bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–10–04
29 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Somatic DDX41 mutations confer neomorphic splicing activity in the pathogenesis of myelodysplastic neoplasms.
  2. Two cases of an imatinib-sensitive PRKG2::PDGFRA-positive chronic myeloid neoplasm with basophilia.
  3. Clinical and molecular characteristics of clonal monocytosis with and without cytopenia(s).
  4. Exploiting an epigenetic resistance mechanism to PI3-kinase inhibition in leukemic stem cells.
  5. CALR-mutated myeloproliferative neoplasms: Refining molecular risk beyond the driver.
  6. CSF3R compound mutations produce a hyperproliferative leukemia driven by overexpression of PIM kinases.
  7. Adult hematopoietic stem cells activate a normally fetal-restricted program to functionally expand ex vivo.
  8. Greatwall kinase regulates acute myeloid leukaemia cell division through a non-canonical mechanism.
  9. Functional Classification of Monoallelic TP53 Mutations Refines Prognostic Stratification in Myelodysplastic Neoplasms.
  10. PIM1 in myeloproliferative neoplasms: potential pathogenic and therapeutic implications.
  11. The Fanconi anemia pathway restrains MLL-rearranged leukemogenesis through suppressing non-homologous end joining-mediated genomic instability.
  12. Very Long Chain Fatty Acid Synthesis is a Targetable Dependency in RAS Pathway Mutant Leukemia.
  13. Germline homologous recombination deficiency influences TP53-mutant clonal hematopoiesis fitness during platinum and PARP inhibitor treatment.
  14. Loss of TCA cycle turning promotes stem cell function.
  15. Age over sibling: Younger unrelated donors provide superior outcomes compared to sibling donors in fully matched HCT in older AML/MDS patients.
  16. Alterations in 3D-DNA architecture drive unique leukemic profiles in IDH1- and DNMT3A-mutant acute myeloid leukemia.
  17. Allogeneic hematopoietic stem cell transplantation rather than specific front-line therapy is associated with long-term survival in blastic plasmacytoid dendritic cell neoplasm: the Mayo Clinic experience.
  18. DNA methylation status at diagnosis in MDS predicts response to azacitidine.
  19. Prefibrotic bone marrow microenvironment is a hallmark of clonal hematopoiesis.
  20. Single-allele nanoscale mapping of regulatory variants.
  21. Human genetics implicates a BACH2-NRF2 axis in fetal haemoglobin activation.
  22. NicheScribe: consistent and generalizable annotation of stromal cells in the murine bone marrow niche.
  23. The Role of Aldehyde Dehydrogenase 2 in Hematopoiesis is Stress-Severity Dependent.
  24. Protocol for ribosome-protected fragment isolation from rare leukemia cell populations.
  25. Targeting ClpP Rewires the Metabolic-Immune Axis in Acute Myeloid Leukemia.
  26. Clonal hematopoiesis-associated DNMT3A mutations derepress bivalent Polycomb target genes and enhance macrophage migration.
  27. Impaired Mevalonate-Dependent NAD⁺ Regeneration Suppresses Serine Biosynthesis and Enhances Sensitivity to PHGDH Inhibition.
  28. Reactivation of the embryonic ζ-globin gene ameliorates severe forms of α-thalassemia.
  29. Opposing functions of gut immunomodulatory metabolites on CAR-T therapy.
  1. bioRxiv. 2026 Sep 24. pii: 2026.09.23.753593. [Epub ahead of print]
    Somatic DDX41 mutations confer neomorphic splicing activity in the pathogenesis of myelodysplastic neoplasms.
    Rasika Venkataraman, Noemi Puccio, Tun-Yun Hsueh, Elizabeth A Bonner, Fu-Yen Chang, Erica A Arriaga-Gomez, Axia Song, Takero Miyagawa, Jahan Rahman, Oluwanifemi Akinwande, Sayantani Sinha, Ettaib El Marabti, Robert S Welner, Rui Lu, P Brent Ferrell, Martin Carroll, Jacob S Appelbaum, Derek L Stirewalt, Omar Abdel-Wahab, Anthony Rongvaux, Xueyan Chen, Kikkeri N Naresh, Sebastian M Fica, Stanley C Lee.
      Germline mutations in the RNA helicase DDX41 are the most common genetic predisposition to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), representing 5-7% of AML. Over 70% of patients acquire a somatic mutation at specific hotspots ( R525H/G530D ) in the helicase domain of DDX41 in trans , which is linked to disease progression. DDX41 has diverse cellular functions, including RNA splicing, ribosome biogenesis, R-loop resolution and inflammation. However, the mechanisms by which somatic DDX41 mutations drive MDS/AML pathogenesis are yet to be determined. Here, we systematically evaluated the function of pathogenic, missense germline and somatic DDX41 mutations. We report that DDX41 somatic mutations are gain of function alleles and fail to rescue AML cell growth, distinct from germline DDX41 mutations. DDX41 somatic mutations R525H and G530D drive widespread splicing changes in isogenic AML cell lines, consistent in genetically engineered murine bone marrow HSPCs and CD34 + cells from DDX41 -mutant MDS/AML patients. Mechanistically, DDX41-R525H exhibits increased RNA binding affinity compared to wildtype, with aberrantly spliced RNA targets overlapping with enriched binding. Strikingly, aberrant splicing of SEPTIN7 is enriched exclusively in CD34 + HSPCs of patients harboring both germline and somatic DDX41 mutations but absent in samples with germline mutation alone or lacking DDX41 mutations altogether. SEPTIN7 mis-splicing introduces a premature stop codon resulting in its downregulation at the protein level. SEPTIN7 is a known regulator of cytokinesis, HSC polarity and repopulation capacity. Our results identify a novel mis-spliced candidate, SEPTIN7, whose deregulation implicates a mechanism by which the DDX41 somatic mutations promote dysplastic hematopoiesis.
    DOI:  https://doi.org/10.64898/2026.09.23.753593
  2. Leukemia. 2026 Sep 28.
    Two cases of an imatinib-sensitive PRKG2::PDGFRA-positive chronic myeloid neoplasm with basophilia.
    Johannes Lübke, Olaposi Yomade, Manja Meggendorfer, Jan-Hendrik Kozik, Marietta Truger, Wencke Walter, Stephan Hutter, Uwe Martens, Martina Rudelius, Nicole Naumann, Alice Fabarius, Matthew Salmon, Carl Crodel, Jenny Rinke, Hans-Peter Horny, Florian H Heidel, Jan Hinrich Bräsen, Hans-H Kreipe, Georgia Metzgeroth, Wolf-Karsten Hofmann, Nicholas C P Cross, Torsten Haferlach, Juliana Schwaab, Andreas Hochhaus, Andreas Reiter.
