian Wu, Xinqi Li, Ruiyang Pan, Li Liu, Tingting Huang, Linlu Ma, Guopeng Chen, Qian Wang, Nan Zhang, Xiqin Tong, Yuxin Tan, Hongqiang Jiang, Yuxing Liang, Min Shen, Ruihang Li, Wanyue Yin, Zhang Xian, Fuling Zhou.
      The role of inflammation in the regulation of acute myeloid leukemia (AML) and stressed hematopoiesis is significant, though the molecular mechanisms are not fully understood. Here, we found that mesenchymal stromal cells (MSCs) had dysregulated expression of the inflammatory cytokine S100A8 in AML. Upregulating S100A8 in MSCs increased the proliferation of AML cells in vitro. In contrast, removing S100A8 from MSCs in the murine MLL-AF9 AML model resulted in longer survival and less infiltration of leukemia cells. S100A8 binds to the TLR4 receptor on leukemia cells, activating the PI3K/Akt pathway. In addition, removing S100A8 from MSCs caused a temporary decline in hematopoietic stem cells (HSCs) number, but facilitated long-term hematopoietic recovery under stress. Furthermore, S100A8 inhibited MSC differentiating into osteoblasts and reduced the expression of osteopontin, which is required to support HSCs. Our findings highlight the importance of niche inflammation in promoting AML development while impeding hematopoietic regeneration.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015762
  7. Semin Hematol. 2025 Aug 14. pii: S0037-1963(25)00034-4. [Epub ahead of print]
    Menin inhibition for the treatment of acute leukemia.
    Daniela V Wenge, Scott A Armstrong.
      Menin inhibitors are emerging as targeted therapies for acute leukemias with high HOXA gene expression. These leukemias harbor mutations including KMT2A-rearrangements, NPM1c mutations, NUP98-fusions, UBTF tandem duplications and potentially others. Mechanistically, each of these oncoproteins depend on the KMT2A:Menin interaction to maintain critical gene expression. Several Menin inhibitors have entered clinical trials and have shown impressive efficacy in heavily pretreated patients with acute myeloid leukemia (AML). Revumenib received FDA approval for patients with relapsed or refractory acute myeloid leukemia with KMT2A-rearrangements in November 2024. Despite the success of Menin inhibitors, leukemia progression due to therapeutic resistance is a common occurrence with monotherapy. Hence, current clinical trials focus on Menin inhibition in combination with chemotherapy and/or standard-of-care targeted therapies to potentially overcome or prevent resistance. Menin inhibitors are also being investigated in patients with newly diagnosed acute leukemia or as a maintenance therapy post allogeneic stem cell transplantation. This review provides an overview of the mechanism of action of Menin inhibitors and the disease subsets that show sensitivity. We explain the current understanding of genetic resistance, mediated by Menin mutations that reduce drug binding affinity, and the emerging understanding of other types of resistance. Ongoing clinical trials are summarized, and we discuss the future role of Menin inhibition as a potentially practice-changing treatment for up to 50% of patients with AML.
    Keywords:  Acute leukemia; Clinical trials; Combination therapy; Drug resistance; Epigenetics; Menin inhibitors
    DOI:  https://doi.org/10.1053/j.seminhematol.2025.08.001
  8. Blood Neoplasia. 2025 Nov;2(4): 100126
    A phase 1 study of IO-202, an anti-LILRB4 antibody, in chronic myelomonocytic leukemia and acute myeloid leukemia.
    Ahmed Aribi, Gabriel N Mannis, Yazan F Madanat, Brian A Jonas, Neil Dunavin, Gail J Roboz, Deepa Jeyakumar, Guillermo Garcia-Manero, Hongtao Liu, Hetty E Carraway, Jennifer N Saultz, William Blum, Gary Schiller, Tao Huang, Paul Woodard, Barbara Klencke, X Charlene Liao, Hong Xiang, Daniel A Pollyea, Courtney D DiNardo.
      IO-202 is a humanized immunoglobulin G1 monoclonal antibody with high affinity and specificity for leukocyte immunoglobulin-like receptor B4 (LILRB4; ILT3), which is predominantly expressed in monocytes and monocytic blasts. IO-202 induces antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vitro and in patients with leukemia. Herein, we present the phase 1a dose escalation data of IO-202 as monotherapy and in combination with azacitidine (AZA) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and R/R chronic myelomonocytic leukemia (CMML), and the phase 1b dose expansion data of IO-202 combined with AZA for the treatment of hypomethylating agent (HMA)-naïve CMML. IO-202 was well tolerated as monotherapy and in combination with AZA. Patients with R/R monocytic AML expressing high LILRB4 on leukemia blasts demonstrated clinical activity, including a complete response (CR) in dose escalation with IO-202 + AZA. In patients with HMA-naïve CMML, IO-202 + AZA led to a 27.8% CR rate and 66.7% overall response rate, based on the 2015 International Working Group response criteria for myelodysplastic/myeloproliferative neoplasms. All 18 efficacy-evaluable patients with HMA-naïve CMML (100%) achieved some form of investigator-assessed clinical benefit, including symptomatic improvement, a decrease in transfusions, reduced blasts and/or monocytes, and resolution of thrombocytopenia. Seven patients (38.9%) proceeded to allogeneic hematopoietic cell transplantation. Translational data suggest that efficacy favors patients with high LILRB4 expression, supporting the mechanism of action of IO-202. Overall, the data support a future pivotal study of IO-202 + AZA in patients with HMA-naïve CMML. This trial was registered at www.clinicaltrials.gov as #NCT04372433.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100126
  9. Hemasphere. 2025 Sep;9(9): e70202
    Outcome of patients with accelerated and blast-phase myeloproliferative neoplasms not eligible for intensive chemotherapy or allogeneic hematopoietic cell transplantation treated by azacitidine alone or in combination-A FIM study.
