bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–02–22
twenty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. TP53 Mutations and Circulating Blasts ≥ 20% Are the Primary Determinants of Survival in Accelerated/Blast-Phase Myeloproliferative Neoplasms Treated With Frontline Venetoclax Plus Hypomethylating Agent.
  2. A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid leukemia.
  3. Clinical outcomes of patients with lower risk myelodysplastic syndrome from EUMDS registry eligible for transplantation: Implications for transplantation strategies.
  4. Modeling the evolutionary dynamics of clonal hematopoiesis.
  5. Current perspectives on KMT2A fusion proteins and menin inhibition in paediatric acute myeloid leukaemia.
  6. Risk of Transformation to Acute Myeloid Leukaemia and Myelodysplastic Syndromes in Patients With Myeloproliferative Neoplasms Over Attained Age and Time Since Diagnosis: A Nationwide Cohort Study.
  7. Development of a prognostic scoring system for chronic myeloid leukemia in blast phase.
  8. TET2 loss enhances early response to inflammation in primitive and committed myeloid cells.
  9. Outcomes of therapy-related non-core binding factor acute myeloid leukemia with venetoclax-based therapies.
  10. Dissecting clonal hematopoiesis in the myeloid compartment of chronic lymphocytic leukemia and Richter transformation.
  11. The FGFR1 N546K mutation confers resistance to pemigatinib in MLN-ZMYM2::FGFR1.
  12. Artificial intelligence differentiates prefibrotic primary myelofibrosis with thrombocytosis from essential thrombocythemia using digitized bone marrow biopsy images.
  13. Expanding the phenotypic spectrum of DNAJC21-associated bone marrow failure syndrome: A single-centre experience.
  14. IMPDH inhibition enhances cytarabine efficacy in SAMHD1-expressing leukaemia cells via guanine nucleotide depletion.
  15. FOSL2 drives acute myeloid leukemogenesis through suppression of ERAD-induced proteostatic collapse.
  16. FLAG-IDA LITE: A Reasonable Induction Regimen for Elderly AML Patients.
  17. Single-cell multiomic atlas of healthy pediatric bone marrow reveals age-dependent differences in lineage differentiation driven by stromal signaling.
  18. Deep cytomorphology identifies erythroid skewing and monocytic morphology to predict TKI sensitivity in CML patients.
  19. Hematopoietic JAK2V617F Mutation-Induced Reprograming of Blood and Bone Marrow Megakaryocytes.
  20. Heme Synthesis Inhibition Induces the Intrinsic Apoptosis Pathway in Leukemia with OSGIN1 Upregulation.
  21. Characterization of a Newly Discovered Non-Coding Variant in the EPO Gene Identified in Two Unrelated Italian Pedigrees With Erythrocytosis.
  22. Real-world outcomes in refractory chronic graft-versus-host disease: the Italian multicenter experience with belumosudil.
  1. Am J Hematol. 2026 Feb 18.
    TP53 Mutations and Circulating Blasts ≥ 20% Are the Primary Determinants of Survival in Accelerated/Blast-Phase Myeloproliferative Neoplasms Treated With Frontline Venetoclax Plus Hypomethylating Agent.
    Naseema Gangat, Momna Warraich, Sudhesh Kumar, Mahnoor Fatima, Kristen McCullough, Kebede H Begna, Aref Al-Kali, Mrinal M Patnaik, William J Hogan, Abhishek Mangaonkar, Antoine N Saliba, Mehrdad Hefazi Torghabeh, Hassan Alkhateeb, Mithun V Shah, James M Foran, Talha Badar, Jeanne M Palmer, Cecilia Arana Yi, Animesh Pardanani, Ayalew Tefferi.
      Survival outcome among 82 Mayo Clinic patients with blast/accelerated phase myeloproliferative neoplasm (MPN-BP/AP).
    Keywords:   JAK2 ; hypomethylating; myelofibrosis; polycythemia; thrombocythemia
    DOI:  https://doi.org/10.1002/ajh.70248
  2. Leukemia. 2026 Feb 17.
    A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid leukemia.
    Samarpana Chakraborty, Claudia Morganti, Kimberly Zaldana, Bianca Rivera Pena, Hui Zhang, Divij Verma, Nadege Gitego, Feiyang Ma, Srinivas Aluri, Kith Pradhan, Shanisha Gordon-Mitchell, Ioannis Mantzaris, Mendel Goldfinger, Eric Feldman, Kira Gritsman, Yang Shi, Stefan Hubner, Yi Hua Qiu, Brandon D Brown, Abdullah Khasawneh, Anna Skwarska, Eduardo Sabino de Camargo Magalhães, Amit Verma, Marina Konopleva, Yoko Tabe, Evripidis Gavathiotis, Simona Colla, Jared Gollob, Joyoti Dey, Steven M Kornblau, Sergei B Koralov, Keisuke Ito, Aditi Shastri.
      Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with a poor prognosis. Venetoclax (Ven), a BCL2 inhibitor, has shown promising results but often leads to relapse due to mitochondrial dysregulation, particularly due to upregulation of the anti-apoptotic protein MCL1. Overexpression of the transcription factor STAT3 has been linked to poor survival in AML patients. Overexpression of STAT3 in a transgenic murine model induces a myeloid malignancy with a short latency period and inflammatory upregulation. The current study identifies STAT3 upregulation as a key mechanism of Ven resistance. A clinically relevant STAT3 degrader effectively reduces both total and phosphorylated STAT3, corrects mitochondrial structural and functional dysregulation, and induces apoptosis in Ven-resistant AML cell lines. KT-333 significantly decreases STAT3 and MCL1 protein levels and improves survival in Ven-resistant (Ven-Res) AML murine models. In summary, STAT3 hyperactivation is leukemogenic, is further potentiated in Ven-resistance and can be clinically targeted with a novel and specific STAT3 degrader. Pictorial representation depicting upregulation of STAT3 and MCL1 in venetoclax resistant myeloid malignancies such as MDS and AML causing mitochondrial structural abnormalities and dysfunction. By using specific STAT3 degrader, STAT3 inhibition, and thereby indirect downregulation of MCL1 can be a promising therapeutic intervention to target drug resistant clones in MDS and AML.
    DOI:  https://doi.org/10.1038/s41375-026-02883-9
  3. Br J Haematol. 2026 Feb 18.
    Clinical outcomes of patients with lower risk myelodysplastic syndrome from EUMDS registry eligible for transplantation: Implications for transplantation strategies.
    EUMDS registry
      Selecting eligible allogeneic haematopoietic stem cell transplantation (allo-HSCT) candidates with low-risk and intermediate-risk myelodysplastic syndrome (MDS) remains controversial. The International Working Group (IWG) for MDS prognosis identified a Revised International Prognostic Scoring System (IPSS-R) score >3.5 for benefits from early transplantation; the MDS-RIGHT group uses a broader set of poor risk features. We analysed 1145 lower risk MDS (lower risk and intermediate-risk IPSS-R) patients aged <75 years, using real-world European Myelodysplastic Syndromes registry data and identifying those meeting IWG or MDS-RIGHT criteria for allo-HSCT at baseline and 6-month follow-up. Fit patients were characterised by Karnofsky score ≥70 and Haematopoietic Cell Transplantation-specific Comorbidity Index <3. We evaluated clinical outcomes of transplant candidates, including survival, disease progression risk, new comorbidity risk and performance status decline. The IWG criterion, and not MDS-RIGHT criteria, identified patients with lower risk and intermediate-risk MDS with poorer baseline survival. Fit lower risk patients showed 2-year cumulative risks of incident comorbidity and performance status deterioration of 20% and 5% respectively. In summary, IWG and MDS-RIGHT features identify patients with lower or intermediate-risk MDS as candidates for early transplantation. Lower risk patients fit for transplantation have a cumulative incidence of adverse outcomes possibly jeopardising transplantation eligibility and should be carefully selected when planning delayed transplantation strategies.
    Keywords:  allogeneic haematopoietic stem cell transplantation; comorbidity; myelodysplastic syndrome; performance status; survival
    DOI:  https://doi.org/10.1111/bjh.70384
  4. Nat Genet. 2026 Feb 16.
    Modeling the evolutionary dynamics of clonal hematopoiesis.
    Sadegh Marzban, Thomas Stiehl, Zhuoer Xie, Morten Andersen, Jordan Snyder, Johanne Gudmand-Høyer, Johnny T Ottesen, Nathaniel V Mon Père, Benjamin Werner, Weini Huang, Amy E DeZern, Mikkael A Sekeres, Matthew J Walter, Eric Padron, Nancy Gillis, Jeffrey West.
      Clonal hematopoiesis (CH) results from the acquisition and expansion of somatic mutations in hematopoietic stem and progenitor cells and is associated with age-related clinical sequelae, including an increased risk for cardiovascular disease, myeloid neoplasms and complications related to cancer therapy. Chemotherapy and radiation can accelerate CH expansion and further elevate the risk of adverse events, including cardiotoxicity and therapy-related myeloid neoplasms. Although CH is increasingly recognized as a clinically relevant precursor state and predictive biomarker, the long-term dynamics of CH expansion in humans remain poorly understood. Longitudinal data are often collected but not integrated with mathematical prediction. Mathematical modeling is essential for characterizing CH evolution, estimating clone fitness, inferring stem cell pool dynamics and enabling patient-level predictions. This study summarizes the current evidence on CH dynamics in humans, compares mathematical models used to predict CH progression, assesses the validity of model assumptions and discusses the implications for clinical management of individuals with these precursor conditions.
    DOI:  https://doi.org/10.1038/s41588-026-02504-2
  5. FEBS J. 2026 Feb 18.
    Current perspectives on KMT2A fusion proteins and menin inhibition in paediatric acute myeloid leukaemia.
    Lydia Elaine Roets, Graeme Greenfield, Katrina Mairead Lappin.
