bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–08–30
twenty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Impact of Response to Hypomethylating Agent-Based Therapy on Survival Outcomes in the Context of Baseline Clinical-Molecular Risk and Transplant Status in Patients With Higher-Risk Myelodysplastic Syndromes/Neoplasms: An analysis From the International Consortium for MDS (icMDS).
  2. Older Age, STAG2, and DNMT3A Mutations Predict Superior Posttransplant Survival in Newly Diagnosed Acute Myeloid Leukemia Treated With Venetoclax Plus Hypomethylating Agents.
  3. Inhibition of nucleoporin 214 depletes leukemia stem cells by promoting heme catabolism and lipid peroxidation.
  4. Clonal memory of cell division in humans diverges between healthy haematopoiesis and acute myeloid leukaemia.
  5. Ivosidenib monotherapy in IDH1 mutated myelodysplastic neoplasm/syndrome.
  6. Cheminformatic identification of small molecules targeting acute myeloid leukemia.
  7. PTBP1 controls oncogenic transcript processing and maintenance of acute myeloid leukemia.
  8. Final results of a phase II study of the combination of azacitidine and ruxolitinib in patients with myelofibrosis.
  9. TP53-mutant CHIP defines a pro-inflammatory phenotype and predicts adverse outcomes after CAR T-cell therapy.
  10. The PRIME trial: An investigator-initiated, multicentre, phase II study of the poly(ADP-ribose) polymerase inhibitor olaparib in isocitrate dehydrogenase (IDH)-mutated relapsed/refractory acute myeloid leukaemia and myelodysplastic syndromes.
  11. Homozygosity of germ line JAK2 46/1 haplotype contributes to phenotype and outcome diversity in polycythemia vera.
  12. Hematopoietic Stem Cell Metabolism during Stress and Aging.
  13. Spatial profiling of the spleen in mouse and human myelofibrosis reveals complement-driven immune-stromal interactions as a therapeutic target.
  14. Ferroptotic stress promotes hematopoietic stem cell aging through S1P-dependent epigenetic and lipid remodeling.
  15. Splenic extramedullary hematopoiesis in myelofibrosis is shaped by transcriptomic and epigenetic dysregulation.
  16. PML-driven sumoylation of PML::RARA-bound repressors drives hematopoietic progenitor immortalization.
  17. Consolidation Therapy Based on Mutation Clearance in Acute Myeloid Leukemia.
  18. Epigenetic markers expand genetic risk estimation in acute myeloid leukemia.
  19. Mitigating HLA Disparity in AML Transplantation: Comparable Outcomes After Haploidentical and 9/10 Mismatched Unrelated Donor Transplantation With Treosulfan and PTCy.
  20. The role of the adenosinergic pathway in resistance to hypomethylating agents in patients with high-risk myelodysplastic syndromes.
  21. Functional assessment of inherited myeloid neoplasm-associated SAMD9L germline variants via Monoallelic CRISPR modelling.
  22. International Consensus Criteria for the Diagnosis, Treatment Initiation, and Response Assessment for T-LGL Leukemia.
  1. Am J Hematol. 2026 Aug 27.
    Impact of Response to Hypomethylating Agent-Based Therapy on Survival Outcomes in the Context of Baseline Clinical-Molecular Risk and Transplant Status in Patients With Higher-Risk Myelodysplastic Syndromes/Neoplasms: An analysis From the International Consortium for MDS (icMDS).
    Benjamin Rolles, Jan Philipp Bewersdorf, Tariq Kewan, Ondrej Blaha, Jessica M Stempel, Luca Lanino, Najla H Al Ali, Amy E DeZern, Mikkael A Sekeres, Geoffrey L Uy, Samuel Urrutia, Hetty E Carraway, Pinkal Desai, Elizabeth A Griffiths, Eytan M Stein, Andrew M Brunner, Christine McMahon, Rory M Shallis, Joshua F Zeidner, Michael R Savona, Shougat Barua, Namrata Sonia Chandhok, Constantine Logothetis, Aram Bidikian, Ted M Getz, Gail J Roboz, Eunice S Wang, Amyah C Harris, Maria L Amaya, Hayley Hawkins, Somedeb Ball, Justin Grenet, Parisa Abedi, Shai Shimony, R Coleman Lindsley, Zhuoer Xie, Yazan F Madanat, Yasmin Abaza, Talha Badar, Torsten Haferlach, Jaroslaw P Maciejewski, David Sallman, Anoop Enjeti, Kamal Al-Rabi, Khalid Halahleh, Devendra Hiwase, Maria Diez-Campelo, David Valcarcel, Claudia Haferlach, Lisa Pleyer, Ioannis Kotsianidis, Vasiliki Pappa, Valeria Santini, Angela Consagra, Aref Al-Kali, Seishi Ogawa, Yasuhito Nannya, Matteo Giovanni Della Porta, Rami S Komrokji, Amer M Zeidan, Maximilian Stahl.
      Baseline IPSS-M risk, response to hypomethylating agent (HMA) therapy, and receipt of allogeneic stem cell transplant (allo-HCT) have all been individually shown to impact overall survival (OS) in patients with myelodysplastic syndromes (MDS). However, the prognostic impact of response when adjusting for IPSS-M risk and treatment strategy remains unclear. Hence, we used the VALIDATE database of the International Consortium for MDS (icMDS) to evaluate the impact of International Working Group (IWG) 2023 best response on OS in 715 HMA-treated, higher-risk MDS patients stratified by baseline IPSS-M risk and their treatment strategy (subsequent allo-HCT vs. medical therapy alone) treating both best response and allo-HCT as time-dependent variables. Baseline IPSS-M risk (hazard ratio (HR): 0.5, p < 0.001) and receipt of allo-HCT (HR: 0.5, p < 0.001) were the strongest independent predictors of OS, whereas achievement of composite complete response (cCR) had a more modest impact on OS (HR: 0.8, p = 0.004). Among patients treated with medical therapy alone, achieving cCR improved OS significantly (HR: 0.7, p = 0.006). In contrast, among transplanted patients, cCR did not retain independent prognostic value for post-transplant survival after adjusting for baseline IPSS-M (HR: 0.9, p = 0.634). Achieving cCR did not fully overcome adverse disease biology as OS continued to segregate according to baseline IPSS-M risk. In summary, achieving cCR improves outcomes in non-transplanted patients, but it does not significantly impact post-transplant OS, suggesting that failure to achieve cCR with HMA may not warrant delay or preclude allo-HCT. Clinical trials should consider response in the context of IPSS-M risk distribution and treatment strategy (subsequent allo-HCT vs. medical therapy alone) to avoid overinterpretation of high response rates.