    Corentin Orvain, Suzanne Tavitian, Clémence Mediavilla, Françoise Boyer, Alberto Santagostino, Geoffroy Venton, Samia Madene, Tony Marchand, Pascal Turlure, Diane Lara, Lenaig Le Clech, Katell Le Du, Jean-Baptiste Robin, Lise Willems, Anaïse Blouet, Thomas Systchenko, Mathieu Wemeau, Hélène Pasquer, Mélanie Mercier, Christophe Nicol, Laurence Legros, Antoine Machet, Franck-Emmanuel Nicolini, Lydia Roy, Clémentine Salvado, Guillaume Denis, Elsa Lestang, Kamel Laribi, Damien Luque Paz, Jean-Jacques Kiladjian, Eric Lippert, Lina Benajiba, Jean-Christophe Ianotto.
      Accelerated-phase (AP) or blast-phase (BP) myeloproliferative neoplasms (MPNs) are associated with dismal prognosis, with non-curative therapies such as hypomethylating agents (HMAs) considered in patients not eligible for intensive therapy, while some studies advocate for combination therapy with either ruxolitinib (RUXO) or venetoclax (VEN). To assess the relationship between treatment modalities and outcome, herein, we report a multicentric cohort of 149 patients (median age, 75 years) with AP/BP MPN not eligible for intensive therapy and/or allogeneic hematopoietic cell transplantation who received azacitidine (AZA) alone (n = 60) or in combination (n = 89; VEN [n = 51], RUXO [n = 27], or both [n = 9], isocitrate dehydrogenase inhibitors [n = 2]) between January 2019 and October 2023. With a median follow-up of 15 months, the median overall survival of the full cohort was 8.04 months, with a 3-year overall survival (OS) of 13%. Among disease characteristics, OS was lower in patients with BP (6.24 vs. 18.00 months in patients with AP disease, P = 0.03), complex karyotype (6.00 vs. 13.08 months, P = 0.005), and TP53 mutations (8.04 vs. 11.04 months, P = 0.009). OS was nonsignificantly higher in patients receiving AZA combinations (10.08 vs. 6.96 months in patients receiving AZA monotherapy, P = 0.12). When analyzing AZA combinations separately, patients who were treated with AZA-RUXO had higher OS (18.00 vs. 9.00 vs. 10.08 months in patients receiving AZA-VEN and AZA-VEN-RUXO, P = 0.015). The improved survival with AZA-RUXO in the absence of complex karyotype and/or TP53 mutations warrants further prospective validation. New therapeutic options are urgently needed, especially in patients with complex karyotype and/or TP53 mutations.
    DOI:  https://doi.org/10.1002/hem3.70202
  10. Leukemia. 2025 Sep 11.
    Acute myeloid leukaemia cells express high levels of androgen receptor but do not depend on androgen signaling for survival.
    Farideh Miraki-Moud, Linda Ariza-McNaughton, Thinzar KoKo, Jad Othman, Randal Stronge, Johann de Bono, Nigel Russell, Ian Thomas, Amanda Gilkes, Alan Burnett, Leandro Rodrigues Santiago, Fay Cafferty, Leo Taussig, Allan Thornhill, Simon O'Connor, Dominique Bonnet, David C Taussig.
      Male sex is associated with worse outcome in acute myeloid leukemia (AML) in many studies. We analyzed the survival of 4281 patients treated with intensive chemotherapy in the AML17 and AML19 trials based on sex. Men had a significantly lower remission rate than women. Men had a higher incidence of adverse cytogenetic features and a lower incidence of the relatively favorable NPM1 mutation. However, male sex was an independent risk factor for survival in multi-variate analysis. We hypothesized that androgen signaling in men could worsen outcomes by protecting AML cells from chemotherapy. We demonstrated high levels of androgen receptor (AR) expression in AML across cytogenetic risk groups. We showed the AR expression was induced by IL-6 signaling in vitro and correlates with poor overall survival. Androgens had no effect on survival of primary AML cells in vitro, nor did they impact gene expression. Androgens did not protect AML cells against chemotherapy either in vitro or in vivo. Similar results were observed with estrogen signaling through estrogen receptor in vitro in AML cells. In conclusion, targeting the androgen pathway may not be a promising clinical strategy and sex hormone signaling in AML cells does not explain the poorer outcomes of men.
    DOI:  https://doi.org/10.1038/s41375-025-02752-x
  11. Blood Adv. 2025 Sep 09. pii: bloodadvances.2025017084. [Epub ahead of print]
    Allogeneic hematopoietic stem cell transplantation in germline DDX41 mutated patients with myeloid malignancies.
    Michael Loschi, Marie-Charlotte Villy, Jacques-Emmanuel Galimard, Marie-Mathilde Auboiroux, Nathalie Gachard, Alexandre Perani, Matthieu Duchmann, Laetitia Largeaud, Stephanie Nguyen, Flore Sicre de Fontbrune, Marie Robin, Ibrahim Yakoub-Agha, Etienne Daguindau, Sylvain P Chantepie, Amandine Charbonnier, Delphine Lebon, Sebastien Maury, Helene Labussiere-Wallet, Anne Huynh, Edouard Forcade, Cristina Castilla-Llorente, Thomas Cluzeau, Lionel Adès, Maud D'Aveni, Raynier Devillier, Natacha Maillard, Sami Benachour, Hervé Dombret, Christian Récher, Arnaud Pigneux, Emmanuelle Clappier, Eric Delabesse, Nicolas Duployez, Pascal Turlure, Régis Peffault De Latour, Marie Sebert.