      The therapeutic landscape of acute myeloid leukaemia (AML) has evolved beyond the classic '7 + 3'/DA regimen, through the approval and incorporation of targeted treatments in both front-line and relapsed/refractory settings. Indeed, the use of selective BCL-2 antagonists (e.g. venetoclax) and FLT3 inhibitors (e.g. midostaurin, gilteritinib) which target specific molecular characteristics of leukaemic cells, has enhanced outcomes and survival rates. Arguably one of the most exciting advancements has been the clinical development of menin inhibitors for the treatment of patients harbouring specific genetic aberrations. These abnormalities include rearrangements of the lysine methyltransferase 2A (KMT2A) gene, and they occur in approximately one fifth of childhood/paediatric (i.e. infant, adolescent and young adult) AML patients. Spurred on by the recent FDA approval of revumenib, menin inhibitors hold the potential to further shift the treatment paradigm for this patient population. Here, we aim to provide a comprehensive overview of the pathogenesis of KMT2A rearrangements, with a focus on KMT2A fusion genes and proteins within paediatric AML patients. Additionally, we summarise the challenges arising from resistance to menin inhibitors, and we touch on the potential of combination therapies to expand the efficacy of menin inhibition and mitigate some of the resistance mechanisms employed by leukaemic clones.
    Keywords:  KMT2A fusion proteins; KMT2A rearrangements; acute myeloid leukaemia; childhood AML; paediatric AML
    DOI:  https://doi.org/10.1111/febs.70460
  6. Eur J Haematol. 2026 Feb 20.
    Risk of Transformation to Acute Myeloid Leukaemia and Myelodysplastic Syndromes in Patients With Myeloproliferative Neoplasms Over Attained Age and Time Since Diagnosis: A Nationwide Cohort Study.
    Nurgul Batyrbekova, Anna Ravn Landtblom, Malin Hultcrantz, Robert Szulkin, Paul W Dickman, Therese M-L Andersson.
       BACKGROUND: Individuals with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) face transformation risks to acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). While older age is linked to increased risk, it remains unclear whether risk increases with age or with disease duration.
    OBJECTIVES: To examine how age and disease duration affect AML and MDS transformation in MPN.
    METHODS: We used Swedish nationwide register data to model transformation rates as continuous functions of age and disease duration for each subtype and outcome. Cumulative incidences were estimated accounting for competing risk of death.
    RESULTS: This study included 7156 patients with PV, 6810 with ET, and 1080 with PMF diagnosed in 2001-2021. In PV and ET, AML rates increased with disease duration. In PMF, AML rates were highest soon after diagnosis and declined over time. The 10-year cumulative incidence of AML at diagnosis age 70 was 3.5% in PV, 4.7% in ET, and 18.2% in PMF; for MDS, it was 1.7%, 3.1%, and 10.7%, respectively.
    CONCLUSION: AML and MDS transformation risks vary by MPN subtype and depend on age and disease duration, with disease duration elevating AML risk in PV and ET; incorporating both factors is essential for individualized risk assessment.
    Keywords:  AML; MDS; cohort study; disease duration; myeloproliferative neoplasms
    DOI:  https://doi.org/10.1111/ejh.70141
  7. Leukemia. 2026 Feb 19.
    Development of a prognostic scoring system for chronic myeloid leukemia in blast phase.
    Michael Lauseker, Tomasz Sacha, Hana Klamova, Julia Yakoleva, Elza Lomaia, Dragana Milojkovic, Christian Fabisch, Franck E Nicolini, Ulla Olsson-Stromberg, Daniela Zackova, Krzysztof Lewandowski, Philipp Ernst, Fausto Castagnetti, Klaus Hirschbühl, Irena Zupan, Astghik Voskanyan, Aleksandra Gołos, Jochen J Frietsch, Justyna Gil, Edgar Faber, Stefan W Krause, Anne Parry, Susanne Saussele, Sonja Heibl, Georg-Nikolaus Franke, Luis Felipe Casado, Edyta Paczkowska, Holger Hebart, Matthias Eder, Peter Anhut, Karolin Trautmann-Grill, Elzbieta Szczepanek, Thomas Südhoff, Elzbieta Patkowska, Alexander Kiani, Thomas Ernst, Jane Apperley, Jiri Mayer, Andreas Hochhaus, Markus Pfirrmann, Annamaria Brioli.
      Currently there is no established prognostic scoring system for patients with chronic myeloid leukemia (CML) in blast phase (BP). This study aimed to identify prognostic factors of CML-BP in a large cohort of prospectively and retrospectively collected patients and to develop a readily available prognostic scoring system at the onset of BP to enable future comparison between different trials and series. The analyses were based on 275 patients from thirteen countries, collected within the European LeukemiaNet Blast Phase Registry with a median observation time of 45 months and a median OS of 18.9 months. A Cox proportional hazards model for overall survival (OS) was employed, missing values were imputed. The study identified six independent prognostic factors: blast percentage, platelet count, age (all at onset of CML-BP), immunophenotype of BP, extramedullary disease, and previous history of CML. The low-risk group, encompassing 14% of patients, had a median OS of 97 months, the intermediate-risk group (59% of patients) of 22 months, and the high-risk group (27% of patients) of 9 months. Cross-validation demonstrated a good performance of the score, although external validation is strongly recommended. Despite the inherent limitations of registry data, the findings offer robust insights into prognostic factors for CML-BP.
    DOI:  https://doi.org/10.1038/s41375-026-02875-9
  8. Exp Hematol. 2026 Feb 17. pii: S0301-472X(26)00016-0. [Epub ahead of print] 105383
    TET2 loss enhances early response to inflammation in primitive and committed myeloid cells.
    Matthew T Jenkins, Rebecca Dubin, Kirsten M Dickerson, Phoebe Nguyen, Jing Wang, Stanley C Lee, Rui Lu, Robert S Welner, P Brent Ferrell.