      
    DOI:  https://doi.org/10.1038/s41375-026-03132-9
  3. Leukemia. 2026 Sep 28.
    Clinical and molecular characteristics of clonal monocytosis with and without cytopenia(s).
    Tariq Kewan, Hadil Zureigat, Pradeep Pankaj, Rong He, Dragan Jevremovic, Patricia Greipp, Antoine N Saliba, Aasiya Matin, Mehrdad Hefazi Torghabeh, Naseema Gangat, William Hogan, Hassan Alkhateeb, Cecilia Arana Yi, James Foran, Mark Litzow, Mithun Vinod Shah, Kebede Begna, Badar Talha, Yael Kusne, Abhishek A Mangaonkar, Aref Al-Kali, Kaaren Reichard, Mrinal M Patnaik.
      Clonal monocytosis of undetermined significance (CMUS) and clonal cytopenia with monocytosis of undetermined significance (CCMUS) are recently defined precursor states, with unclear progression rates to myeloid neoplasms (MN), including chronic myelomonocytic leukemia (CMML). We evaluated a cohort of 958 patients with sustained monocytosis ( ≥ 0.5 ×109/L, ≥10%) and stringently excluded MN. Among 958 patients, 74 met criteria for CMUS (n = 10) and CCMUS (n = 64), respectively. These patients were compared with a cohort with oligo monocytic-CMML (OM-CMML; n = 47). CMUS patients were younger (median age: 63 years), whereas CCMUS demonstrated lower BM blast %, in comparison to OM-CMML (median blast %: 1 vs. 2). OM-CMML was enriched for TET2 (60% vs. 32%, p = 0.012), ASXL1 (40% vs. 9%, p < 0.001), and SRSF2 (45% vs. 8%, p < 0.001) mutations, while CMUS/CCMUS had higher rates of DNMT3A (36% vs. 9%, p < 0.001) and PPM1D (12% vs. 0, p = 0.029) mutations. Mutation burden and VAF for most mutations (except SRSF2) were significantly higher in OM-CMML. DNMT3A mutations in CMUS/CCMUS often involved the methyltransferase (MT) domain, and MT domain mutations and co-mutations were associated with progression of CCMUS to CMML. With a median follow-up of 31 months, there were no progression events in CMUS patients, while 13% of CCMUS patients progressed to MN, mainly CMML (7/8). Median OS was inferior in OM-CMML (71 months) compared to CMUS/CCMUS (not reached), p < 0.001. Our findings demonstrate that CMUS and CCMUS represent biologically distinct clonal states with variable progression risk and highlight the importance of integrating morphologic and genomic data to refine classification.
    DOI:  https://doi.org/10.1038/s41375-026-03140-9
  4. Leukemia. 2026 Sep 28.
    Exploiting an epigenetic resistance mechanism to PI3-kinase inhibition in leukemic stem cells.
    Shira G Glushakow-Smith, Imit Kaur, Simone Sidoli, Shayda Hemmati, Ellen Angeles, Taneisha Sinclair, Samarpana Chakraborty, Aaliyah Battle, Kristina Ames, Swathi-Rao Narayanagari, Rotila Hyka, Mark Soto, Melissa Tracy, Jayaram Vankudoth, Seiya Kitamura, Linde A Miles, Ulrich Steidl, Aditi Shastri, Amit Verma, Kira Gritsman.
      Acquired non-genetic resistance mechanisms to existing therapies contribute to poor outcomes for acute myeloid leukemia (AML) patients, and the inability to target leukemic stem cells (LSCs) can lead to relapse. To overcome these challenges, we tested whether LSCs have dependencies on PI3- kinase (PI3K). We found that LSCs are susceptible to isoform-selective targeting of PI3K and are particularly dependent on the p110 alpha isoform of PI3K. We discovered that PI3K inactivation leads to dynamic changes in EZH2/PRC2 function in leukemic cells, and we uncovered downregulation of EZH2 protein levels as an adaptive resistance mechanism in response to PI3K inhibition. We found that PI3K inhibition in AML cells can lead to compensatory upregulation of EZH1, and that EZH1 knockdown can sensitize AML cells to PI3K inhibition. We leveraged this resistance mechanism by combining a PI3K inhibitor with an EZH1/2 dual inhibitor, which successfully overcomes the acquired resistance and leads to sustained targeting of AML cells ex vivo and in murine AML and PDX models in vivo. This study identifies a promising novel therapeutic regimen for targeting LSCs in AML.
    DOI:  https://doi.org/10.1038/s41375-026-03145-4
  5. Br J Haematol. 2026 Sep 27.
    CALR-mutated myeloproliferative neoplasms: Refining molecular risk beyond the driver.
    Giuseppe G Loscocco.
      Calreticulin (CALR)-mutated myeloproliferative neoplasms (MPNs) are generally associated with favourable outcomes, yet considerable heterogeneity persists across the disease course. Mawalkar et al. provide long-term data across essential thrombocythaemia (ET), post-ET myelofibrosis (MF) and primary MF, highlighting the prognostic relevance of additional somatic mutations. The contribution of co-mutational context, variant allele frequency (VAF), disease origin and timing of molecular assessment remains incompletely defined. Commentary on: Mawalkar et al. Outcome heterogeneity in CALR-mutated myeloproliferative neoplasms. Br J Haematol 2026 (Online ahead of print). doi: 10.1111/bjh.70859.
    Keywords:  CALR mutation; clonal evolution; essential thrombocythaemia; high‐molecular‐risk; myelofibrosis; variant allele frequency
    DOI:  https://doi.org/10.1111/bjh.70860
  6. Blood. 2026 Sep 09. pii: blood.2026034085. [Epub ahead of print]
    CSF3R compound mutations produce a hyperproliferative leukemia driven by overexpression of PIM kinases.
    Breanna N Maniaci, Jacob Edward Porter, Hanqian L Carlson, Grace Potter, Thai T Nguyen, Amara Pang, Jeffrey W Tyner, Andrew Emili, Theodore P Braun, Julia E Maxson.