      Germline DDX41 mutations (DDX41mut) are identified in approximately 5% of myeloid malignancies with excess of blasts, representing a distinct MDS/AML entity. The disease is associated with better outcomes compared to DDX41 wild-type (DDX41WT), but patients who do not undergo allogeneic hematopoietic stem cell transplantation (HSCT) may experience late relapse. Due to the recent identification of DDX41mut, data on post-HSCT outcomes remain limited. Here, we first report the HSCT outcomes of 83 DDX41mut MDS/AML patients. With a median follow-up (FU) of 4.4 years, the 2-year leukemia-free survival (LFS) was 68.6% (95% CI, 57.1 - 77.6), with a 2-year non-relapse mortality (NRM) of 21.1% (95% CI, 12.9 - 30.6). We then assessed the impact of DDX41mut using a pair match analysis performed on patients who underwent transplantation in AML clinical trials. No significant differences were observed between DDX41mut and DDX41WT patients in terms of LFS at 2 years (HR: 1.06, 95% CI, 0.59-1.90, p=0.84), overall survival (OS), NRM, relapse, or graft-versus-host disease (GVHD) incidence. The CIR for DDX41mut showed a trend toward a lower relapse rate during the first year and a higher relapse rate after 1 year. Given the familial nature of the disease, we specifically examined patients who relapsed after HSCT with a related donor, identifying 7 cases of DDX41mut donor cell leukemia (DCL). In our study, HSCT in DDX41mut AML patients was not associated with an increased risk of toxicity. However, we observed a potential for later relapse, which could potentially be mitigated by selecting related donors based on DDX41 status.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017084
  12. Leukemia. 2025 Sep 10.
    PML::RARα+ myeloid cells display metabolic alterations that can be targeted to treat resistant/relapse acute promyelocytic leukemias.
    Alessandra Zaza, Giuseppe Zardo, Cristina Banella, Sara Tucci, Elisabetta de Marinis, Martina Gentile, Serena Travaglini, Mariadomenica Divona, Tiziana Ottone, Germana Castelli, Anna Maria Cerio, Daniela F Angelini, Isabella Faraoni, Raffaele Palmieri, Paquale Niscola, Emanuele Ammatuna, Adriano Venditti, Clara Nervi, Maria Teresa Voso, Gianfranco Catalano, Nelida Ines Noguera.
      At present there is no metabolic characterization of acute promyelocytic leukemia (APL). Pathognomonic of APL, PML::RARα fusion protein rewires metabolic pathways to feed anabolic tumor cell's growth. All-trans retinoic acid (ATRA) and arsenic trioxide (ATO)-based therapies render APL the most curable subtype of AML, yet approximately 1% of cases are resistant and 5% relapse. We characterized the metabolic peculiarity and fuel requirement of PML::RARα expressing cells, to identify new targets for tailored therapies in resistant or relapsed APL patients. We analyzed cell metabolism in primary samples from seven APL patients, comparing them with normal CD34+ cells differentiated to promyelocyte and granulocyte, and different PML::RARα expressing cell lines. We show that the PML::RARα oncoprotein inhibits glycolysis, promotes tricarboxylic acid cycle (TCA), and favors long chain fatty acids (LCFA) catabolism. Targeting CD36 function, that promotes the cellular uptake of fatty acids to feed oxidative phosphorylation (OXPHOS), effectively restores sensitivity to ATO in NB4 ATO-resistant clones. Notably, our data demonstrate that glycolytic impairment via AKT inhibition by PML::RARα renders APL cells reliant on OXPHOS. This dependency confers high sensitivity to the VTX-AZA combination, suggesting the therapeutic efficacy of targeted combination treatment in resistant or relapsed APLs.
    DOI:  https://doi.org/10.1038/s41375-025-02738-9
  13. Hematol Oncol Stem Cell Ther. 2025 Sep 12.
    Myeloablative and Reduced Intensity Allogeneic Transplant in Patients with Myeloproliferative Neoplasms.
    Andrew D Trunk, Yanwen Chen, Aaron T Gerds, Akriti Jain, Sudipto Mukherjee, Sophia Balderman, Hetty Carraway, Betty K Hamilton, Ronald Sobecks, Matt Kalaycio, Craig Sauter, Claudio Brunstein.
       BACKGROUND: Allogeneic hematopoietic cell transplant (allo-HCT) is the only potentially curative treatment for myelofibrosis (MF) and chronic myelomonocytic leukemia (CMML). Older age, comorbidities, and often advanced disease make patient selection and optimal transplant timing challenging. This study sought to understand allo-HCT outcomes for these myeloproliferative neoplasms in a contemporary era, including molecular data, to define a uniform transplant approach.
    METHODS: Retrospective analysis was performed on patients with MF or CMML who received allo-HCT at the Cleveland Clinic between January 1, 2010 and April 1, 2023. All donor types and graft sources were included. MF and CMML outcomes were analyzed separately.
    RESULTS: Fifty-nine MF and 33 CMML patients were included. JAK2 V617F was detected in 57.6% of MF patients; only 34 (57.6%) had next-generation sequencing (NGS) performed. Most MF transplants were reduced intensity (RIC; 69.5%) and peripheral blood stem cell (PBSC; 91%). At median follow-up of 41 months, 28/59 (47.5%) MF patients were alive. MF patients who were JAK2+ with additional cytogenetic changes or concurrent mutations had better overall survival. In CMML, 69.7% had myeloid NGS, with ASXL1 identified in 51.9% of cases. Most transplants were RIC (66.7%) and PBSC (72.7%). At median follow-up of 46.8 mos, 13/33 (39.4%) patients were alive. Relapse accounted for 9/20 CMML deaths; 8 of these received RIC. Mutational signature did not significantly impact survival, though the presence of any cytogenetic aberrancy was associated with worse OS (12 mos, 95% CI, 7.13-NA vs. 24.2 mos, 9.6-NA; P = 0.19).
    CONCLUSION: For MF and CMML, older patients (≥65) and RIC transplants trended toward worse survival. Strategies to reduce relapse and optimize patient selection utilizing molecular and cytogenetic data should be considered.
    Keywords:  Allogeneic hematopoietic cell transplant; chronic myelomonocytic leukemia; intensity; myelofibrosis; myeloproliferative neoplasm
    DOI:  https://doi.org/10.4103/hemoncstem.HEMONCSTEM-D-25-00008
  14. Blood Neoplasia. 2025 Nov;2(4): 100123
    V-FAST: a phase 1b master trial to investigate CPX-351 combined with targeted agents in adults with newly diagnosed AML.
    Vinod A Pullarkat, Mark Levis, James McCloskey, Gabriel N Mannis, Stephen A Strickland, Amir T Fathi, Tara L Lin, Vijaya R Bhatt, Thuva Vanniyasingam, Divya Chakravarthy, Yana Lutska, Stefan Faderl, Ronald S Cheung, Harry P Erba.