      In vivo IL-1β exposure elicits enhanced hematopoietic stem cell (HSC) self-renewal and myeloid priming in Tet2KO mice, but information on how Tet2KO affects the early transcriptional response to IL-1β is lacking. To address this, we used an inducible, in vitro model of myeloid differentiation coupled with RNA-sequencing (RNAseq) to study the effects of Tet2KO on short-term IL-1β stimulation. In both Tet2KO progenitor and differentiated states, we identified baseline increases in expression of several cytokine signaling receptors, including Il1r1, as well as increases in inflammasome components. Interaction effect modeling revealed that loss of TET2 and IL-1β stimulation collaborate, leading to significant increases in both inflammatory cytokine expression and regulators of proliferation and differentiation in the progenitor state, and elevated cytokine production in differentiated cells. We then show that IKK-complex inhibition prevents both the IL-1β-induced proliferation of Tet2KO progenitors and TNFα production in differentiated myeloid cells, highlighting a potential therapeutic target in TET2-deficient cells. Teaser Abstract: TET2 loss and IL-1β stimulation collaborate to induce cytokine expression as well as proliferation and differentiation related transcription factors in myeloid progenitors, while differentiated myeloid cells lacking TET2 produce a much larger, more diverse repertoire of inflammatory cytokine transcripts. Both of these cell-state specific effects of TET2 loss were countered with IKK-complex inhibition, highlighting a potential therapeutic avenue for clonal blood disorders.
    Keywords:  IL-1β stimulation; RNAseq; TET2; clonal hematopoiesis; flow cytometry; inflammation; myeloid differentiation
    DOI:  https://doi.org/10.1016/j.exphem.2026.105383
  9. Hemasphere. 2026 Feb;10(2): e70317
    Outcomes of therapy-related non-core binding factor acute myeloid leukemia with venetoclax-based therapies.
    Jayastu Senapati, Jennifer Croden, Guillermo Garcia-Manero, Koichi Takahashi, Naval G Daver, Tapan M Kadia, Gautam Borthakur, Nicholas James Short, Elias Jabbour, Fadi Haddad, Jennifer Marvin-Peek, Hussein A Abbas, Prithviraj Bose, Guilin Tang, Sanam Loghavi, Elizabeth J Shpall, Jeremy Ramdial, Uday R Popat, Richard E Champlin, Farhad Ravandi, Hagop M Kantarjian, Courtney D Dinardo.
      Prognosis in therapy-related acute myeloid leukemia (T-AML) remains poor, but understanding outcomes with venetoclax (VEN)-based therapy is relevant. We retrospectively analyzed 317 adult patients with newly diagnosed T-AML focusing on lower intensity therapy (LIT) VEN-containing regimens. Patients with an antecedent myeloid disorder before AML diagnosis were excluded. The median age was 69 years (range 21-92); 50% evaluated patients had a complex karyotype, and 40% evaluated patients had a TP53 mutation. Composite complete response rates were higher with LIT + VEN compared to LIT (58% vs. 40%, P = 0.003) but were similar in intensive chemotherapy (IC) + VEN versus IC alone (68% vs. 61%, P = 0.59). Rates of allogeneic hematopoietic stem cell transplantation (HSCT) were higher in VEN-treated patients: 22% versus 7% in LIT + VEN and LIT, and 64% versus 39% in IC + VEN and IC, respectively. At a median follow-up of 46.4 months, the median relapse-free survival (RFS) and overall survival (OS) of the full cohort were 7.2 and 8.4 months, respectively. Among LIT + VEN-treated patients, the median RFS and OS were 8.0 and 9.0 months, respectively; in patients with ELN2024 favorable risk, the median OS was 25.4 months (1-year OS rate of 62%), compared to 9.4 months in the intermediate (FLT3-ITD and/or RAS mutated) and 4.8 months in the adverse risk (TP53 mutated) group. Patients with NPM1 and/or IDH mutations had 2-year OS over 60%. On multivariate analysis in LIT + VEN-treated patients, HSCT and NPM1/IDH2 mutations were favorable, while TP53/RAS mutations were associated with inferior survival. VEN-based therapy improves outcomes in patients with T-AML, especially in those with VEN-sensitizing genomics and receiving an HSCT.
    DOI:  https://doi.org/10.1002/hem3.70317
  10. Hemasphere. 2026 Feb;10(2): e70322
    Dissecting clonal hematopoiesis in the myeloid compartment of chronic lymphocytic leukemia and Richter transformation.
    Chiara Cosentino, Samir Mouhssine, Antonella Zucchetto, Ilaria Romano, Matin Salehi, Luca Vincenzo Cappelli, Fabio Iannelli, Mohammad Almasri, Nawar Maher, Lorenzo Fumagalli, Deborah Cardinali, Andrea Visentin, Jana Nabki, Luca Cividini, Bashar Al Deeban, Milena Lazzaro, Francesca Maiellaro, Annalisa Gaglio, Francesca Perutelli, Valentina Griggio, Riccardo Dondolin, Matteo Bellia, Maura Nicolosi, Silvia Rasi, Eleonora Secomandi, Valeria Caneparo, Abdurraouf Mokhtar Mahmoud, Clara Deambrogi, Sreekar Kogila, Joseph Ghanej, Mohammad Reshad Nawabi, Ilaria Del Giudice, Elisa Albi, Candida Vitale, Lydia Scarfò, Marta Coscia, Livio Trentin, Stefano Pileri, Paolo Ghia, Roberto Chiarle, Valter Gattei, Lodovico Terzi di Bergamo, Davide Rossi, Robin Foà, Gianluca Gaidano, Riccardo Moia.