      Colony Stimulating Factor 3 Receptor (CSF3R) mutations are the molecular hallmark of chronic neutrophilic leukemia (CNL). A subset of these patients (~25%) have two mutations in CSF3R on the same allele. These "compound" CSF3R mutations include both an activating point mutation and a cytoplasmic truncating mutation. While compound mutations are prevalent, we have a limited understanding of their molecular characteristics. In this study, we interrogated the mechanisms driving the evolution of compound mutations. We found that CSF3R compound mutations induce a hyperproliferative leukemia compared to single mutations. Compound mutations also markedly enhance activation of STAT5 and ERK1/2 downstream of CSF3R. Utilizing a proteomics approach, we identified enrichment of MYC and mTOR pathways in compound mutant-cells. The most differentially expressed protein in this dataset was the kinase PIM1. We find that in CSF3R compound mutant-cells with high STAT activity there is increased transcription of PIM kinases. We further validated that PIM1 transcript levels are high in a human CSF3R mutant-cohort. High PIM levels drive stabilization of MYC protein, and the downstream activation of MYC-driven leukemogenic transcriptional programs. Indeed, inhibitors of PIM reverse MYC stabilization. Finally, we show promising therapeutic potential for PIM-inhibition in CSF3R mutant-disease using both human cell lines and CNL patient samples. Together, these findings uncover a novel and targetable vulnerability in CSF3R compound mutant-CNL, thus opening a new avenue of treatment for patients with this devastating disease.
    DOI:  https://doi.org/10.1182/blood.2026034085
  7. Blood. 2026 Nov 04. pii: blood.2025030268. [Epub ahead of print]
    Adult hematopoietic stem cells activate a normally fetal-restricted program to functionally expand ex vivo.
    Kyomi J Igarashi, Matthew Nicholls, Leonid Olender, Apapist Panichewa, Toshiya Nishimura, Paul K Mack, Shady Saad, Wesley Huang, Alia Mn Welsh, Dean C Pask, Ryo Yamamoto, Stefan A Muljo, Hiromitsu Nakauchi, Adam C Wilkinson.
      The ability to robustly expand transplantable hematopoietic stem cells (HSCs) ex vivo enables basic science and clinical therapies otherwise hindered by the scarcity of these self-renewing multipotent cells. Despite recent improvements in long-term ex vivo HSC expansion conditions, the molecular mechanisms required for successful ex vivo expansion of functional HSCs remain unknown. Here we characterized the ex vivo expansion potential of HSCs from mouse fetal liver, young bone marrow, and aged bone marrow at the functional and molecular levels. We find that Lin28b, the in vivo fetal-restricted gene, contributes to the mechanism of both fetal and adult ex vivo HSC expansion. The expression of Lin28b correlates with reconstitution potential, with higher levels observed in HSCs expanded from the fetal liver and young adults. By contrast, expanded aged HSCs fail to robustly express Lin28b and also fail to stably reconstitute the hematopoietic system following transplantation. Consistent with a functional role for this fetal program in ex vivo expanded HSCs, Lin28b-deficient HSCs display aging-associated molecular and functional features following ex vivo expansion cultures. Importantly, Lin28b overexpression during ex vivo expansion was sufficient to enhance reconstitution potential of aged HSCs. In summary, we identify Lin28b as an important regulator of functional HSC expansion ex vivo, suggesting novel opportunities for HSC rejuvenation and clinical applications.
    DOI:  https://doi.org/10.1182/blood.2025030268
  8. EMBO Rep. 2026 Sep 30.
    Greatwall kinase regulates acute myeloid leukaemia cell division through a non-canonical mechanism.
    Sandra M Martin-Guerrero, Tommy Shields, Pedro Casado, Róbert Zach, Vinothini Rajeeve, Nadia Afroz-Nishat, Irbaz I Badshah, Megan Meredith, William R Foster, Helfrid Hochegger, Pedro R Cutillas.
      Greatwall kinase regulates mitotic progression by phosphorylating ENSA and ARPP19, thereby inhibiting PP2A-B55. Moreover, Greatwall has been implicated in oncogenesis, particularly in solid tumours, but the mechanisms by which Greatwall regulates the cell cycle in other malignancies remain unclear. Here, we show that Greatwall regulates cytokinesis and cell cycle progression in acute myeloid leukaemia (AML) cells through a pathway distinct from ENSA-PP2A-B55. AML cells require Greatwall expression and activity to proliferate, as revealed by pharmacological and systematic genetic perturbation experiments. Mechanistically, Greatwall inactivation or genetic depletion does not measurably affect the ENSA-PP2A-B55 pathway. Instead, loss of Greatwall function alters cytokinesis, and the phosphorylation of proteins involved in cytoskeletal organisation and cytokinesis, including MARK3, which we identify as a direct Greatwall substrate in AML cells. Together, these findings reveal that the Greatwall kinase signalling network is wired differently in leukemic cells, thus uncovering a novel mechanism of cell cycle regulation.
    DOI:  https://doi.org/10.1038/s44319-026-00955-6
  9. Blood. 2026 Oct 01. pii: blood.2026034224. [Epub ahead of print]
    Functional Classification of Monoallelic TP53 Mutations Refines Prognostic Stratification in Myelodysplastic Neoplasms.
    Alexander Streuer, Yotaro Ochi, Stephan Hutter, Vladimir Riabov, Yasuhito Nannya, Laurenz Steiner, Mohammed Abba, Georgia Metzgeroth, Eva Altrock, Felicitas Rapp, Verena Nowak, Edin Hepgülüm, Steffen Boettcher, Torsten Haferlach, Daniel Nowak, Wolf-Karsten Hofmann, Seishi Ogawa, Nanni Schmitt.
      TP53 mutations represent one of the strongest adverse prognostic factors in myelodysplastic neoplasms (MDS). While multi-hit TP53 (TP53multiHit) alterations uniformly lead to very poor outcomes, the prognostic relevance of monoallelic TP53 (TP53mono) mutations remains controversial. TP53 variants can cause dominant-negative, loss-of-function, or gain-of-function effects. We hypothesized that functional heterogeneity among TP53 variants contributes to the variable clinical behavior observed in TP53mono-mutated MDS. Therefore, we analyzed pretreatment samples from 4,505 patients with MDS from two independent cohorts (IWG: n=3,173; J-MDS: n=1,332), including 271 patients with TP53mono and 499 with TP53multiHit. Functional annotation of TP53 variants was performed using a previously published phenotype score (PS) derived from saturation mutagenesis screens, capturing dominant-negative and loss-of-function effects. Median leukemia-free survival (LFS) differed significantly by TP53 allelic state (TP53 wild-type (TP53wt) 37.2 months; TP53mono 19.2 months; TP53multiHit 7.8 months; p<0.001). Within the TP53mono subgroup, functional annotation identified marked heterogeneity. Patients with high PS (≥7) showed a significantly inferior median LFS compared with those with low PS (12.6 vs. 43.3 months; p<0.001), particularly for IPSS-R and IPSS-M low-risk cases. Combining PS and variant allele frequency (VAF) further improved risk stratification. TP53mono patients with PS ≥7 and VAF ≥22% had a median LFS comparable to TP53multiHit cases (9.2 vs. 7.8 months, p=0.3), whereas those with PS <7 and VAF <22% exhibited a median LFS similar to TP53wt cases (44.7 vs. 37.2 months, p=0.8). Overall, functional annotation of TP53 variants refines prognostication in TP53mono-mutated MDS and may enhance individualized risk assessment.