      Preclinical data suggest CPX-351, approved for patients with newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes, may exhibit synergy with targeted agents, suggesting a rationale for combining targeted agents with CPX-351 as a chemotherapy backbone. The V-FAST (Vyxeos - First Phase ASsessment With Targeted Agents) phase 1b trial evaluated CPX-351 with the targeted agents venetoclax (arm A), midostaurin (arm B), and enasidenib (arm C) in adults with newly diagnosed AML fit for intensive chemotherapy. The dose exploration phase used a 3+3 design to determine the recommended phase 2 dose (RP2D) for each combination. The expansion phase enrolled additional patients to confirm the RP2D. Primary end points were the RP2D and safety. Secondary end points included initial efficacy assessments. Overall, 57 patients were enrolled (arm A, n = 27; arm B, n = 23; arm C, n = 7). In arms A and B, the RP2D was established: CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) plus venetoclax 400 mg or midostaurin 50 mg, respectively. Arm C was stopped early by the sponsor (not due to safety concerns), and the RP2D was not determined. The safety profiles of the combinations were consistent with those known for CPX-351, venetoclax, and midostaurin alone; the most common adverse events were hematologic and gastrointestinal. The best response (complete remission [CR]/CR with incomplete/partial hematologic recovery) was 44% (12/27 patients) and 86% (19/22 patients) in arms A and B, respectively. Although few patients received CPX-351 with enasidenib, these results suggest that CPX-351 may be safely combined with venetoclax or midostaurin. This trial was registered at www.clinicaltrials.gov as #NCT04075747.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100123
  15. Clin Lymphoma Myeloma Leuk. 2025 Aug 17. pii: S2152-2650(25)00288-5. [Epub ahead of print]
    Impact of Measurable Residual Disease Status on Outcomes After HLA-Matched Donor Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia.
    Moazzam Shahzad, Muhammad Kashif Amin, Sohaib Irfan, Abhinav Vyas, Rania Ahsan, Sibgha Gull Chaudhary, Iqra Anwar, Matthew McGuirk, Raheel Iftikhar, Haitham Abdelhakim, Anurag K Singh, Mehdi Hamadani, Joseph P Mcguirk, Muhammad Umair Mushtaq.
       BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a key treatment for acute myeloid leukemia (AML). Measurable residual disease (MRD) predicts post-transplant outcomes. This study evaluates the impact of pretransplant MRD status on outcomes in AML patients undergoing allo-HCT.
    METHODS: We retrospectively analyzed AML patients who underwent allo-HCT from matched related or unrelated donors (2013-2018) using the CIBMTR P-5646 dataset. Patients were stratified by pretransplant MRD status. Outcomes included overall survival (OS), disease-free survival (DFS), relapse, nonrelapse mortality (NRM), acute graft-versus-host disease (aGVHD), GVHD-free relapse-free survival (GRFS), and engraftment. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using multivariate Cox regression, adjusted for significant univariate variables (P < .05).
    RESULTS: Of 2404 AML patients (354 MRD-positive, 2050 MRD-negative), MRD-positive patients had a lower Karnofsky performance status (≥90%: 46.1% vs. 55.1%, P = .004) and were more likely to undergo myeloablative conditioning (66.6% vs. 52.7%, P < .001). MRD positivity predicted worse OS (HR 1.91, 95% CI 1.62-2.23, P < .001), DFS (HR 2.05, 95% CI 1.77-2.36, P < .001), relapse (HR 2.25, 95% CI 1.91-2.64, P < .001), aGVHD grade II to IV (HR 1.24, 95% CI 1.03-1.50, P = .024), GRFS (HR 1.59, 95% CI 1.41-1.81, P < .001), and slower platelet engraftment (HR 0.71, 95% CI 0.63-0.81, P < .001). NRM (P = .387) and neutrophil engraftment (P = .159) were similar.
    CONCLUSION: Pretransplant MRD status predicts post-allo-HCT outcomes, with MRD positivity associated with reduced overall and disease-free survival and increased relapse risk. Personalized MRD-directed strategies are needed to optimize outcomes in AML patients undergoing allogeneic transplantation.
    Keywords:  Acute Myeloid Leukemia; Allo-HCT; Allogeneic hematopoietic stem cell transplant; Minimal residual disease; Pretransplant MRD
    DOI:  https://doi.org/10.1016/j.clml.2025.08.011
  16. Am J Hematol. 2025 Sep 09.
    CHEK2 Germline Variants in Early-Onset and Familial Myeloproliferative Neoplasms.
    Oscar Borsani, Elisabetta Molteni, Daniela Pietra, Anna Gallì, Virginia Valeria Ferretti, Silvia Catricalà, Ettore Rizzo, Luca Malcovati, Elisa Rumi.
      Of 313 patients with early-onset or familial MPN, 7 (2.2%) patients had pathogenic/likely pathogenic (P/LP) germline heterozygous loss of function mutations in CHEK2. The presence of CHEK2 variants was associated with a familial history of malignancies and a higher risk of leukemic evolution, reinforcing the hypothesis of CHEK2 variants as tumor predisposing risk allele.
    Keywords:   CHEK2 ; germline; myeloproliferative; predisposition
    DOI:  https://doi.org/10.1002/ajh.70072
  17. Br J Haematol. 2025 Sep 09.
    UK recommendations for chimerism testing and monitoring following allogeneic haematopoietic stem cell transplantation (HSCT): Best practice consensus guidelines from the British Society for Blood and Marrow Transplant and Cellular Therapies (BSBMTCT), NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group, UK Cancer Genetics Group (UKCGG) and the UK National External Quality Assessment Service for Leucocyte Immunophenotyping (UK NEQAS LI).
    Andrew Clark, Hazel Clouston, Kanchan Rao, Najeem Folarin, Josu De la Fuente, Angela Hamblin, Eduardo Olavarria, Debbie Richardson, Polly Talley, Victoria Potter, Justin Loke, Terri McVeigh, John Snowden.