    Keywords:  MDS; myelodysplastic neoplasms; myelodysplastic syndrome
    DOI:  https://doi.org/10.1002/ajh.70474
  2. Am J Hematol. 2026 Aug 23.
    Older Age, STAG2, and DNMT3A Mutations Predict Superior Posttransplant Survival in Newly Diagnosed Acute Myeloid Leukemia Treated With Venetoclax Plus Hypomethylating Agents.
    Momna Warraich, Sudhesh Kumar, Mahnoor Fatima, Kristen McCullough, Aref Al-Kali, Hassan B Alkhateeb, Kebede H Begna, Abhishek Mangaonkar, Antoine N Saliba, Aasiya Matin, Mark R Litzow, William Hogan, Mithun V Shah, Mrinal M Patnaik, Animesh Pardanani, James Foran, Lisa Sproat, Nandita Khera, Ayalew Tefferi, Naseema Gangat.
      Venetoclax (Ven) plus hypomethylating agents (HMA) is standard frontline therapy for newly diagnosed AML (ND-AML) patients unfit for intensive chemotherapy and is also considered in younger, fit patients. However, consolidation with allogeneic stem cell transplant (ASCT) is often required to secure durable remission. The current study examines posttransplant outcomes in patients with ND-AML treated with frontline Ven-HMA who subsequently underwent ASCT. A total of 111 ND-AML patients (58% male, 60% secondary/therapy-related, median age 70 years [range, 37-80]) received a median of 3 cycles of Ven-HMA. Mutations at the time of diagnosis included RUNX1 (18%), SRSF2 (17%), TP53 (16%), ASXL1, IDH2, K/NRAS, TET2 (14% each), STAG2 (11%), DNMT3A (8%). All patients were in CR/CRi at the time of transplant including 88% after Ven-HMA. Measurable residual disease (MRD) by flow cytometry was detectable in 18/76 (24%) patients. Donors were mostly HLA-matched unrelated (75%); 51% receiving fludarabine/melphalan conditioning and 67% posttransplant cyclophosphamide. At a median follow-up of 15 months, 42 (38%) of patients have died and 18 (16%) experienced posttransplant relapse. Median posttransplant survival was not reached (NR), with 1-, 2-, 3-year survival rates of 69%/60%/57%, respectively. On multivariate analysis, age ≥ 65 years, STAG2 mutation (STAG2MUT), and DNMT3AMUT were associated with superior posttransplant survival. Patients were stratified into low- (0-1 point), intermediate- (2 points), and high-risk (3 points); age < 65 years, STAG2 wild type, and DNMT3A wild type, with 3-year survival rates of 89%, 59%, and 19%, respectively (p < 0.01). Taken together, age, STAG2MUT and DNMT3AMUT stratified posttransplant survival in Ven-HMA treated patients with ND-AML.
    Keywords:  graft‐versus‐host disease; karyotype; measurable residual disease; mutations; nonrelapse mortality; relapse‐free survival
    DOI:  https://doi.org/10.1002/ajh.70480
  3. Blood. 2026 Aug 25. pii: blood.2026033244. [Epub ahead of print]
    Inhibition of nucleoporin 214 depletes leukemia stem cells by promoting heme catabolism and lipid peroxidation.
    Zhe Chen, Feng Wu, Wei Zhang, Wei Guo, Yan Li, Qiang Gong, Yue Wei, Linfeng Li, Tao Chen, Xueya Zhao, Jianwen Xiao, Hanqing Zeng, Jianchuan Deng, Hua-Bing Li, Li Wang, Zufeng Guo, Yu Hou.
      Chromosomal translocations involving nucleoporin (NUP) loci, such as NUP98 and NUP214, are recurrent in acute myeloid leukemia (AML). However, the intrinsic functions of wild-type nucleoporins in AML remain largely unknown. By screening the NUP family, we identified NUP214 as a frequently overexpressed gene and a critical fitness determinant in leukemia stem cells (LSCs). NUP214 acts as a conserved driver of LSC survival by restricting heme catabolism, limiting Fe²⁺ accumulation, and suppressing lipid peroxidation. Conversely, NUP214 deficiency leads to upregulation of heme oxygenase 1 (HMOX1) and arachidonate 15-lipoxygenase (ALOX15), causing heme exhaustion and excessive lipid peroxidation, which ultimately triggers ferroptosis in LSCs and impairs AML progression. Mechanistically, NUP214 translocates into the nucleoplasm where it blocks Sub1-mediated RNA polymerase II recruitment to repress transcription of the key pro-ferroptotic genes HMOX1 and ALOX15, revealing a non-canonical role beyond its nuclear pore function. Furthermore, we developed the small-molecule compound 0449-b, which acts as a selective NUP214 degrader by recruiting NUP214 to the Cullin5-Rbx2 E3 ligase complex, inducing its neddylation and proteasomal degradation. 0449-b potently triggers LSC ferroptosis and exhibits anti-leukemic activity in vivo, while sparing normal hematopoietic stem cells. Collectively, our findings establish NUP214 as a critical oncoprotein that orchestrates heme metabolism and lipid peroxidation to sustain LSCs, and highlight NUP214-targeted degradation as a promising intervention strategy for AML.