      The clinical and biological significance of clonal hematopoiesis (CH) has not been investigated in the myeloid compartment of chronic lymphocytic leukemia (CLL). By studying 488 newly diagnosed CLL through CAPP-seq using a 28-gene panel on granulocyte genomic DNA (gDNA), CH occurred in 231 (47.3%) patients. Cell sorting of cases that never developed Richter transformation (RT) confirmed that CH mutations, including CH-related TP53 mutations, were restricted to the myelomonocytic compartment and absent in CLL cells, as also documented by single-cell DNA sequencing. CH associated with shorter overall survival (OS) (hazard ratio [HR] 1.36, 95% CI 1.04-1.77, P = 0.023); specifically, TET2 mutations independently predicted inferior OS (HR 1.62, 95% CI 1.15-2.28, P = 0.01) after adjusting for age and for CLL-related prognostic biomarkers, namely IGHV and TP53 status. Regarding therapy-related toxicities, CH correlated with a higher incidence of Grade ≥ 3 neutropenia (P = 0.004) after venetoclax-based regimens. Sequential samples (n = 57) analysis showed that Bruton tyrosine kinase (BTK) and BCL2 inhibitors do not induce CH expansion, which was instead driven by chemotherapy. CH is significantly associated with a higher risk of second hematological malignancies only in chemo-exposed patients. Single-cell RNA sequencing of seven CH+ and six CH- CLL revealed that the T-cell compartment of CH+ patients exhibits a less exhausted phenotype, documented by lower expression of TOX, the master regulator of T-cell exhaustion, and a higher pro-inflammatory profile. CH also influenced RT, since CH ASXL1 mutations independently associated with higher RT risk (HR 11.19, 95% CI 4.09-30.62, P < 0.001). Overall, CH in CLL impacts survival, therapeutic toxicity, and transformation risk while also influencing the T-cell immune compartment.
    DOI:  https://doi.org/10.1002/hem3.70322
  11. Leukemia. 2026 Feb 20.
    The FGFR1 N546K mutation confers resistance to pemigatinib in MLN-ZMYM2::FGFR1.
    Khalid Shoumariyeh, Stefan Haug, Juliana Schwaab, Julie K Pfeil, Jannis Stappenbeck, Annette Schmitt-Graeff, Nicole Naumann, Greta Waltemode, Robert Zeiser, Cornelius Miething, Wolf-Karsten Hofmann, Manja Meggendorfer, Sven Diederichs, Justus Duyster, Andreas Reiter.
      
    DOI:  https://doi.org/10.1038/s41375-026-02890-w
  12. Leukemia. 2026 Feb 20.
    Artificial intelligence differentiates prefibrotic primary myelofibrosis with thrombocytosis from essential thrombocythemia using digitized bone marrow biopsy images.
    Andrew Srisuwananukorn, Giuseppe Gaetano Loscocco, James M Dolezal, Andrew T Kuykendall, Raffaella Santi, Ling Zhang, Avani M Singh, Paola Guglielmelli, Alessandro Maria Vannucchi, Mohamed E Salama, Alexander T Pearson, Ronald Hoffman.
      Prefibrotic primary myelofibrosis (prePMF) and essential thrombocythemia (ET) are distinct myeloproliferative neoplasms (MPNs) with overlapping clinical features, often leading to diagnostic uncertainty. We developed an artificial intelligence (AI) framework with human interpretability to distinguish prePMF from ET using digitized hematoxylin and eosin-stained bone marrow biopsy (BMB) slides. Trained on an initial cohort of MPN patients with thrombocytosis, the AI model achieved an AUROC of 0.89 and accuracy of 92.3%. To assess the image features guiding predictions, we generated synthetic images which potentially exaggerate disease-specific morphologies. In a blinded survey, hematopathologists reviewed both real and AI-generated images. While human experts frequently agreed with AI predictions on diagnosis with real images, diagnostic discordance reached up to 88% for AI-generated ET images despite being correctly predicted by AI. We further quantified marrow cellularity and adiposity in the real and generated images, which revealed a higher proportion of fat content in all ET images (42.0%) compared to prePMF (28.9%). These findings suggest that AI can utilize morphological cues distinct from current established diagnostic criteria, such as proportion of adiposity to distinguish types of MPNs. Thus, an AI-assisted diagnostic tool underscores the potential of AI to augment histopathologic evaluation and allow identification of more specific subpopulations of forms of MPNs.
    DOI:  https://doi.org/10.1038/s41375-026-02893-7
  13. Br J Haematol. 2026 Feb 19.
    Expanding the phenotypic spectrum of DNAJC21-associated bone marrow failure syndrome: A single-centre experience.
    A Deshpande, R Mathur, M Velangi, A Norton, A Cherungonath, S Lawson, S Hughes.