      In allogeneic haematopoietic stem cell transplantation (HSCT), important clinical decisions depend upon assessment of chimerism, including immunosuppressant dosing and donor lymphocyte infusions (DLI), which in turn can have major impacts on disease control, graft-versus-host disease (GVHD), immunity and ultimately patient survival. There is a complex range of clinical and laboratory procedural considerations including methodology of testing, types of cell subset selection, frequency of testing, urgency of turnaround times (TATs), interplay with measurable residual disease (MRD) monitoring and duration of testing post-transplant. These aspects are routinely adapted according to disease indication, patient characteristics, donor source and intensity of transplant technique. To encourage the harmonisation of clinical and laboratory practice in the United Kingdom, we held a national workshop meeting to bring together key stakeholders to review the current literature with a view to producing a state-of-the-art position paper. Here, we present best practice consensus recommendations and identify key areas for future audit and research from the UK Cancer Genetics Group (UKCGG), NHS England Genomic Laboratory Hub (GLH) Haematological Oncology Malignancies Working Group, UK National External Quality Assessment Service for Leucocyte Immunophenotyping (UK NEQAS LI) and the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT).
    Keywords:  BMT; DLI; PBSCT; allogeneic stem cell transplant; chimerism
    DOI:  https://doi.org/10.1111/bjh.70061
  18. Bone Marrow Transplant. 2025 Sep 11.
    Improved GVHD-free relapse-free survival when rATG/ATLG is used in allo-HCT from matched sibling donors - an EBMT registry study by the Transplant Complications Working Party.
    Agnieszka Piekarska, Mouad Abouqateb, William Boreland, Christophe Peczynski, Jan Maciej Zaucha, Nicolaus Kröger, Robert Zeiser, Fabio Ciceri, Thomas Schroeder, Thomas Luft, Jakob Passweg, Desiree Kunadt, Matthias Stelljes, Igor Wolfgang Blau, Uwe Platzbecker, Ibrahim Yakoub-Agha, Didier Blaise, Anna Maria Raiola, Johanna Tischer, Eva Maria Wagner-Drouet, Julia Winkler, Christoph Schmid, Gerald Wulf, Matthias Edinger, Johan Maertens, Friedrich Stölzel, Jan Vydra, Pavel Zak, Ivan Moiseev, Hélène Schoemans, Olaf Penack, Zinaida Peric.
      The EBMT recommends rabbit anti-thymocyte or anti-T-lymphocyte globulin (rATG/ATLG) as GVHD prophylaxis in matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). However, discrepancies between recommendations and clinical practice were reflected in the EBMT survey. Therefore, we performed retrospective EBMT registry analysis from 2014 to 2021 to reinforce the real-world evidence context of rATG/ATLG impact on post-transplantation outcomes. This study included 11,420 adult patients (non-ATG n = 7680 and ATG n = 3740) with hematological malignancies after the first allo-HCT from peripheral blood. Use of ATG was associated with a reduced risk of aGVHD II-IV (Day +100: non-ATG vs ATG, 27.6% vs. 21.6%; adjusted HR 0.7, p < 0.001) and cGVHD (2-year: non-ATG vs ATG, 48.9% vs 30%; adjusted HR 0.45, p < 0.001), improved OS (2-year: 62.9% vs 63.3%; adjusted HR 0.89, p = 0.009), reduced NRM (2-year: 16% vs 12.5%; adjusted HR 0.63, p < 0.001), and higher GRFS (2-year: 32.2% vs 40.7%; adjusted HR 0.72, p < 0.001). While RI was higher in the ATG group (2-year: non-ATG vs ATG, 30.2% vs 34.7%; adjusted HR 1.22, p < 0.001) it did not translate into a significantly lower PFS (2-year: 53.9% vs 52.8%; adjusted HR not significant). Overall, outcomes were favorable for the intermediate rATG/ATLG dose ranges compared to the low and high dose ranges. Administration of rATG/ATLG improved outcomes in MSD allo-HCT recipients, supporting the EBMT recommendation for its use.
    DOI:  https://doi.org/10.1038/s41409-025-02692-1
  19. Mol Ther. 2025 Sep 05. pii: S1525-0016(25)00716-6. [Epub ahead of print]
    Targeting O-GlcNAcylated METTL3 impedes MDS/AML progression via diminishing SRSF1 m6A modification.
    Junjie Gou, Yi Wang, Jingjing Feng, Kaijing Chang, Kexin Wang, Jingjing Bi, Junqi Ge, Chongfu Zhao, Songdi Wu, Zengqi Tan, Feng Guan, Xiang Li.
      N6-methyladenosine (m6A) modification, primarily regulated by methyltransferase-like protein 3 (METTL3), plays a pivotal role in RNA metabolism and leukemogenesis. However, the post-translational mechanisms governing METTL3 stability and function remain incompletely understood. Given the widespread occurrence of O-GlcNAcylation on nuclear and cytosolic proteins, we hypothesized that METTL3 might undergo O-GlcNAcylation, thereby influencing its stability and oncogenic function in myeloid malignancies. In this study, we found that METTL3 is O-GlcNAcylated in both myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) , and its expression positively correlates with O-GlcNAcylation levels. Functional assays demonstrated that O-GlcNAcylation enhances METTL3 protein stability and promotes leukemic cell survival. Mechanistically, O-GlcNAcylated METTL3 stabilizes mRNA of serine and arginine-rich splicing factor 1 (SRSF1), leading to increased expression of the anti-apoptotic protein MCL-1. This, in turn, suppresses apoptosis and supports MDS/AML cell viability. Targeting the O-GlcNAcylated form of METTL3 using a competitive peptide significantly inhibited MDS/AML progression in preclinical models. In conclusion, our findings reveal a novel O-GlcNAcylation-dependent mechanism that regulates METTL3 stability and oncogenic activity through the m6A-SRSF1-MCL1 axis, highlighting a potential therapeutic strategy for MDS and AML.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.08.042
  20. Elife. 2025 Sep 11. pii: RP102324. [Epub ahead of print]14
    Dissecting infant leukemia developmental origins with a hemogenic gastruloid model.