    DOI:  https://doi.org/10.1182/blood.2026033244
  4. Nat Commun. 2026 07 28. pii: 9133. [Epub ahead of print]17(1):
    Clonal memory of cell division in humans diverges between healthy haematopoiesis and acute myeloid leukaemia.
    Alessandro Donada, Gurvan Hermange, Tiziana Tocci, Adil Midoun, Giulio Prevedello, Louisa Hadj Abed, Délia Dupré, Wenjie Sun, Idan Milo, Sabrina Tenreira Bento, Constandina Pospori, Andrew J Innes, Christophe Willekens, Jacques Vargaftig, David Michonneau, Cristina Lo Celso, Nicolas Servant, Ken R Duffy, Hervé Isambert, Paul-Henry Cournède, Lucie Laplane, Leïla Perié.
      Clonal memory, a cellular property inherited across at least two divisions, is a key driver of cell heterogeneity. To uncover its roles in human haematopoiesis, we develop high-resolution ex vivo tools that track both division and fate commitment of individual primary human haematopoietic stem and progenitor cells (HSPCs). We show that human HSPCs display a clonal memory of division, as cells descending from the same ancestor cell divide synchronously over multiple generations. In parallel, HSPCs inherit a clonal memory of fate commitment, independently of lineage identity. Both forms of clonal memory persist over at least two divisions, across different HSPC commitment stages and cell culture conditions. In contrast, malignant haematopoiesis exhibits lower synchronicity, revealing a disruption of clonal memory in leukaemic cells. Epigenetic remodelling using a bromodomain inhibitor partially restores the clonal memory in division in leukaemic HSPCs, highlighting the plasticity of this trait and its potential for therapeutic modulation. Our findings position clonal memory as a key regulator of human haematopoietic stem cell behaviour. Demonstrating that clonal memory can be modulated opens avenues for tuning cell heterogeneity in healthy and pathological tissues.
    DOI:  https://doi.org/10.1038/s41467-026-75250-y
  5. Leukemia. 2026 Aug 25.
    Ivosidenib monotherapy in IDH1 mutated myelodysplastic neoplasm/syndrome.
    Marie Sébert, Emmanuelle Clappier, Sylvie Chevret, Hugo Bergugnat, Odile Rauzy, Aspasia Stamatoullas, Sophie Dimicoli-Salazar, Lamya Ait Si Selmi, Cendrine Chaffaut, Fatiha Chermat, Lise Larcher, Lauriane Goldwirt, Sylvain Thepot, Pierre Peterlin, Sophie Park, Marie-Pierre Gourin, Norbert Vey, Cécile Bally, Sébastien Maury, Gaelle Fossard, Maud D'Aveni, Anne-Laure Taksin, Thomas Cluzeau, Pierre Fenaux, Lionel Adès.
      Ivosidenib (IVO) is an oral inhibitor of mutant IDH1 (IDH1m) approved for treatment of IDH1m acute myeloid leukemia (AML) in association with Azacitidine (AZA). We investigated safety and efficacy of IVO monotherapy in patients with IDH1m myelodysplastic neoplasm/syndrome (MDS). This multicenter phase 2 trial enrolled three cohorts: high-risk (HR-) relapse or refractory (R/R) patients after AZA (cohort A), treatment-naïve HR-patients (cohort B) and low-risk patients refractory to erythropoiesis-stimulating agents (cohort C). All patients received 28-day cycles of IVO at 500 mg once daily. Between 2019 and 2023, 48 patients were included (median age 76.5 years). The ORR after 3 cycles was 63.6% (95%CI, 40.7-82.8) in cohort A, and 78.3% (95%CI, 56.3-92.5) in cohort B; the 12-month OS rate in cohorts A and B was 18.2% (95%CI, 7.5-44.1) and 91.3% (95%CI, 80.5-100), respectively. In cohort C, no significant toxicities were reported. Higher baseline IDH1 mutant clone size predicted response, whereas TP53 or IDH2 co-mutations were associated with resistance. Molecular clearance was not required for clinical benefit. IVO monotherapy was well tolerated and demonstrated sustained clinical activity across all IDH1m cohorts representing a potential therapeutic breakthrough in this frail population, particularly as a first-line therapeutic option in treatment naïve IDH1m HR-MDS patients (IDIOME, NCT03503409).
    DOI:  https://doi.org/10.1038/s41375-026-03100-3
  6. Leukemia. 2026 Aug 27.
    Cheminformatic identification of small molecules targeting acute myeloid leukemia.
    Megan R Daneman, Bernadetta Meika, Lois Armendariz, Elissa Tjahjono, Alexey V Revtovich, Leonid A Stolbov, Natthakan Thongon, Natalia Baran, Scott R Gilbertson, Vladimir V Poroikov, Natalia V Kirienko.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor prognosis and high relapse rates when treated with cytotoxic chemotherapeutics. Previously, we identified a family of small molecules that modulate mitochondrial function, referred to as PS127-family compounds. These drugs were selectively toxic to AML and were characterized by two predicted functions: apoptotic agonism and thioredoxin/glutathione reductase inhibition. Here, we uncovered a third critical predicted function, autophagic induction. Using a cheminformatic screen of ~4.2 million compounds for molecules with high predicted probability for all three functions, we found and validated hits that selectively killed AML cells, activated apoptosis, were dependent upon autophagic activation, and compromised glutathione metabolism by interfering with glutathione reductase, all of which are consistent with predictions. Compound treatment increased pools of cytosolic and mitochondrial ROS, decreased oxygen consumption, and reduced ATP synthesis. Structurally unrelated compounds caused the same phenotypes, validating our approach of screening for predicted function. Finally, we also observed strong synergy between these compounds and midostaurin and venetoclax, underscoring their therapeutic potential. Key phenotypes, including the compounds' impact on glutathione metabolism and synergy with doxorubicin and midostaurin, were confirmed in AML-patient-derived primary cells, validating the potential of these compounds for the development of future AML treatments.