    DOI:  https://doi.org/10.1182/blood.2026034224
  10. Leukemia. 2026 Sep 28.
    PIM1 in myeloproliferative neoplasms: potential pathogenic and therapeutic implications.
    Avik Dutta, Lilian Varricchio, Ronald Hoffman, Golam Mohi.
      Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies characterized by the overproduction of mature myeloid lineage cells. Although JAK2 inhibitors, such as ruxolitinib, can alleviate constitutional symptoms, they typically fail to eradicate malignant clones or reverse bone marrow fibrosis. Moreover, treatment failure and drug intolerance often limit their long-term use. Recent studies have identified PIM1 kinase as an important mediator of MPN pathogenesis. PIM1 expression is upregulated in MPN hematopoietic progenitors, which may contribute to aberrant proliferation and disease progression by regulating key downstream effectors, including mTORC1, BAD, MYC, HIF-1α, and TGF-β. Notably, PIM1 contributes to JAK2 inhibitor-persistent cell growth, and its inhibition restores ruxolitinib sensitivity in JAK2 mutant cells. Preclinical studies using genetic ablation and pharmacological inhibition of PIM1 have shown significant attenuation of the myelofibrosis phenotype in mouse models, providing a strong rationale for targeting this kinase. PIM kinase inhibitors are currently being evaluated in clinical trials for patients with myelofibrosis. This review summarizes the current understanding of PIM1 biology in the context of MPNs, details the molecular mechanisms underlying its pathogenic contributions, and evaluates the translational potential of PIM1-targeted therapies for MPNs.
    DOI:  https://doi.org/10.1038/s41375-026-03144-5
  11. Nat Commun. 2026 09 01. pii: 10384. [Epub ahead of print]17(1):
    The Fanconi anemia pathway restrains MLL-rearranged leukemogenesis through suppressing non-homologous end joining-mediated genomic instability.
    Jian Xu, Logan M Sund, Emily V Wolff, Anthony Z Zhu, Rui Wang, Zhenxia Gao, Sawa Ito, Wei Du.
      Mixed lineage leukemia (MLL) rearrangements drive approximately 10% of acute leukemias, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Individuals with Fanconi anemia (FA), a hereditary DNA damage repair (DDR) disorder, are at markedly increased risk of AML, yet the interplay between FA deficiency and MLL-rearranged (MLL-r) leukemia remains unclear. Using murine models and human MLL-r leukemia cells, we show that the FA pathway suppresses leukemogenesis by limiting error-prone non-homologous end joining (NHEJ)-mediated genomic instability. Loss of FA components accelerates leukemia development, promotes leukemic stem cell expansion, and increases DNA damage through hyperactive NHEJ. Pharmacological NHEJ inhibition selectively impairs the survival of FA-deficient MLL-r leukemia cells, revealing a synthetic lethal vulnerability. Consistent with these findings, reduced FA pathway gene expression in patient samples correlates with poor prognosis and increased sensitivity to NHEJ inhibition. These findings identify NHEJ blockade as a promising targeted therapeutic strategy for high-risk MLL-r leukemia.
    DOI:  https://doi.org/10.1038/s41467-026-77335-0
  12. Blood Cancer Discov. 2026 Sep 30.
    Very Long Chain Fatty Acid Synthesis is a Targetable Dependency in RAS Pathway Mutant Leukemia.
    Rebecca Gelfer, Maya Bagish, Merve Sahin, Kaitlyn H Ko, Maria Sirenko, Matthew Wereski, Gabriel San Miguel-Matos, Angelica C Romero-Vega, Shoron Mowla, Nathaniel B Long, Michelle Saoi, Clementina Strozek, Su-Fern Tan, Christopher A Famulare, Kevin Chen, B Bishal Paudel, Madhuri Madavaram, Zhuoning Li, Michael R Waarts, Xiaodi Wu, Justin R Cross, Wenbin Xiao, Iannis Aifantis, Tak Wah Mak, Todd E Fox, David J Feith, Elisa de Stanchina, Mara Monetti, Richard P Koche, Sheng F Cai, Ross L Levine.
      Oncogenic RAS pathway mutations are associated with therapeutic resistance in acute myeloid leukemia, and identification of therapeutic vulnerabilities has been hindered by a lack of clinically relevant models and tractable ex vivo platforms. We utilize a bone marrow endothelial cell co-culture system to perform CRISPR screens on wild-type hematopoietic cells and isogenic leukemias with and without mutant Nras. We credentialed Elovl1, a very long chain fatty acid elongase, as a dependency in RAS pathway mutant leukemia using genetic and pharmacologic approaches. Metabolic and genetic studies in primary leukemias revealed that the fitness defect from Elovl1 loss reflects a mutant-specific dependency on de novo sphingolipid biosynthesis, specifically sphingomyelin production, as Sgms1 deletion phenocopies Elovl1 loss. Sphingomyelin-mediated generation of lipid rafts, key scaffolds for multiple signaling pathways, is essential to the survival of Nras-mutant AML cells. Our work leverages a new leukemia model to identify a targetable dependency in this treatment-refractory leukemia.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-26-0274
  13. Nat Genet. 2026 Sep 28.
    Germline homologous recombination deficiency influences TP53-mutant clonal hematopoiesis fitness during platinum and PARP inhibitor treatment.
    Jeremy T Baeten, Irenaeus C C Chan, Lea Moukarzel, Giulia E M Petrone, Jie Liu, Duc Tran, Jacob Tabs, Imene Tabet, Sumedha Agashe, Elaheh Nasrollahzadeh, Ankush Vasireddy, Amber Carter, Minal Patel, Konrad H Stopsack, Philip W Kantoff, Weiyin Zhou, Armel L Batchi-Bouyou, J Scott Beeler, Griffen Mustion, Paul Pharoah, James Brenton, Kenneth Offit, Ethan Barnett, Bob Li, Wassim Abida, Alison M Schram, Britta Weigelt, David Mutch, Alessandro Vindigni, Mary Mullen, Carlos Cruchaga, Howard Scher, Ross Levine, Elli Papaemmanuil, Mitchell J Machiela, Karen Cadoo, Daniel C Link, Kelly L Bolton.