    Denise Ragusa, Chun Wai Suen, Gabriel Torregrosa Cortes, Fabio Pastorino, Ayona Johns, Ylenia Cicirò, Liza Dijkhuis, Susanne van den Brink, Michele Cilli, Connor Byrne, Giulia-Andreea Ionescu, Joana Cerveira, Kamil R Kranc, Victor Hernandez-Hernandez, Mirco Ponzoni, Anna Bigas, Jordi Garcia-Ojalvo, Alfonso Martínez Arias, Cristina Pina.
      Current in vitro models of developmental blood formation lack spatio-temporal accuracy and weakly replicate successive waves of hematopoiesis. Herein, we describe a mouse embryonic stem cell (SC)-derived 3D hemogenic gastruloid (haemGx) that captures multi-wave blood formation, progenitor specification from hemogenic endothelium (HE), and generates hematopoietic progenitors capable of short-term engraftment of immunodeficient mice upon maturation in an in vivo niche. We took advantage of the haemGx model to interrogate the origins of infant acute myeloid leukemia (infAML). We focused on MNX1-driven leukemia, representing the commonest genetic abnormality unique to the infant group. Enforced MNX1 expression in haemGx promotes the expansion and in vitro transformation of yolk sac-like erythroid-myeloid progenitors at the HE-to-hematopoietic transition to faithfully recapitulate patient transcriptional signatures. By combining phenotypic, functional, and transcriptional profiling, including at the single-cell level, we establish the haemGx as a useful new model for the study of normal and leukemic embryonic hematopoiesis.
    Keywords:  cancer biology; development; developmental biology; gastruloid; hematopoiesis; leukemia; mouse
    DOI:  https://doi.org/10.7554/eLife.102324
  21. Exp Hematol. 2025 Sep 06. pii: S0301-472X(25)00536-3. [Epub ahead of print] 105247
    KMT2A-rearranged leukemia: from mechanism to drug development.
    Patricia Ernst, Perpetual Kyei, Akihiko Yokoyama.
      Gene rearrangements of the human MLL gene (also known as KMT2A) generate multiple fusion oncoproteins which cause leukemia with poor prognosis. MLL is an epigenetic regulator that reads and writes epigenetic information and has an evolutionarily conserved role maintaining expression of Homeotic (HOX) genes during embryonic development. Most MLL gene rearrangements found in leukemia generate a constitutively active version of the wild-type protein, which causes overexpression of HOX and other genes and leukemic transformation of normal hematopoietic progenitors. Elucidating the molecular mechanisms underlying how MLL activates gene expression and how gene rearrangements affect this gene-regulating activity provided therapeutic opportunities to block fusion oncoprotein-specific activities. One uniform molecular dependency of MLL fusion oncoproteins is its interaction with the chromatin-binding partner MENIN that is essential to maintain leukemic transformation. MENIN inhibitors that interfere with the MLL-MENIN interaction have been developed and are now entering clinical practice. Also, the MLL complex physically interacts with several histone acetyl transferases (HATs), including MOZ/MORF, HBO1, and EP300/CREBBP to effect MLL-MENIN-dependent gene activation. Aberrant recruitment of these HATs and other transcriptional effector complexes are key differences between MLL and MLL fusion oncoproteins. In this review, we first summarize our current understanding of wild-type MLL function and aberrant function of its oncogenic variants. We then discuss in detail how chromosomal translocations generate constitutive active forms of MLL and categorize them into five major classes. We touch on the collaborative gene activation by MLL and specific interacting HATs. Lastly, we discuss how these mechanistic insights have led to the development of the first-in-class MENIN inhibitors and discuss efforts to anticipate and treat both genetic and non-genetic mechanisms of resistance. Teaser abstract: MLL fusion oncoproteins often transform cells in particular developmental states without the need for additional mutations. Insights gained studying how this occurs has yielded a wealth of mechanistic and biological insights. Here we review some of the detailed molecular mechanisms leading to leukemia development as well as how understanding these mechanisms resulted in the development of targeted therapies, and ongoing efforts to anticipate and prevent resistance to targeted therapies.
    Keywords:  KMT2A; Leukemia; MENIN; MLL; protein-interaction inhibitors
    DOI:  https://doi.org/10.1016/j.exphem.2025.105247
  22. Cell Signal. 2025 Sep 06. pii: S0898-6568(25)00527-3. [Epub ahead of print]136 112112
    An inhibitor of UHM splicing factors exerts anti-leukemic activity by altering cell cycle progression and reducing lysosome acidification.
    Mona Kazemi Sabzvar, Eun Bee Cho, Xinrui Yuan, Arda Durmaz, Amol D Patil, Daniel M Collier, Jianxiong Jiang, Valeria Visconte, Chao-Yie Yang.
      Mature mRNAs are generated by spliceosomes that recruit factors to aid RNA splicing in which introns are removed and exons joined. Among the splicing factors, a family of proteins contain a homologous U2 Auxiliary Factor (U2AF) Homology Motif (UHM) to bind with factors containing U2AF ligand motifs (ULM) and recruit them to regulate 3' splice site selection. Mutations and overexpression of UHM splicing factors are frequently found in cancers. Although a few UHM inhibitors have been reported, their activities in cancer cells were not investigated. Here, we studied our recently discovered UHM inhibitor, SF-153, that targeted RBM39 and SPF45, and found SF-153 exerted anti-tumor activities in three leukemia cell lines. In the cell cycle and apoptosis analysis, SF-153 induces p53 mediated DNA damage response to give protracted S phase in NKM-1 but p53-independent G1 arrest in p53nullK562 cells. RNA-seq analysis of NKM-1 treated with SF-153 revealed downregulation of Myc target genes and genes involved in nucleotides and protein synthesis. Western blot analysis confirmed decreased proteins levels of Myc, EEF1A1, and MCM7 suggesting reduced DNA replication activity in NKM-1. Transcript analysis derived from the RNA-seq data indicated six genes changed isoform patterns but downregulation of only one DOCK2 isoform was confirmed in qRT-PCR. RNA-seq analysis additionally uncovered that SF-153 impaired lysosome acidification and inhibited autophagy to enhance the anti-leukemic activities. Taken together, our study characterized the multimodal mechanisms of inhibition by SF-153 in leukemia cells and laid the foundation for studying selective UHM inhibitors in future.