      
    Keywords:  DNAJC21; inherited bone marrow failure syndromes
    DOI:  https://doi.org/10.1111/bjh.70372
  14. Mol Oncol. 2026 Feb 19.
    IMPDH inhibition enhances cytarabine efficacy in SAMHD1-expressing leukaemia cells via guanine nucleotide depletion.
    Miriam Yagüe-Capilla, Christopher Dirks, Caroline Eiden, Sonja K Fesenmayer, Femke M Hormann, Yolande Klootsema, Ingrid Lilienthal, Si Min Zhang, Nikolas Herold, Sean G Rudd.
      The nucleoside analogue cytarabine (ara-C) is part of standard treatment against acute myeloid leukaemia (AML). The efficacy of this therapy is dependent upon accumulation of the active triphosphate metabolite ara-CTP, which mis-incorporates into genomic DNA, triggering cell death. The deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) SAMHD1 can hydrolyse ara-CTP and thereby convert the active metabolite back to its inactive prodrug form. This constitutes a barrier to treatment efficacy and thus strategies to target SAMHD1 are warranted. SAMHD1 activity is allosterically regulated by nucleotides, which are synthesised in cells via distinct pathways. We screened a collection of drugs targeting nucleotide biosynthetic enzymes and identified that inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH), responsible for catalysing the rate-limiting step in guanine nucleotide biosynthesis, sensitises AML cell lines to ara-C in a SAMHD1-dependent manner. We show that approved drugs inhibiting IMPDH-mycophenolic acid and ribavirin-imbalance deoxyribonucleoside triphosphate pools and increase ara-C efficacy in SAMHD1-proficient, but not deficient, leukaemic cells. Altogether, we provide insight into SAMHD1 regulation in leukaemic cells and show how this process can be exploited by approved drugs to improve ara-C therapy.
    Keywords:  acute myeloid leukaemia; chemoresistance; dNTP metabolism; drug repurposing
    DOI:  https://doi.org/10.1002/1878-0261.70226
  15. Biochem Biophys Res Commun. 2026 Feb 18. pii: S0006-291X(26)00257-3. [Epub ahead of print]809 153493
    FOSL2 drives acute myeloid leukemogenesis through suppression of ERAD-induced proteostatic collapse.
    Wangshi Li, Meiling Sun, Binyu Yao, Xinyu Li, Ting Qiu, Xingzhi Lv, Yue Wu, Xingxing Du, Fukai Liu, Ruolin Xiu, Yanhong Zhao, Shengjin Fan, Keyang Luo, Huitao Fan.
      Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by poor clinical outcomes and high relapse rates, driven largely by intrinsic or acquired chemoresistance. Despite advances, the standard "7 + 3″ chemotherapy backbone offers limited long-term survival, underscoring the urgent need for novel molecular targets to overcome therapeutic bottlenecks. While the AP-1 transcription factor FOSL2 is implicated in solid tumors, its role in AML remains unexplored. Here, we identify and validate FOSL2 as a critical oncogenic driver in AML. Comprehensive bioinformatic analysis across multiple independent patient cohorts reveals that its aberrant overexpression is a key feature and robust biomarker, correlating significantly with adverse clinical outcomes. Functional studies using shRNA-mediated silencing demonstrated that FOSL2 is indispensable for leukemic cell survival and proliferation. Its genetic depletion profoundly abrogated clonogenic potential, induced G0/G1 cell-cycle arrest and apoptosis, and promoted myeloid differentiation in vitro. In a xenograft mouse model, FOSL2 knockdown markedly suppressed leukemic tumor burden and significantly extended overall survival. Mechanistically, transcriptomic profiling revealed that FOSL2 depletion upregulates the E3 ubiquitin ligase HRD1 suggesting that FOSL2 depletion may hyperactivate the endoplasmic reticulum-associated degradation (ERAD) pathway. This uncontrolled ERAD activity dismantles cellular proteostasis, culminating in heightened ER stress and significant DNA damage, as evidenced by comet assays. Consequently, this FOSL2-deficient state profoundly sensitizes AML cells to conventional chemotherapies, including doxorubicin and cytarabine, as well as ER stress-inducing agents. Collectively, these findings establish that FOSL2 orchestrates a key proteostatic vulnerability. Targeting the FOSL2-ERAD axis represents a compelling therapeutic strategy to dismantle chemoresistance and improve patient outcomes in AML.
    Keywords:  Acute myeloid leukemia; DNA damage; ERAD; FOSL2; HRD1
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153493
  16. Clin Lymphoma Myeloma Leuk. 2026 Jan 19. pii: S2152-2650(26)00001-7. [Epub ahead of print]
    FLAG-IDA LITE: A Reasonable Induction Regimen for Elderly AML Patients.
    Mercedes Colorado, Mª Aranzazu Bermúdez, Carmen Montes, Juan José Domínguez-García, Guillermo Martín, Iñigo Romon, Enrique M Ocio.
       INTRODUCTION: Treatment of acute myeloid leukemia (AML) in elderly or medically unfit patients remains challenging. Although low-intensity regimens are now standard, intermediate-intensity approaches may still be relevant in selected clinical scenarios. FLAG-IDA LITE was developed as a reduced-intensity adaptation of fludarabine- and cytarabine-based induction to preserve antileukemic activity while improving tolerability.