      Poly(ADP-ribose) polymerase inhibitors (PARPi) are commonly used in tumors with homologous recombination deficiency (HRD) but are associated with an increased risk of therapy-related myeloid neoplasms (tMN). Clonal hematopoiesis (CH) driven by DNA damage response (DDR) mutations is the origin of most tMN. Here, to better understand the causes of tMN following PARPi therapy, we studied the relationship between PARPi use and CH. We observed a high frequency of DDR CH following PARPi therapy, largely explained by prior carboplatin exposure. Among patients with serial blood sampling, DDR CH expanded during carboplatin and to a lesser extent, during PARPi treatment. Surprisingly, this expansion was largely reduced in patients with germline HRD. We validated these findings in a mouse model of Trp53-mutated CH. Our findings suggest that the increased risk of tMN following PARPi is largely influenced by prior oncologic therapies, including carboplatin, and may vary by germline HRD status.
    DOI:  https://doi.org/10.1038/s41588-026-02752-2
  14. bioRxiv. 2026 Sep 22. pii: 2026.09.21.753355. [Epub ahead of print]
    Loss of TCA cycle turning promotes stem cell function.
    Yafeng Li, Joseph Rose, Edward O Kwarteng, Xiaotong Yang, Jacob Zielke, Li Li, Zhiyu Zhao, Ji Hyung Jun, Michalis Agathocleous.
      The citric acid cycle (TCA cycle) is the common terminal pathway for the oxidation of all nutrients. Citrate oxidation to oxaloacetate produces CO 2 , and citrate synthase (CS) uses nutrient-derived acetyl groups to regenerate citrate and fuel cycle turning. However, the essentiality of cycle fueling and turning in vivo remains unclear. Here, we use hematopoiesis, the most proliferative system in the body, as a model to show that, contrary to common assumptions, TCA cycle turning is dispensable for respiration, survival, and proliferation of stem and progenitor cells in vivo and its loss promotes stem cell function. Hematopoietic-specific Cs deletion in adult mice blocked citrate cycling without reducing the frequency of hematopoietic stem (HSC) and progenitor cells. HSCs and progenitor cells adapted to TCA cycle loss by markedly increasing nutrient consumption and biosynthesis. Disruption of cycle turning increased HSC regeneration, myeloid progenitor proliferation, and myelopoiesis in vivo. HSCs without a turning TCA cycle outcompeted wild-type HSCs within the same environment. The effect of CS deletion on HSC function was not phenocopied by genetic ablation of cytosolic citrate use and was rescued by ablation of glutamine use in biosynthesis. Therefore, TCA cycle turning restrains nutrient uptake, biosynthesis, cell proliferation, and stem cell function. These results suggest an explanation for the reduction in cycle activity observed in many normal proliferating cells and cancer cells.
    DOI:  https://doi.org/10.64898/2026.09.21.753355
  15. Leuk Res. 2026 Sep 24. pii: S0145-2126(26)00172-4. [Epub ahead of print]171 108328
    Age over sibling: Younger unrelated donors provide superior outcomes compared to sibling donors in fully matched HCT in older AML/MDS patients.
    Witold Prejzner, Alicja Sadowska-Klasa, Johannes Lakner, Anastazja Szlauer-Stefańska, Anna Łojko-Dankowska, Maciej Majcherek, Ewa Karakulska-Prystupiuk, Patrycja Mensah-Glanowska, Anna Czyż, Christian Junghanss, Jan Maciej Zaucha.
      Elderly adults represent a substantial proportion of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS); however, preferential selection of matched related donors (MRD) for elderly allogeneic hematopoietic cell (HCT) recipients is challenged by the excellent outcomes of HCT from unrelated matched donors (MUD). In this retrospective multicenter study, we analyzed overall survival (OS), relapse-free survival (RFS), and non-relapse mortality (NRM at 2 and 5 years) of patients aged ≥ 60 years undergoing HCT for AML/MDS between 2014 and 2024, stratified by donor type and donor age. Among 293 patients (median follow-up 21 months), 75% received MUD transplants. Median donor age was 31 years (MUD) versus 61 years (MRD). Grade 3-4 acute GVHD was more frequent in MRD recipients (14% vs 6%). Two- and five-year OS were 58.2% and 46.8%. MUD recipients had superior 2-year OS (62% vs 47%, p = 0.02) and a trend toward improved 5-year OS. Relapse occurred in 31% (MUD) and 36% (MRD), with 85% within 24 months. Two-year NRM was 16%, primarily infection-related. In multivariable analysis (n = 221), donor age < 30 years independently predicted improved OS and reduced early NRM. Younger unrelated donors, particularly < 30 years, were associated with improved survival, supporting prioritization over elderly siblings.
    Keywords:  Acute myeloid leukemia; Allogeneic hematopoietic cell transplantation; Donor age; Donor selection; Myelodysplastic syndrome
    DOI:  https://doi.org/10.1016/j.leukres.2026.108328
  16. Leukemia. 2026 Oct 01.
    Alterations in 3D-DNA architecture drive unique leukemic profiles in IDH1- and DNMT3A-mutant acute myeloid leukemia.
    Sophie Steinhäuser, Varun K A Sreenivasan, David Baden, Miriam Denker, Thomas Beder, Kathrin Richter, Theodor Hutter, Britta Steer, Verónica Yumiceba, Kristin Schultz, Alina Maria Hartmann, Nadine Wolgast, Simone Lipinski, Lorenz Bastian, Sonja Bendig, Monika Brüggemann, Lars Fransecky, Martin Neumann, Patricia Silva, Christoph Röllig, Malte Spielmann, Claudia Dorothea Baldus.
      Acute myeloid leukemia (AML) is characterized by complex molecular alterations including mutations in epigenetic regulators such as IDH1 and DNMT3A, which are associated with globally altered DNA methylation affecting gene transcription, treatment choices, and outcomes. Additionally, IDH1 mutations are linked to changes in DNA-loop formation leading to oncogene upregulation. Here, we assessed 3D-DNA conformational changes in IDH1- and DNMT3A-mutated (mut) AML on a genome-wide scale as a global driver of leukemic signaling to identify novel therapeutic vulnerabilities. Using a cellular model with either IDH1 p.R132H or DNMT3A p.R882H mutation and primary AML samples, we analyzed mutation-specific 3D-DNA architecture by chromatin-conformation-capture (HiC) and transcriptional alterations by RNA sequencing. We identified both shared and distinct changes in compartmentalization and underlying DNA-loop formation in both DNMT3A- and IDH1-mut AML, which were linked to differential gene expression, supporting that 3D-genome architecture broadly influences transcription. Thereby, loop-mediated upregulation of IGF1R was identified in IDH1-mut AML, corresponding to specific sensitivity to IGF1R inhibitor BMS-754807 as mono- and combination therapy with ivosidenib, while DNMT3A-mut AML exhibited sensitivity to p38/MAPK inhibitor ralimetinib. Our data present a comprehensive map of global 3D-DNA alterations associated with IDH1- and DNMT3A mutations as a basis for further assessment of novel therapeutic strategies for both AML entities.