    Keywords:  Cell cycle; Dual inverted selective plane of illumination microscope; Lysosome acidification; Small-molecule inhibitors; Splicing factor; U2AF homology motif
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112112
  23. Blood Neoplasia. 2025 Nov;2(4): 100122
    Targeting scavenger receptor class B type 1 with a bioinspired ligand induces apoptosis or ferroptosis in AML.
    Adam Y Lin, Jonathan S Rink, Eva Yang, Sara Small, Jessica J Gerber, Taylor J Zak, Jessica Altman, Yasmin Abaza, Leonidas C Platanias, Leo I Gordon, C Shad Thaxton.
      Despite progress in research and treatment strategies for acute myeloid leukemia (AML), the prognosis for patients with AML, particularly for individuals aged >60 years and those with adverse risk factors, remains poor. Cellular receptors that affect cholesterol homeostasis may present a new target for treating AML. Scavenger receptor class B type 1 (SR-B1), which plays an important role in cellular cholesterol uptake and redox balance, is expressed by AML cells and correlates with poor patient outcomes. Previously, we targeted SR-B1 in various hematologic and solid malignancies with a synthetic bioinspired high-density lipoprotein nanoparticle (HDL NP) ligand that disrupted cholesterol metabolism, inhibited protective antioxidant mechanisms, and induced ferroptosis. This study demonstrates that HDL NPs are effective at low nanomolar drug concentrations in AML, surpassing the effectiveness of cytarabine, a standard-of-care chemotherapy agent. The HDL NP reduced glutathione peroxidase 4, leading to reactive oxygen species accumulation, which causes some AML cells to undergo ferroptosis while others undergo apoptosis and pyroptosis. HDL NP treatment was synergistic with standard AML therapies, including cytarabine, venetoclax, and gilteritinib for fms-like tyrosine kinase 3-mutated leukemia cells. Notably, HDL NP treatment induced the differentiation of AML cells into mature granulocytes. Overall, this study provides a foundation for further investigations into the underlying mechanisms and clinical applications of SR-B1 targeting in AML treatment.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100122
  24. Leukemia. 2025 Sep 10.
    Longitudinal single-cell analysis reveals treatment-resistant stem and mast cells with potential treatments for pediatric AML.
    Denis Ohlstrom, Mojtaba Bakhtiari, Hope Mumme, Marina Michaud, Alejandro De Janon Gutierrez, Deborah DeRyckere, Katherine E Ferguson, Frank Chien, William Pilcher, Sarthak Satpathy, Sean Jordan, Douglas Graham, Swati Bhasin, Manoj Bhasin.
      Pediatric acute myeloid leukemia (pAML) is a heterogeneous malignancy driven by diverse cytogenetic mutations. While identification of cytogenetic lesions improved risk stratification, prognostication remains inadequate with 30% of standard-risk patients experiencing relapse within 5 years. To deeply characterize pAML heterogeneity and identify poor outcome-associated blast cell profiles, we performed an analysis on 708,285 cells from 164 bone marrow biopsies of 95 patients and 11 healthy controls. The longitudinal analysis on cell abundances at the time of disease diagnosis, end of induction, and relapse identified treatment resistant stem-like blast cells specific to RUNX1::RUNX1T1, FLT3-ITD, and CBFB::MYH11 patients that are associated with poor outcomes. Treatment resistant blast cells from RUNX1::RUNX1T1 were found to associate with T cell exhaustion, while those from FLT-ITD utilized enriched antioxidant metabolism to persist through treatment. Interestingly, the analysis also identified novel mast cell-like pAML associated with treatment resistance and poor outcomes. Deconvolution of ex vivo treatment data and subsequent in vitro validation identified bortezomib (RUNX1), ponatinib, and venetoclax (FLT3) as specifically potent against treatment resistant blasts from the respective cytogenetic groups. Our findings indicate immature and mature pAML subtypes are promising biomarkers for enhanced patient risk stratification and identifies targeted agents to increase their clearance after treatment.
    DOI:  https://doi.org/10.1038/s41375-025-02748-7
  25. Blood Adv. 2025 Sep 12. pii: bloodadvances.2025017375. [Epub ahead of print]
    Induction of Moderate DNA Damage Enhances Megakaryopoiesis and Platelet Production.
    Virginia Camacho, Roelof Bekendam, Andrew P Stone, Maria N Barrachina, Siobhan Branfield, Estelle Carminita, Isabelle C Becker, Dong H Lee, Ethan Walsey, Clementine Payne, Jakub Piotr Kaplan, Julia Tilburg, Sharmistha Pal, Luis Francisco Zirnberger Batista, Joseph E Italiano, Kellie R Machlus.
      Megakaryocytes (MKs) are large, hematopoietic cells with a polyploid, multi-lobulated nucleus. While DNA replication in MKs (endomitosis) is well studied, limited investigations have examined the impact of DNA instability on megakaryopoiesis. Poly-ADP ribose polymerase (PARP) inhibitors are chemotherapeutics that result in accumulation of DNA damage and are commonly associated with thrombocytopenia, presumably mediated through platelet progenitors, MKs. To explore PARP inhibitor-induced thrombocytopenia, we treated mice with the PARP inhibitor Niraparib. While high dose Niraparib treatment led to thrombocytopenia, consistent with clinical observations, lower dosage treatment led to a significant increase in bone marrow MKs, MK progenitors, and circulating platelets. This increase was accompanied by elevated DNA damage in both MKs and MK progenitors, as measured by gH2AX accumulation and comet assays. Notably, platelets from Niraparib-treated mice were functionally normal in their response to ADP, TRAP, and collagen. Treatment of mice with low-dose gamma-irradiation similarly led to DNA damage in MKs and resulted in increased MK and platelet counts, suggesting that moderate DNA damage is a common mechanism that enhances megakaryopoiesis and platelet counts. These data reveal a previously unknown relationship between MKs and DNA damage and present a novel target for triggering enhanced platelet production in vivo.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017375
  26. Ann Hematol. 2025 Sep 12.
    An unconquered challenge in MDS: review of pathophysiology, clinical manifestations, and management options of MDS with thrombocytopenia.