    DOI:  https://doi.org/10.1038/s41375-026-03104-z
  7. Leukemia. 2026 Aug 24.
    PTBP1 controls oncogenic transcript processing and maintenance of acute myeloid leukemia.
    Zhendong Cao, Kurtis N McCannell, Sixiang Yu, Krista A Budinich, Won Jun Kim, Yuqing Jing, Michelle Y Wang, Steven Tittley, Zhuoyu Wen, Kathy Fange Liu, Junwei Shi, Omar Abdel-Wahab.
      RNA-binding proteins are critical regulators of gene expression in both normal physiology and cancer. Here we set out to systematically annotate the functions of RNA-associated proteins across multiple cancer types via domain-focused CRISPR screens targeting RNA-modifying enzymes and RNA-binding proteins. We utilized 3182 sgRNAs targeting 527 RNA-enzymatic and binding domains in 341 RNA-associated proteins and identified multiple RNA-binding proteins as dependencies in acute myeloid leukemia (AML), including the RNA splicing factor PTBP1 and the N6-methyladenosine reader RBM15, with a bias toward the aggressive KMT2A-rearranged (KMT2A-r) subtype of AML. Genetic and cellular validation confirmed all four RNA-binding domains of PTBP1 as required for KMT2A-r AML proliferation. In contrast to the lack of requirement for PTBP1 in myelopoiesis, PTBP1 suppression in AML caused cell cycle arrest, apoptosis, and induction of myeloid differentiation programs. Transcriptomic analysis revealed that PTBP1 loss disrupted the KMT2A-r-essential transcriptional program and caused widespread dysregulation of splicing. CLIP-seq analysis further identified that PTBP1 preferentially binds to a subset of transcripts critical for KMT2A-r AML proliferation, including IKZF1, MEF2C, EZH2, SIK3, and PBX3. Collectively, these findings demonstrate that PTBP1 supports AML proliferation by fine-tuning the expression and splicing of AML-essential genes, providing a workflow for systematically annotating RNA-associated protein dependencies in cancer.
    DOI:  https://doi.org/10.1038/s41375-026-03098-8
  8. Haematologica. 2026 Aug 27.
    Final results of a phase II study of the combination of azacitidine and ruxolitinib in patients with myelofibrosis.
    Sankalp Arora, Jayastu Senapati, Victoria Chu, Naveen Pemmaraju, Prithviraj Bose, Elias Jabbour, Tapan Kadia, Jing Ning, Dyana Saenz, Linghsa Zhou, Habiba Halim, Yesid Alvarado, Maro Ohanian, Courtney DiNardo, Koichi Takahashi, Nitin Jain, Farhad Ravandi, Hagop Kantarjian, Guillermo Garcia-Manero, Lucia Masarova, Naval Daver.
      Monotherapy with JAK2 inhibitors reduces splenomegaly and symptom burden but has limited effect on natural progression of myelofibrosis. We conducted a phase 2 clinical trial evaluating the combination of azacitidine (AZA) and ruxolitinib (RUX) in myelofibrosis. The interim analysis with 46 patients (median follow-up 28 months) demonstrated a response rate of 72%. We now report the final results of this clinical trial. The study primary endpoint was objective response rate by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria. From 3/2013 to 10/2021, 61 patients were treated (median age 66 years; range, 46-87 years). By baseline blast count, 54 patients had chronic phase disease (.
    DOI:  https://doi.org/10.3324/haematol.2026.301178
  9. Leukemia. 2026 Aug 24.
    TP53-mutant CHIP defines a pro-inflammatory phenotype and predicts adverse outcomes after CAR T-cell therapy.
    Giulia Rappa, Frank Ziemann, Kieron White, Linus Kruk, Samar Shamas, Amelie Muth, Kayleen Shi, Cristina Zucchinetti, Savanna Süß, Maja Rothenberg-Thurley, Alessandra Holzem, Tobias Tix, Agnese Petrera, Bianka Ksienzyk, Charlotte Bentenrieder, Katharina S Götze, Fabian Müller, Veit Bücklein, Kai Rejeski, Marion Subklewe.
      Clonal hematopoiesis of indeterminate potential (CHIP) has been well-characterized in patients receiving chemotherapy and hematopoietic cell transplantation. However, its immunologic relevance and potential role in modulating chimeric antigen receptor T-cell (CAR-T) therapy-related toxicities, inflammation, and clinical outcomes remains incompletely defined. In this exploratory study of 104 CAR-T recipients, we investigated the prognostic impact of pre-existing CHIP clones on toxicity and survival, and examined CHIP-associated inflammatory proteomic signatures leveraging longitudinal serum samples. Overall CHIP status was not associated with inflammatory toxicities, outcomes, or systemic inflammatory profiles. Analysis of clonal dynamics revealed TP53- and ASXL1-mutated clones to be the dominant expanding CHIP clones post-infusion, whereas DNMT3A- and PPM1D-mutated clones showed reduced clonal abundance over time. Notably, TP53-mutated CHIP was linked to lower platelet and hemoglobin levels, a higher baseline CAR-HEMATOTOX score, inferior clinical outcomes, and a distinct inflammatory signature. These findings identify TP53-mutated CHIP in CAR-T-treated patients as a high-risk CHIP genotype compared with other CHIP mutations. Importantly, patients who developed treatment-emergent myeloid neoplasms after CAR T-cell therapy exhibited distinct patterns of clonal expansion and inflammatory profiles. Together, these findings support a risk-adapted approach prioritizing longitudinal monitoring of TP53-mutated CHIP, especially in patients with high CAR-HEMATOTOX scores who develop cytopenias.