    DOI:  https://doi.org/10.1038/s41375-026-03152-5
  17. Haematologica. 2026 Oct 01.
    Allogeneic hematopoietic stem cell transplantation rather than specific front-line therapy is associated with long-term survival in blastic plasmacytoid dendritic cell neoplasm: the Mayo Clinic experience.
    Naseema Gangat, Erica Andres, Buraq Ahmed, Clifford M Csizmar, Momna Warraich, Kristen McCullough, Aref Al-Kali, Luis Porrata, Hassan Alkhateeb, Kebede Begna, James Foran, William Hogan, Mark R Litzow, Abhishek A Mangoankar, Aasiya Matin, Hemant Murthy, Cecilia Arani Yi, Antoine N Saliba, Mithun Shah, Mehrdad Hefazi Torghabeh, Mrinal M Patnaik, Mohamed A Kharfan-Dabaja, Ayalew Tefferi.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.301790
  18. J Clin Invest. 2026 Sep 29. pii: e208317. [Epub ahead of print]
    DNA methylation status at diagnosis in MDS predicts response to azacitidine.
    Qin Yang, Miguel Torres-Martin, Masataka Taguchi, Alice Brogi, Irene Casalin, Eleonora Ceneri, Stephanie Halene, Amy E DeZern, Elizabeth A Griffiths, Matilde Y Follo, Carlo Finelli, Jerald P Radich, Michael J Rauh, Rafael Bejar, Mikkael A Sekeres, Valeria Santini, Maria E Figueroa.
       BACKGROUND: Myelodysplastic syndromes (MDS) are characterized by aberrant DNA methylation, and mutations in epigenetic modifiers are frequently found in these patients. Although DNA methyltransferase inhibitors (DNMTi) are used to treat MDS, response variability remains a challenge in the clinic, with limited predictive markers.
    METHODS: We integrated genomic, epigenomic, and transcriptomic analyses of 98 MDS patients. Patients were classified into epigenetic subtypes via hierarchical clustering. Random forest classifiers were developed and validated using internal stratified testing and an independent external cohort to predict AZA response.
    RESULTS: MDS is characterized by widespread DNA hypomethylation affecting distal regulatory elements. We identified seven epigenetic clusters correlated with distinct molecular drivers. Notably, Cluster VI exhibited low mutational burden but a high AZA response rate of 71% (P ≤ 0.01). While transcriptional profiles alone failed to distinguish responders, a DNAme-based classifier achieved an area under the curve (AUC) of 0.82. An integrative model combining DNAme, gene expression, mutations, and clinical parameters achieved an AUC of 0.93 in internal validation and 0.88 in the external cohort.
    CONCLUSION: Epigenetic signatures at distal genomic elements provide superior predictive power for AZA response compared to promoter-centric or transcriptional analyses. These findings establish a robust framework for personalized treatment strategies in MDS.
    Keywords:  Epigenetics; Genetics; Hematology
    DOI:  https://doi.org/10.1172/JCI208317
  19. Nat Immunol. 2026 Sep 30.
    Prefibrotic bone marrow microenvironment is a hallmark of clonal hematopoiesis.
    Alicia G Aguilar-Navarro, Gibran Edun, Mark Gower, Joan Kant, Ximing Li, Dustin Yang, Mursal Nader, Minerva Fernandez, Soheil Jahangiri, Emily Tsao, Pratik Joshi, Pathum Kossinna, Loic Cameron Caloren, John Roderick Davey, Michael G Zywiel, R Peter Suderman, Anoushka I Kapoor, Margarete K Akens, Adele Changoor, Minna Woo, Robert F Stanley, Kira A Young, Christine Tran, Valentin Sotov, Ben X Wang, Sagi Abelson, Omar Abdel-Wahab, Shruti Naik, Jennifer J Trowbridge, Robert Vanner, Kristin J Hope, Hubert Tsui, Federico Gaiti, Anastasia N Tikhonova.
      Clonal hematopoiesis of indeterminate potential is associated with systemic inflammation and increased malignant risk in humans, yet understanding of how it reshapes the bone marrow (BM) microenvironment has been limited. Using single-cell transcriptomic profiling of freshly isolated BM samples, combined with histological and spatial transcriptomic analyses, we identified fibro-inflammatory remodeling as a hallmark of clonal hematopoiesis of indeterminate potential. Fibroblasts were markedly expanded and acquired cancer-associated fibroblast-like transcriptional states, while mesenchymal and vascular cells upregulated collagen production and extracellular matrix remodeling pathways. Spatial transcriptomics revealed discrete fiber-enriched regions populated by active and CXCL12+ fibroblasts, macrophages and lymphoid cells. These regions exhibited major enrichment of proinflammatory pathways, including transforming growth factor-beta and tumor necrosis factor signaling, identifying them as spatially confined inflammatory hubs within the BM. Collectively, these findings establish fibro-inflammatory BM remodeling as a defining feature of clonal hematopoiesis of indeterminate potential, linking it to prefibrotic stromal changes and niche reorganization that may facilitate progression to overt malignancy.
    DOI:  https://doi.org/10.1038/s41590-026-02668-3
  20. Nat Genet. 2026 Oct 02.
    Single-allele nanoscale mapping of regulatory variants.
    Joseph C Hamley, Weijiao Zhang, Daniel Willmott, Lucia Y Chen, Vassilena Sharlandjieva, Hangpeng Li, James L T Dalgleish, Nicholas Denny, Gaurav Agarwal, Lance Hentges, Bora Ozcan, Roman M Doll, Ye Wei, Simone G Riva, Samvida S Venkatesh, Marta Arachi, Devika Agarwal, Evgeny E Akkuratov, Matthew Baxter, Tatjana Sauka-Spengler, Calliope A Dendrou, Thomas A Milne, Jim R Hughes, James O J Davies.
      Millions of genetic variants are linked to human disease but identifying underlying mechanisms is challenging because most variants are noncausal and lie within the noncoding genome. We developed a Micro Capture-C variant-to-function platform (MCCv) based on analysis of single-allele chromatin structure. This can identify changes in nanoscale chromatin architecture and link variants in cis-regulatory elements to target genes. Furthermore, MCCv can phase other heterozygous variants within a locus to link regulatory variants to allelically imbalanced gene expression and directly read out variant effects on chromatin interactions after genome editing. With this approach, we investigated 405 cis-regulatory elements linked to immune-mediated inflammatory disease in CD4+ T cells. We uncovered a previously undescribed gain-of-function mechanism, which increases risk of autoimmunity through creation of a neo-CTCF motif that blocks super-enhancer contacts with the SESN3 promoter. We showed that SESN3 regulates mammalian target of rapamycin by sensing tryptophan and demonstrated its role in autoimmunity using mouse models.