    PATIENTS AND METHODS: We conducted a retrospective analysis of elderly or unfit patients with de novo or secondary AML treated with FLAG-IDA LITE at a single institution between 2006 and 2020. Responses were assessed according to Cheson criteria, and cytogenetic risk was classified using the 2010 Medical Research Council (MRC) criteria. Overall survival (OS) was calculated from day 1 of treatment.
    RESULTS: Ninety-one patients were included, with a median age of 76 years and a high burden of comorbidities and adverse disease features. Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 52 patients (57%). Thirty-day mortality was 9.8%, mainly due to infectious complications during induction. Median OS for the entire cohort was 7 months. Patients achieving CR/CRi had a significantly prolonged median OS compared with nonresponders (19 vs. 4 months). Adverse-risk cytogenetics were associated with lower response rates and inferior survival.
    CONCLUSIONS: In conclusion, FLAG-IDA LITE yielded modest overall outcomes in a highly vulnerable AML population but provided meaningful survival benefit in patients achieving remission. These findings support a selective role for intermediate-intensity induction regimens in carefully chosen elderly or unfit patients, particularly when rapid disease control is required.
    DOI:  https://doi.org/10.1016/j.clml.2026.01.001
  17. Nat Immunol. 2026 Feb 17.
    Single-cell multiomic atlas of healthy pediatric bone marrow reveals age-dependent differences in lineage differentiation driven by stromal signaling.
    Evelyn S Hanemaaijer, Konradin F Müskens, Ireen J Kal, Li-Ting Chen, Brigit M Te Pas, Patrycja Fryzik, Nina Epskamp, Merel van der Meulen, Aleksandra K Balwierz, Akshaya K Saikumar Jayalatha, Marijn Scheijde-Vermeulen, Olaf Heidenreich, Tito Candelli, Wim J de Jonge, Thanasis Margaritis, Mirjam E Belderbos.
      Childhood is a critical period for hematopoietic development and susceptibility to hematologic disease. Here we generated a multimodal single-cell atlas of healthy human bone marrow, capturing mRNA and surface protein expression in 90,710 cells, including over 20,000 hematopoietic stem and progenitor cells (HSPC) and mesenchymal stromal cells (MSC) from nine donors ranging from infancy to young adulthood (2-32 years). Young pediatric (YP) bone marrow (<10 years) was compositionally and molecularly distinct from adolescent and young adult (AYA) bone marrow (≥13 years), with hematopoietic output shifting from B cell dominance in YP bone marrow to myeloid and T cell bias in AYA bone marrow. Spatial transcriptomics of six bone marrow biopsies (0-23 years) confirmed these age-dependent changes. Two lymphoid progenitor (LyP) subsets regulated this lineage shift: CD127+ LyP cells with B cell-biased output were enriched before age 10, whereas CD127- LyP cells with combined lymphoid and myeloid features predominated thereafter. Stromal signaling showed corresponding age-dependent changes, with increased interleukin-7 production by bone marrow MSC in YP compared to AYA, indicating niche-mediated regulation of HSPC lineage potential during ontogeny. This single-cell atlas provides a comprehensive resource for understanding hematopoietic development and early-life origins of hematologic disease.
    DOI:  https://doi.org/10.1038/s41590-026-02422-9
  18. Hemasphere. 2026 Feb;10(2): e70319
    Deep cytomorphology identifies erythroid skewing and monocytic morphology to predict TKI sensitivity in CML patients.
    Katariina Luukkainen, Mikko Purhonen, Mikael Tatun, Kevin Hung, Oda Tafjord, Henri Sundquist, Stina Söderlund, Shady Adnan-Awad, Anni Dohlen, Johanna Heikkinen, Perttu Koskenvesa, Lotta Joutsi-Korhonen, Anna Lempiäinen, Sanna Siitonen, Satu Mustjoki, Naranie Shanmuganathan, Coral Bryce, Signe Danielsson, Henrik Hjorth-Hansen, Ulla Olsson-Strömberg, Takashi Kumagai, Shinya Kimura, David M Ross, Oscar Brück.
      The cellular composition of the chronic myeloid leukemia (CML) bone marrow (BM) beyond granulocyte enrichment remains poorly understood. We analyzed 1548 routinely stained BM aspirate slides from 598 patients across seven sites using deep learning-based image analysis to identify cytomorphological markers predictive of major molecular response. Erythroid precursor enrichment, monocyte nuclear lobulation, and low peripheral leukocyte count were associated with improved tyrosine kinase inhibitor (TKI) response. These features were validated both visually and computationally in two independent cohorts. We developed a Morphoclinical model integrating these image-derived and clinical variables, outperforming (area under the receiver-operating curve [AUROC] 0.76) the clinically used EUTOS long-term survival score (AUROC 0.53) and BCR::ABL1 halving time (AUROC 0.61). Notably, poor-risk patients treated with second-generation TKIs achieved outcomes similar to favorable-risk patients on imatinib. These results underline the overlooked prognostic value of BM cytomorphology to refine risk stratification and support more personalized frontline therapy in CML.
    DOI:  https://doi.org/10.1002/hem3.70319
  19. Blood Adv. 2026 Feb 18. pii: bloodadvances.2025019504. [Epub ahead of print]
    Hematopoietic JAK2V617F Mutation-Induced Reprograming of Blood and Bone Marrow Megakaryocytes.