    Xiaoyi Chen, Mihir Shukla, Jun H Choi.
      Myelodysplastic syndromes (MDS) is a heterogeneous group of myeloid clonal disorder resulting in bone marrow failure with a tendency to acute myeloid leukemia transformation. MDS is characterized by a variable degree of clonal cytopenia. Compared to anemia, thrombocytopenia is less common but presents more significant challenges due to high risk of acute complications and dearth effective treatment options. Platelet transfusions are effective in increasing platelet counts but provide limited and transient benefits, along with associated risks of transfusions. Anti-fibrinolytic drugs have been attempted including in clinical trial settings but its efficacy remains unproven. Successful development of thrombopoietin agonists appeared promising especially in other conditions associated with thrombocytopenia but its utility in MDS has been controversial. Two of the novel thrombopoietin receptor agonists (TPO-RA), romiplostim and eltrombopag have established clinical activity in immune thrombocytopenic purpura (ITP) and have been explored for the treatment of thrombocytopenia in MDS. Due to early research data showing TPO-RA leading to a small increase in blast counts and possibly promoting leukemic transformation, subsequent clinical trials sought to establish its safety and efficacy in MDS. Despite considerable amount of evidence demonstrating favorable safety profiles in lower risk MDS, many hematologists are often hesitant to use TPO-RA to treat thrombocytopenia in MDS due to theoretical concern of stimulating blasts. In higher risk MDS the safety is not proven and certainly requires more investigation. In this review, we aim to highlight pathophysiology of thrombocytopenia in MDS and provide comprehensive management strategies supported by past and current clinical research data.
    Keywords:  Eltrombopag; Myelodysplastic syndrome; Romiplostim; Thrombocytopenia; Thrombopoietin
    DOI:  https://doi.org/10.1007/s00277-025-06374-2
  27. Sci Adv. 2025 Sep 12. 11(37): eadt3873
    Somatic mtDNA mutations at intermediate levels of heteroplasmy are a source of functional heterogeneity among primary leukemic cells.
    Kelly McCastlain, Catherine Welsh, Yonghui Ni, Liang Ding, Ti-Cheng Chang, Robert J Autry, Besian I Sejdiu, Qingfei Pan, Melissa Franco, Wenan Chen, Huiyun Wu, Veronica Gonzalez-Pena, Patrick Schreiner, Sasi Arunachalam, Joung Hyuck Joo, Samuel Brady, Jinghui Zhang, Charles Gawad, William E Evans, M Madan Babu, Konstantin Khrapko, Jiyang Yu, Gang Wu, Stanley Pounds, Mondira Kundu.
      Somatic mitochondrial DNA (mtDNA) mutations are frequently observed in tumors, yet their role in pediatric cancers remains poorly understood. The heteroplasmic nature of mtDNA-where mutant and wild-type mtDNA coexist-complicates efforts to define its contribution to disease progression. In this study, bulk whole-genome sequencing of 637 matched tumor-normal samples from the Pediatric Cancer Genome Project revealed an enrichment of functionally impactful mtDNA variants in specific pediatric leukemia subtypes. Collectively, the results from single-cell sequencing of five diagnostic leukemia samples demonstrated that somatic mtDNA mutations can arise early in leukemogenesis and undergo positive selection during disease progression, achieving intermediate heteroplasmy-a "sweet spot" that balances mitochondrial dysfunction with cellular fitness. Network-based systems biology analyses link specific heteroplasmic mtDNA mutations to metabolic reprogramming and therapy resistance. We reveal somatic mtDNA mutations as a potential source of functional heterogeneity and cellular diversity among leukemic cells, influencing their fitness and shaping disease progression.
    DOI:  https://doi.org/10.1126/sciadv.adt3873
  28. Nature. 2025 Sep 10.
    Fluctuating DNA methylation tracks cancer evolution at clinical scale.
    Calum Gabbutt, Martí Duran-Ferrer, Heather E Grant, Diego Mallo, Ferran Nadeu, Jacob Househam, Neus Villamor, Madlen Müller, Simon Heath, Emanuele Raineri, Olga Krali, Jessica Nordlund, Thorsten Zenz, Ivo G Gut, Elias Campo, Armando Lopez-Guillermo, Jude Fitzgibbon, Chris P Barnes, Darryl Shibata, José I Martin-Subero, Trevor A Graham.
      Cancer development and response to treatment are evolutionary processes1,2, but characterizing evolutionary dynamics at a clinically meaningful scale has remained challenging3. Here we develop a new methodology called EVOFLUx, based on natural DNA methylation barcodes fluctuating over time4, that quantitatively infers evolutionary dynamics using only a bulk tumour methylation profile as input. We apply EVOFLUx to 1,976 well-characterized lymphoid cancer samples spanning a broad spectrum of diseases and show that initial tumour growth rate, malignancy age and epimutation rates vary by orders of magnitude across disease types. We measure that subclonal selection occurs only infrequently within bulk samples and detect occasional examples of multiple independent primary tumours. Clinically, we observe faster initial tumour growth in more aggressive disease subtypes, and that evolutionary histories are strong independent prognostic factors in two series of chronic lymphocytic leukaemia. Using EVOFLUx for phylogenetic analyses of aggressive Richter-transformed chronic lymphocytic leukaemia samples detected that the seed of the transformed clone existed decades before presentation. Orthogonal verification of EVOFLUx inferences is provided using additional genetic data, including long-read nanopore sequencing, and clinical variables. Collectively, we show how widely available, low-cost bulk DNA methylation data precisely measure cancer evolutionary dynamics, and provides new insights into cancer biology and clinical behaviour.
    DOI:  https://doi.org/10.1038/s41586-025-09374-4
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