    DOI:  https://doi.org/10.1038/s41375-026-03083-1
  10. Br J Haematol. 2026 Aug 26.
    The PRIME trial: An investigator-initiated, multicentre, phase II study of the poly(ADP-ribose) polymerase inhibitor olaparib in isocitrate dehydrogenase (IDH)-mutated relapsed/refractory acute myeloid leukaemia and myelodysplastic syndromes.
    Rory M Shallis, Jennifer VanOudenhove, Namrata Chandhok, Justin Watts, Deepa Jeyakumar, Daniel R Reed, Jan Phillip Bewersdorf, Diane Durecki, Scott Boerner, Richard F Little, Steven D Gore, Jing Li, Xun Bao, Li Chen, Sayak Ghatak, Thomas Prebet, Ranjit S Bindra, Amer M Zeidan, Stephanie Halene.
      
    Keywords:   AML ; IDH ; MDS ; PARP ; acute myeloid leukaemia; myelodysplastic
    DOI:  https://doi.org/10.1111/bjh.70756
  11. Blood Neoplasia. 2026 Aug;3(3): 100256
    Homozygosity of germ line JAK2 46/1 haplotype contributes to phenotype and outcome diversity in polycythemia vera.
    Paola Guglielmelli, Chiara Maccari, Manjola Balliu, Giuseppe Gaetano Loscocco, Naseema Gangat, Valentina Boldrini, Giulio Capecchi, Leonardo Signori, Alessio Enderti, Giada Rotunno, Chiara Paoli, Sofia Danesi, Cecilia Matteoli, Francesco Mannelli, Tiziano Barbui, Ayalew Tefferi, Alessandro Maria Vannucchi.
      
    DOI:  https://doi.org/10.1016/j.bneo.2026.100256
  12. Adv Geriatr Med Res. 2026 Sep;pii: e260018. [Epub ahead of print]8(3):
    Hematopoietic Stem Cell Metabolism during Stress and Aging.
    Devyani Sharma, Marie-Dominique Filippi.
      Hematopoietic stem cells (HSCs) support the lifelong production of blood but undergo substantial changes during aging. Aging causes a progressive decline in the repopulation ability of HSC with changes in the proportion of myeloid and lymphoid lineages. Metabolic remodeling is increasingly recognized not only as a consequence of HSC aging but also as an active contributor to age-associated changes in HSC function. Quiescent HSCs have low metabolic activity, in contrast with their highly proliferative progeny. During regeneration, drastic metabolic remodeling enables HSC to exit quiescent and proliferate to sustain blood production for emergency hematopoiesis. Metabolic activity drifts during aging. Changes in glycolysis, mitochondrial activity, and lysosomal functions all contribute to a slow decline of the hematopoietic system. In this review, we focus on the metabolic needs of HSCs, how they control their quiescence and proliferation, and how a metabolic drift contributes to HSC aging.
    Keywords:  HSC aging; bone marrow niche; fatty acid oxidation; hematopoietic stem cells; metabolic remodeling; mitochondrial metabolism; mitochondrial quality control; oxidative phosphorylation; stem cell quiescence; stress hematopoiesis
    DOI:  https://doi.org/10.20900/agmr20260018
  13. Cell Stem Cell. 2026 Aug 25. pii: S1934-5909(26)00272-9. [Epub ahead of print]
    Spatial profiling of the spleen in mouse and human myelofibrosis reveals complement-driven immune-stromal interactions as a therapeutic target.
    Bérénice Dugué, Pia Wanner, Mayra L Ruiz Tejada Segura, Mohamed Saad, Lucas Greven, Katrin Götz, Carmen Schalla, Stijn Fuchs, Gerjanne Vroeg In de Wei, Hélène F E Gleitz, Anna Katharina Galyga, Jessica Ellen Pritchard, Tobias Schlangen, Niklas Lutterbach, Salim Atakhanov, Lina Schmidt, Marie Parrens, Armelle Peyrat, Damien Luque Paz, Marie-Christine Copin, Alexandre Guy, Victor-Emmanuel Brett, Olivier Mansier, Susanne Schmitz, Paul Wanek, Bella Banjanin, Stephani Schmitz, Martina Crysandt, Marian C Clahsen-van Groningen, Konnie M Hebeda, Sascha Dietrich, Harald Voehringer, Matthias Meyer-Bender, Kristin Séré, Chloé James, Adam Benabid, Ivan Costa, Charles Dussiau, Rebekka K Schneider.
      Splenomegaly is a defining feature of myelofibrosis, yet the contribution of splenic mesenchymal stroma to disease progression remains unclear. We combined spatial and single-nucleus transcriptomics of patient spleens with spatial and single-cell transcriptomics, as well as imaging analyses, of murine spleens to map extramedullary hematopoiesis niches. Activated red pulp reticular cells localize near hematopoietic stem and progenitor cells, and early disease is characterized by marginal zone disruption with lymphoid depletion preceding stromal remodeling. Trajectory analyses reveal a shift in reticular cells from hematopoiesis-supportive to inflammatory and pro-fibrotic states, driven by macrophage- and megakaryocyte-derived signals that activate complement and induce tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), extracellular matrix, and Thbs1 programs. Non-hematopoietic complement component C3 deficiency or pharmacological C3 inhibition suppresses these pathways, restores splenic architecture, and reduces splenomegaly and bone marrow fibrosis. These findings identify complement-dependent stromal reprogramming as a mechanism governing hematopoietic niches and as a targetable axis in myelofibrosis.
    Keywords:  complement C3; extramedullary hematopoiesis; fibrosis; hematopoietic stem and progenitor cells; microenvironment; myelofibrosis; reticular cells; splenic stroma; splenomegaly; stromal reprogramming
    DOI:  https://doi.org/10.1016/j.stem.2026.07.012
  14. Blood. 2026 Aug 24. pii: blood.2026034204. [Epub ahead of print]
    Ferroptotic stress promotes hematopoietic stem cell aging through S1P-dependent epigenetic and lipid remodeling.