    DOI:  https://doi.org/10.1038/s41588-026-02776-8
  21. Nature. 2026 Sep 30.
    Human genetics implicates a BACH2-NRF2 axis in fetal haemoglobin activation.
    Chun-Jie Guo, Uma P Arora, Xiaoheng Cheng, Wanying Xu, Liam D Cato, Rick Li, Henry Y Lu, Andrew J Lee, Fulong Yu, Gaurav Agarwal, Peng Lyu, Tianyi Ye, Mateusz Antoszewski, Mariel Wissmann, Baraka S Mkumbe, Supachai Ekwattanakit, Patrick Deelen, Liberata Mwita, Raphael Sangeda, Thidarat Suksangpleng, Suchada Riolueang, Paola G Bronson, Dirk S Paul, Emily Kawabata, William J Astle, Francois Aguet, Kristin Ardlie, Aitzkoa Lopez de Lapuente Portilla, Guolian Kang, Yingze Zhang, Seyed Mehdi Nouraie, Victor R Gordeuk, Mark T Gladwin, Melanie E Garrett, Allison Ashley-Koch, Marilyn J Telen, Brian Custer, Shannon Kelly, Carla Luana Dinardo, Ester C Sabino, Paula Loureiro, Anna Bárbara Carneiro-Proietti, Cláudia Maximo, Adriana Méndez, Angelika Hammerer-Lercher, Julie Makani, Vivien A Sheehan, Mitchell J Weiss, Lude Franke, Björn Nilsson, Adam S Butterworth, Vip Viprakasit, Siana Nkya, Vijay G Sankaran.
      Human genetic studies have identified key regulators of fetal haemoglobin (HbF) expression, including BCL11A, resulting in therapeutic advances1-8. Yet the mechanisms by which HbF expression is activated remain incompletely understood9. Here we conduct a large multi-ancestry genome-wide association study of HbF levels in 28,279 individuals that identifies 91 conditionally independent associations across 12 genomic regions. In one previously uncharacterized associated region, the high-HbF-linked causal variant rs1010474-C reduces BACH2 expression and elevates HbF levels. Direct perturbation or inhibition of BACH2 likewise increases HbF expression. Mechanistically, BACH2 restrains activation of the HbF-encoding γ-globin genes, while loss of BACH2 enhances NRF2 chromatin occupancy and promotes the formation of activation foci at the γ-globin genes. Although BACH2 and NRF2 binding motifs in the γ-globin promoters overlap, they can be selectively edited to activate or repress γ-globin, respectively, and do so independently of BCL11A. These findings illustrate how human genetic variation continues to advance our understanding of therapeutically relevant regulatory mechanisms underlying HbF expression.
    DOI:  https://doi.org/10.1038/s41586-026-11113-2
  22. bioRxiv. 2026 Sep 24. pii: 2026.09.23.753907. [Epub ahead of print]
    NicheScribe: consistent and generalizable annotation of stromal cells in the murine bone marrow niche.
    James W Swann, Jun Hou Fung, Ruiyuan Zhang, Raul Rabadan, Emmanuelle Passegué.
      Hematopoietic stem and progenitor cells (HSPC) depend on interactions with nearby stromal cells to support their homeostatic functions and mount responses to perturbations. The murine bone marrow (BM) niche can be profiled using single-cell RNA sequencing (scRNA-seq), but there is considerable inconsistency in cell type identification, and uncertainty over how populations can be isolated prospectively by flow cytometry. Here, we produced new scRNA-seq reference datasets using purified populations of murine BM stromal cells, which we used to create a bespoke classifier for stromal cells. Our NicheScribe approach is consistent, accurate, and generalizable to query datasets irrespective of methods used for cell isolation. Moreover, consistent annotation permits comparative analyses of the same stromal cells across different bone types and perturbations like inflammation, neoplasia, and aging. Our work provides new tools for consistent cell type annotation in the murine BM niche and new insights for combined molecular and functional analyses.
    HIGHLIGHTS: New NicheScribe approach for annotation of stromal cells in scRNA-seq datasetsNicheScribe links molecular state to prospective isolation by flow cytometryDifferent bones have distinct complements of stromal cells LepR + mesenchymal stromal cells adopt diverse transcriptional programs upon stimulation.
    eTOC BLURB: Swann et al. develop a computational approach for consistent annotation of stromal cells in murine bone marrow niche, which is applicable to single-cell and spatial transcriptomics. They find that stromal cell frequencies vary in different bones, and that leptin receptor-expressing mesenchymal stromal cells exhibit diverse transcriptional responses to different perturbations.
    DOI:  https://doi.org/10.64898/2026.09.23.753907
  23. Exp Hematol. 2026 Oct 02. pii: S0301-472X(26)00573-4. [Epub ahead of print] 105940
    The Role of Aldehyde Dehydrogenase 2 in Hematopoiesis is Stress-Severity Dependent.
    Liangliang Wu, Xingmin Feng, Felix A Dingler, Zhijie Wu, Shouguo Gao, Jichun Chen, Ketan J Patel, Neal S Young.
      Aldehyde dehydrogenase 2 (ALDH2) is a key mitochondrial enzyme that detoxifies reactive aldehydes including formaldehyde, thereby mitigating their genotoxic effects. While ALDH2 deficiency exacerbates bone marrow (BM) failure in Fanconi anemia models, its role under exogenous genotoxic stress is less clear. In this study, we used Aldh2-/- mice to investigate how ALDH2 deficiency impacts hematopoiesis following treatment with busulfan (BSF), sublethal total body irradiation (TBI), or a combined (BSF+TBI) regimen. Under BSF or TBI monotherapy, Aldh2-/- mice exhibited moderate increases in DNA damage, measured by γH2AX expression in hematopoietic stem and progenitor cells (HSPCs), with a mild decline in BM cell engraftment, compared to Aldh2+/+ controls. However, BSF+TBI treatment triggered more severe HSPC DNA damage confirmed by concordant γH2AX and 53BP1 elevation, and a sharper decline in mature hematopoietic cells. Notably, this dual stress significantly upregulated DNA repair and metabolic adaptation genes, including Ccno, Pold4, Taf1c, Npr2, and Aldh18a1. These results suggest that BSF+TBI treatment drives advanced DNA damage and compensatory gene expression shifts in the absence of ALDH2. We conclude that the impact of ALDH2 deficiency on hematopoiesis is dependent on the severity of exogenous stress. TEASER ABSTRACT: The ALDH2 rs671 loss-of-function polymorphism is carried by 30-40% of East Asian individuals, yet its hematopoietic consequences under clinical genotoxic stress remain poorly understood. Using Aldh2-/- mice, we demonstrate that ALDH2 deficiency increases DNA damage in hematopoietic stem and progenitor cells (HSPCs) following busulfan (BSF) or total body irradiation (TBI) monotherapy, without altering mature hematopoietic cell populations or long-term repopulating capacity. However, combined BSF+TBI treatment unmasks a clear, stress-severity-dependent phenotype: Aldh2-/- mice exhibit significantly greater HSPC apoptosis and DNA damage confirmed by concordant γH2AX and 53BP1 elevation, and more severe peripheral blood cytopenias. Transcriptomic analysis reveals compensatory upregulation of DNA repair pathways and Aldh18a1, suggesting a metabolic adaptation to mitigate genotoxic burden. These findings establish ALDH2 deficiency as a latent hematopoietic risk factor with direct implications for personalizing conditioning regimens in ALDH2 rs671 carriers undergoing hematopoietic stem cell transplantation.