    Simon Liang Lu, Anastasia Iris Karkempetzaki, Nasi Huang, Chao Zhang, George J Murphy, Katya Ravid.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2025019504
  20. Exp Hematol. 2026 Feb 13. pii: S0301-472X(26)00034-2. [Epub ahead of print] 105401
    Heme Synthesis Inhibition Induces the Intrinsic Apoptosis Pathway in Leukemia with OSGIN1 Upregulation.
    Yan Yan, Hiroki Kato, Sayaka Sano, Eijiro Furukawa, Satoshi Ichikawa, Koichi Onodera, Yasushi Onishi, Noriko Fukuhara, Hisayuki Yokoyama, Tohru Fujiwara, Hideo Harigae.
      Acute myeloid leukemia (AML) is one of the hematological malignancies with a poor outcome. AML has a unique metabolic status, and identifying its metabolic vulnerabilities is warranted. Recent genome-wide screenings suggest that heme synthesis might be such a vulnerability. Heme is required not only for hemoglobin synthesis but also for the proper function of hemoproteins. Cytochromes are such hemoproteins and are necessary for mitochondrial respiration. Therefore, heme synthesis inhibition can diminish AML by altering mitochondrial status and function. However, still little is known about the importance of heme synthesis in leukemia cells. To reveal the roles of heme synthesis in leukemia, we treated human leukemia cell lines with heme synthesis inhibitors, succinylacetone (SA) or N-methyl Protoporphyrin IX (NMPP). Heme synthesis inhibition induced cell growth inhibition and cell death in a concentration-dependent manner. Therefore, heme synthesis is required for leukemia cell proliferation and survival. Increased pro-apoptotic factors (cleaved caspase 3 and cleaved PARP) and decreased anti-apoptotic factor (XIAP) were observed following heme synthesis inhibition. Cytochrome c and Smac were released into the cytoplasm by heme synthesis inhibition, suggesting that heme synthesis inhibition led to mitochondrial outer membrane permeabilization and activation of the intrinsic pathway of apoptosis. Comprehensive transcriptomic analysis revealed that heme synthesis inhibition induced OSGIN1 expression, leading to the release of cytochrome c and Smac from mitochondria into the cytoplasm. Therefore, heme synthesis inhibition induced leukemia apoptosis by activating the intrinsic apoptosis pathway.
    Keywords:  OSGIN1; heme; intrinsic apoptosis pathway; leukemia
    DOI:  https://doi.org/10.1016/j.exphem.2026.105401
  21. Am J Hematol. 2026 Feb 18.
    Characterization of a Newly Discovered Non-Coding Variant in the EPO Gene Identified in Two Unrelated Italian Pedigrees With Erythrocytosis.
    Barbara Mora, Valentina Bellani, Daniela Pietra, Elena Tagliaferri, Daniele Cattaneo, Oscar Borsani, Alessandra Iurlo, Elisa Fermo, Paola Bianchi, Elisa Rumi, Francesco Passamonti.
      
    DOI:  https://doi.org/10.1002/ajh.70238
  22. Haematologica. 2026 Feb 19.
    Real-world outcomes in refractory chronic graft-versus-host disease: the Italian multicenter experience with belumosudil.
    Francesca Bonifazi, Marcello Roberto, Maria Teresa Lupo Stanghellini, Patrizia Chiusolo, Nicola Polverelli, Antonella Geromin, Lucia Prezioso, Mattia Algeri, Giorgia Mancini, Giulia Prunotto, Alessandra Algarotti, Chiara Nozzoli, Michele Malagola, Nicola Mordini, Marilena Fedele, Lidia Santoro, Francesco Zallio, Luca Castagna, Alessandra Picardi, Alessandro Busca, Luisa Giaccone, Cristina Skert, Francesca Elice, Luca Facchini, Jacopo Mariotti, Antonio Pierini, Alessandro Spina, Roberta De Marchi, Dalila Salvatore, Massimo Martino, Manuela Tumino, Alessandro Rambaldi, Franco Locatelli.
      Chronic graft-versus-host disease (cGvHD) remains a major late complication of allogeneic hematopoietic stem cell transplantation, leading to impaired quality of life and late non-relapse mortality. Belumosudil, an oral ROCK2 inhibitor with immunomodulatory and antifibrotic properties, represents a novel treatment for steroid-refractory or -dependent cGvHD. We conducted a retrospective, multicenter study of 80 patients treated with belumosudil across 29 Italian transplant centers through a compassionate use program. Patients were heavily pretreated (74% with ≥3 prior lines, 84% previously exposed to ruxolitinib), with severe disease in 86% and a median of three organs involved. The best overall response rate was 62.5%, while overall response rates was 52.6%, 57.6%, and 55.0% at 3, 6, and 12 months, respectively. Median time to response was 3 months, and the 12-month duration of response was 83.4%. Failure-free survival at 12 months was 67.5%. Responses were observed in all involved organs. Patient-reported outcomes assessed through the NIH Severity Index Score (0-10 scale) showed meaningful improvements (≥-2 points) in 33%, 36%, and 29% of patients at 3, 6, and 12 months, respectively. Treatment was well tolerated. These real-world findings confirm the effectiveness of belumosudil in patients with cGvHD refractory to multiple lines of immunosuppressive therapy.
    DOI:  https://doi.org/10.3324/haematol.2025.289302
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