    Yijun Zhao, Yishan Li, Xiaobin Tian, Jingjing Guan, Yixin Ma, Xiaoqi Wang, Hongjian Zhang, Kaitao Wang, Kaizheng Jiang, Yalan Yang, Yuan Pan, Weiwei Liu, Xianzhe Hu, Jiafan Cao, Weiming Liu, Mengyun Xie, Kexin Sun, Jiayin Zheng, Ying Wang, Yucan Zheng, Yanjun Ling, Keyue Yang, Xuying Pei, Xiang-Yu Zhao, Xi Zhang, Pengxu Qian, Changzheng Li, Tian Lan, Linjia Jiang, Meng Zhao.
      Aging of hematopoietic stem cells (HSCs) impairs hematopoietic regeneration and differentiation, contributing to immune aging, systemic inflammation, and reduced lifespan. Strategies to rejuvenate aged HSCs and restore immune homeostasis remain limited. Here, we identify ferroptotic stress as a key contributor to HSC aging. Mechanistically, increased sphingosine metabolism elevates sphingosine-1-phosphate (S1P), which suppresses HDAC activity and enhances H3K9 acetylation to upregulate lysophosphatidylcholine acyltransferase 2 (Lpcat2), thereby promoting the accumulation of pro-ferroptotic phospholipids in aged HSCs. Genetic or pharmacological inhibition of sphingosine kinase 2 (Sphk2) reduces S1P levels, suppresses Lpcat2 expression, and attenuates ferroptotic stress in aged mouse and human HSCs. Notably, Sphk2 inhibition improves HSC function, restores immune homeostasis, and modestly extends lifespan in aged mice. Together, these findings identify an S1P-HDAC-Lpcat2 pathway linking epigenetic and lipid remodeling to ferroptotic stress and highlight sphingosine metabolism as a therapeutic target for HSC aging.
    DOI:  https://doi.org/10.1182/blood.2026034204
  15. Cell Stem Cell. 2026 Aug 25. pii: S1934-5909(26)00303-6. [Epub ahead of print]
    Splenic extramedullary hematopoiesis in myelofibrosis is shaped by transcriptomic and epigenetic dysregulation.
    Rebecca Austin, Madeline H Kowalski, Xiaoli Wang, Ziyan Lin, Bettina Nadorp, Nicholas Ward, Pier Edoardo Rovatti, Audrey Lasry, Zhengxi Sun, Julia Rojo-Tomillo, Giovanni Gambi, Tejas Patel, Hua Zhou, M D Babu Mia, Eduardo Esteva, Igor Dolgalev, Valeria Mezzano, Suhita Ray, Sergei Doulatov, Tatyana Gindin, Sanam Loghavi, Bethan Psaila, Aristotelis Tsirigos, Rahul Satija, Iannis Aifantis, Ronald Hoffman.
      Myelofibrosis (MF) is a chronic, progressive myeloproliferative neoplasm characterized by bone marrow fibrosis, ineffective blood cell production, and neoplastic extramedullary hematopoiesis (EMH) occurring primarily within the spleen. To explore the molecular mechanisms underlying splenic EMH, we performed single-cell transcriptional and chromatin profiling of cells from MF spleens that had been surgically removed. We demonstrate significant expansion of hematopoietic stem and progenitor cells, coupled with aberrant differentiation toward the erythroid and megakaryocytic lineages, associated with a significant enrichment of inflammatory pathways with enhanced NF-κB signaling and IFN responses, as well as dysregulation of the inferred function of differentiation-defining transcription factors. Finally, we report a significant remodeling of the immune microenvironment in MF spleens, characterized by emergence of dysfunctional T cell subsets and inflammatory memory B cells, suggesting the concomitant establishment of a pro-inflammatory and immune-tolerant tumor microenvironment within the spleen that influences hematopoietic cell differentiation and impairs tumor immune surveillance.
    Keywords:  extramedullary hematopoiesis; immune system; inflammation; megakaryocyte; myelofibrosis; spleen
    DOI:  https://doi.org/10.1016/j.stem.2026.08.002
  16. J Exp Med. 2026 Sep 07. pii: e20252333. [Epub ahead of print]223(9):
    PML-driven sumoylation of PML::RARA-bound repressors drives hematopoietic progenitor immortalization.
    Hsin Chieh Wu, Emmanuel Laplantine, Cécile Esnault, Michiko Niwa-Kawakita, Yi Zhang, Viviane De Almeida Bastos, Marie-Claude Geoffroy, Hugues de Thé.
      While acute promyelocytic leukemia (APL) is always driven by fusions involving one of the three retinoic acid receptors, why PML and RARA are the preferred fusion partners has remained largely unsettled. Here, we demonstrate that corepressor (NCoR) binding onto the RARA moiety of PML::RARA is required for hematopoietic progenitor immortalization. We establish that PML-mediated tethering of the UBC9 SUMO-conjugating enzyme onto PML::RARA enforces SUMO2 conjugation of multiple RARA partner proteins, notably the NCoR complex, boosting its repressive power. PML mutants that fail to recruit UBC9 yield PML::RARA fusions that promote neither NCoR sumoylation nor transformation. Conversely, direct UBC9/RARA fusion drives both efficient corepressor complex sumoylation and immortalization. Sumoylation inhibitors reactivate retinoic acid target genes in PML::RARA-expressing, but not in RARA-expressing, progenitors and trigger APL differentiation. Thus, fusion of PML to RARA entails an unexpected gain of function that boosts RARA-mediated transcriptional repression through sumoylation of PML::RARA-bound proteins, explaining the recurrent implication of PML and RARA in APL pathogenesis.
    DOI:  https://doi.org/10.1084/jem.20252333
  17. NEJM Evid. 2026 Sep;5(9): EVIDoa2500352
    Consolidation Therapy Based on Mutation Clearance in Acute Myeloid Leukemia.
    Meagan A Jacoby, David H Spencer, Feng Gao, Geoffrey L Uy, Tasha Burton, Sharon E Heath, Feiyu Du, Michelle O'Laughlin, Robert S Fulton, Christopher A Miller, Eric J Duncavage, Mark A Schroeder, Armin Ghobadi, Iskra Pusic, Keith E Stockerl-Goldstein, Brad S Kahl, Amanda F Cashen, Matthew J Christopher, Nathan Singh, Ravi Vij, Zachary D Crees, Lukas D Wartman, Ryan B Day, Todd A Fehniger, Karolyn A Oetjen, Dilan A Patel, Miriam Y Kim, Michael J Slade, Francesca Ferraro, Matthew J Walter, Camille N Abboud, Ramzi Abboud, Daniel C Link, Zeina A Al-Mansour, Christopher R Cogle, Eric J Huselton, John F DiPersio, Peter Westervelt, Timothy J Ley.
       BACKGROUND: Optimal consolidation therapy for patients with intermediate-risk acute myeloid leukemia (AML) in first complete remission (CR1) is controversial. Retrospective studies have suggested that the clearance of leukemia-associated mutations (LAMs) in CR1 may predict lower relapse risk and better outcomes with high-dose cytarabine (HiDAC) consolidation. We tested this hypothesis prospectively.
    METHODS: We performed a phase II, multicenter study of intermediate-risk, transplant-eligible, de novo AML in patients 18-60 years of age who achieved a complete remission (CR) or CR with incomplete count recovery (CRi) after induction therapy. Tumor and normal whole-exome sequencing was performed at presentation to identify somatic LAMs (median ∼30 LAMs/patient). In remission marrow samples, LAM variant allele frequencies (VAFs) were then remeasured using a VAF cutoff of less than 2.5% to define clearance. Patients who met this LAM clearance threshold received HiDAC consolidation, whereas those with persistent LAMs (VAF ≥2.5%) were recommended to undergo allogeneic hematopoietic cell transplantation. The primary endpoint compared relapse-free survival (RFS) of intermediate-risk patients with complete LAM clearance to historical cohorts with intermediate-risk AML who received HiDAC-based regimens in CR1. To account for an unplanned interim assessment, the significance threshold for the primary analysis was 0.01.
    RESULTS: Among 100 patients who were evaluated, intermediate-risk patients who cleared all LAMs in CR1 (n=33) had a median RFS of 33.1 months (95% confidence interval, 11.7-NA) compared to a median RFS of 11.7 months in the historical cohort (n=239; 95% confidence interval, 9.9-15.6, P=0.015).
    CONCLUSIONS: Among patients with intermediate-risk AML, clearance of LAMs after induction, followed by HiDAC consolidation in CR1, was associated with longer RFS compared with similarly treated historical controls. Although this result did not meet the prespecified threshold for statistical significance, the reported association sets the stage for a randomized trial to further evaluate this strategy. (ClinicalTrials.gov number, NCT02756962.).
    DOI:  https://doi.org/10.1056/EVIDoa2500352
  18. Blood. 2026 Aug 25. pii: blood.2025031899. [Epub ahead of print]
    Epigenetic markers expand genetic risk estimation in acute myeloid leukemia.
    Salma B Abdelbaky, Brian Giacopelli, Jessica Kohlschmidt, Kyoko Yamaguchi, Krzysztof Mrózek, Ada Cleary Sher, Yue-Zhong Wu, Shelley Orwick, Deedra Nicolet, Kevin R Coombes, James S Blachly, Bayard L Powell, Jonathan E Kolitz, William Blum, Maria R Baer, Andrew J Carroll, Richard M Stone, Ann-Kathrin Eisfeld, John C Byrd, Christopher C Oakes.
      Gene mutations and chromosome abnormalities are important components of prognostication in acute myeloid leukemia (AML). Here we assessed whether DNA methylation patterns in AML patients can augment risk assessments provided by genetic and other markers to better predict outcomes. Unsupervised DNA methylation patterns separating patients into 13 DNA methylation subtypes (epitypes) were used to classify 1,262 patients with de novo AML. Epitypes were predominantly comprised of a predominant genetic alteration; however, some patients within epitypes lacked cardinal alterations and were termed genetic alteration-like. Interestingly, patients displaying alteration-like DNA methylation patterns of CEBPAbZIP, FLT3-ITD, core-binding factor, KMT2A-rearrangements and other abnormalities displayed outcomes similar to patients with actual cardinal alterations. We further derived a DNA methylation signature enriched in patients with FLT3-ITD mutations that involved hypomethylation of STAT binding sites, termed the STAT hypomethylation signature (SHS). SHS positivity identified patients with inferior outcomes further adding to the prognostic significance of FLT3-ITD. Machine learning modeling revealed these DNA methylation signatures together significantly added to genetic, demographic and clinical markers to predict remission, relapse and overall survival. In summary, DNA methylation signatures capture patients who mimic cardinal genetic mutations providing additional prognostic information that may be used to in concert with standard genetic markers.
    DOI:  https://doi.org/10.1182/blood.2025031899
  19. Am J Hematol. 2026 Aug 22.
    Mitigating HLA Disparity in AML Transplantation: Comparable Outcomes After Haploidentical and 9/10 Mismatched Unrelated Donor Transplantation With Treosulfan and PTCy.
    Daniele Avenoso, Mirko Farina, Michele Malagola, Yves Chalandon, Giorgia Saporiti, Annalisa Imovilli, Enrico Derenzini, Peter Remenyi, Massimo Martino, Maija Itala-Remes, Renato Fanin, Didier Blaise, Desiree Kunadt, Arancha Bermudez Rodriguez, Franca Fagioli, Thomas Schroeder, Irene Cavattoni, Maud Ngoya, Mohamed Houhou, Mohamad Mohty, Eolia Brissot, Fabio Ciceri.
      Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative strategy for acute myeloid leukemia (AML), but the impact of HLA disparity in the era of posttransplant cyclophosphamide (PTCy) and reduced-toxicity conditioning remains unclear. We performed an EBMT registry study including 275 adult AML patients in first complete remission undergoing first allo-HSCT between 2012 and 2023 using a uniform platform of treosulfan-based conditioning and PTCy. Among them, 206 received haploidentical grafts and 69 underwent 9/10 mismatched unrelated donor (MMUD) transplantation. Median follow-up was 2.5 years. At 2 years, overall survival was 73.1% after haploidentical transplantation and 71.6% after MMUD transplantation (p = 0.96). Leukemia-free survival at 1 year was 66.3% and 65.2%, respectively (p = 0.76). Relapse incidence (17.1% vs. 18.7%, p = 0.84) and nonrelapse mortality (16.6% vs. 16.1%, p = 0.86) were comparable between groups. Rates of Grade II-IV and Grade III-IV acute GVHD were similar, whereas chronic GVHD was higher after haploidentical transplantation (36.4% vs. 12.7%, p = 0.001), without differences in extensive forms. In multivariable analyses, donor type was not associated with overall survival, leukemia-free survival, relapse incidence, or nonrelapse mortality. Increasing age adversely affected outcomes, while Karnofsky performance status ≥ 90 and reduced-intensity conditioning were associated with improved survival. These findings suggest that, within a treosulfan-PTCy platform, major transplant outcomes are comparable between donor types, although haploidentical transplantation was associated with a higher incidence of chronic GVHD.
    DOI:  https://doi.org/10.1002/ajh.70483
  20. Br J Haematol. 2026 Aug 26.
    The role of the adenosinergic pathway in resistance to hypomethylating agents in patients with high-risk myelodysplastic syndromes.
    George Vrachiolias, Eleftheria Lamprianidou, Athanasios Tasis, Theodoros Spyropoulos, Despoina Dimitriou, Chryssa Kymparidou, Christina Misidou, Konstantinos Liapis, Emmanouil Spanoudakis, Maria Koffa, Menelaos Papoutselis, Iliana Stamatiou, Elsa Bernard, Elli Papaemmanuil, Ioannis Mitroulis, Ioannis Kotsianidis.
      
    Keywords:  adenosinergic pathway; ectonucleotidases; hypomethylating agents; hypoxic tumours; immunosuppression; myelodysplastic syndrome
    DOI:  https://doi.org/10.1111/bjh.70778
  21. Br J Haematol. 2026 Aug 28.
    Functional assessment of inherited myeloid neoplasm-associated SAMD9L germline variants via Monoallelic CRISPR modelling.
    Elena Vuelta, Alessandro Liquori, Matias Morín, Lucia Soletto, Miguel Ángel Marugal, Marta Santiago-Balsera, Miguel Gallardo, Miguel Ángel Moreno-Pelayo, José Cervera, Alejandra Sanjuan-Pla.
      While the majority of myeloid neoplasms are sporadic, the increasing application of germline genetic testing has led the World Health Organization to designate 'Myeloid malignancies with germline predisposition' as a distinct clinical entity, carrying major implications for clinical care and research. Germline variants in the Sterile alpha motif domain-containing 9-like (SAMD9L) gene are specifically associated with an increased risk for these malignancies. In this study, we functionally modelled two novel SAMD9L variants-p.N697Y and p.K1294*-alongside two previously reported variants (p.T233N and p.H880Q). We generated heterozygous knock-in cellular models in the Human leukemia (HL-60 myeloid cell line) for each variant using homology-directed repair-based Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9) gene editing. Functional assays, focused on proliferation and protein translation, confirmed that the p.T233N, p.N697Y and p.K1294* variants all caused a decreased rate of protein translation. These results provide functional evidence to fine-tune the classification of these SAMD9L variants and significantly advance our understanding of the molecular mechanisms by which SAMD9L variants drive inherited myeloid neoplasms.
    Keywords:  CRISPR/Cas9 gene editing; SAMD9L; inherited myeloid neoplasms
    DOI:  https://doi.org/10.1111/bjh.70799
  22. Blood. 2026 Aug 21. pii: blood.2025030252. [Epub ahead of print]
    International Consensus Criteria for the Diagnosis, Treatment Initiation, and Response Assessment for T-LGL Leukemia.
    Jonathan E Brammer, Natali Pflug, Renato Zambello, Julia Almeida, Dima El-Sharkawi, Lubomir Sokol, David Feith, Zachary Braunstein, Miguel Ruiz, Till Braun, Tony Marchand, Satu Mustjoki, Carlos Bravo-Perez, Monika Brüggemann, Pierluigi Porcu, Fumihiro Ishida, Jaroslaw P Maciejewski, Marshall E Kadin, Gianpietro Semenzato, Anton W Langerak, Thierry Lamy, Thomas P Loughran, Marco Herling.
      Large granular lymphocytic leukemia (LGLL) is an uncommon and likely under-diagnosed leukemia that causes severe neutropenia and anemia and can have profound effects on the quality of life for afflicted patients. Frequently associated with various auto-immune phenomena, LGLL is a paradigm for a highly interdisciplinary disease. Recent advances in our pathobiological understanding of LGLL, along with the development of novel agents, have stimulated a growing number of clinical trials and innovative approaches targeting this disease. Currently, the absence of uniform diagnostic and response criteria for LGLL results in significant heterogeneity in diagnosis and response assessment across studies. Furthermore, with the emergence of a variety of novel experimental therapeutics and an increasing number of clinical trials, it becomes critical to better define the key diagnostic, treatment and response parameters for this disease. The International LGLL Consortium was created to develop cross-disciplinary expert consensus on uniform diagnostic, treatment, and response criteria for LGLL suitable for both routine clinical use and interventional trials while facilitating cross-study comparisons. Utilizing an evidence-based framework, along with the international panel that comprises the LGLL Consortium, this report delineates the key criteria that will serve as a foundation for both the clinical management and future investigations in LGLL.
    DOI:  https://doi.org/10.1182/blood.2025030252
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