    Keywords:  Aldh2 deficiency; DNA damage; busulfan; hematopoiesis; irradiation
    DOI:  https://doi.org/10.1016/j.exphem.2026.105940
  24. STAR Protoc. 2026 Sep 26. pii: S2666-1667(26)00514-9. [Epub ahead of print]7(4): 104861
    Protocol for ribosome-protected fragment isolation from rare leukemia cell populations.
    Christina Mayerhofer, Ernst Mayerhofer, Dan Li, Trine Kristiansen, Tobias Feuchtinger, David T Scadden.
      Malignant cells under chemotherapy stress alter protein translation, necessitating sensitive methods to profile rare, surviving populations in vivo. We present a protocol for profiling low-input acute myeloid leukemia samples using an optimized ribosome profiling approach. We describe steps for lysing cell inputs, digesting unshielded RNA, enriching ribosome footprints, and gel-based size selection. We then detail procedures for constructing sequencing-ready libraries and using a computational pipeline to align and quantify both protected fragments and matching transcriptomes for reproducible translation analysis. For complete details on the use and execution of this protocol, please refer to Mayerhofer et al.1.
    Keywords:  Cancer; Cell Biology; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2026.104861
  25. Cancer Res. 2026 Sep 28.
    Targeting ClpP Rewires the Metabolic-Immune Axis in Acute Myeloid Leukemia.
    Xinrong Xiang, Baozhu Luo, Lei Zhao, Jing Sui, Yi Wu, Jiasheng Huang, Song Liu, Hexian Li, Fangfang Wang, Mengran Chen, Ying Qu, Aiping Tong, Chong Chen, Yu Wu, Youfu Luo.
      Acute myeloid leukemia (AML) critically depends on oxidative phosphorylation (OXPHOS). Mitochondrial targeted therapies are advancing into clinical trials, but metabolic vulnerabilities have been primarily explored from a tumor-intrinsic perspective. Leukemic cells can actively reshape an immunosuppressive tumor microenvironment through metabolic competition, highlighting the importance of evaluating the impact of mitochondrial targeted therapies on antitumor immunity. Here, we showed that elevated expression of the mitochondrial caseinolytic protease P (ClpP) is associated with advanced AML. Development of IMP125, a potent ClpP agonist, enabled dual targeting of AML to elicit robust anti-leukemic activity. In addition to direct cytotoxicity, IMP125 induced immunometabolic reprogramming of AML models. Owing to differential ClpP expression, IMP125 preferentially suppressed mitochondrial respiration and oxygen consumption in AML cells while exerting minimal direct effects on T-cell respiration. By reducing AML oxygen consumption and metabolic demand, IMP125 alleviated hypoxia and metabolic competition within the leukemic niche. In this remodeled microenvironment, T cells exhibited recovery of OXPHOS, effector function, and memory-associated features, consistent with an indirect mechanism mediated through metabolic suppression in AML cells. The anti-leukemic efficacy of IMP125 was dependent on T cells and was synergistically enhanced by PD-1 blockade. Collectively, this work reframes ClpP agonism from a tumor-intrinsic therapy to a strategy that actively induces metabolic-immune rewiring, bridging ClpP-targeted and immunotherapeutic approaches for mitochondrial-dependent AML.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-0477
  26. bioRxiv. 2026 Sep 25. pii: 2026.09.24.754138. [Epub ahead of print]
    Clonal hematopoiesis-associated DNMT3A mutations derepress bivalent Polycomb target genes and enhance macrophage migration.
    Yuri Lee, Philip K Farahat, Jennifer P Nguyen, Yoshiko Takahashi, Jung-Yeon Lim, Xin Huang, Camille Brzechffa, Marie E S Wheeler, Hye-Ju Yang, Jihye Lee, Zachary S Pope, Daniella J Lu, Akshata N Rudrapatna, Alec P Pankow, Xiaoting Chen, Hongseok Yun, Matthew T Weirauch, Ivan Marazzi, Brad R Rosenberg, Emily R Miraldi, Eirini P Papapetrou, S Armando Villalta, Angela G Fleischman, Minji Byun.
      Somatic mutations in the de novo DNA methyltransferase DNMT3A are frequent in clonal hematopoiesis, but how they alter the function of differentiated myeloid cells remains unclear. Here, we used isogenic human embryonic stem cell-derived macrophage models to define the consequences of DNMT3A dysfunction during myeloid differentiation. DNMT3A -mutant macrophages selectively upregulated bivalent Polycomb target genes, accompanied by DNA hypomethylation, reduced H3K27me3 and increased promoter accessibility. Despite broad epigenetic changes across bivalent promoters, transcriptional derepression occurred at a subset of loci characterized by lower baseline DNA methylation and higher H3K27me3, identifying pre-existing chromatin state as a determinant of transcriptional response. This Polycomb-associated program was conserved in murine macrophages and enriched for genes involved in cell migration and wound repair. DNMT3A -mutant macrophages exhibited enhanced migration and preferential early recruitment to injured tissue. These findings link clonal hematopoiesis-associated epigenetic alterations to selective transcriptional reprogramming and altered function of differentiated myeloid cells.
    DOI:  https://doi.org/10.64898/2026.09.24.754138
  27. Cancer Res. 2026 Sep 28.
    Impaired Mevalonate-Dependent NAD⁺ Regeneration Suppresses Serine Biosynthesis and Enhances Sensitivity to PHGDH Inhibition.
    Thi Thinh Nguyen, Jane Ding, Mohit Bansal, Sunil Sudarshan, Han-Fei Ding.
      The mevalonate pathway generates sterols and isoprenoids essential for membrane biosynthesis and signaling. Increased activity of the mevalonate pathway is a common feature of cancer and has emerged as a potential therapeutic vulnerability. Here, we showed that the mevalonate pathway sustains de novo serine biosynthesis and aspartate production by maintaining NAD⁺ regeneration through ubiquinone-dependent electron transport. Statin-mediated inhibition of the mevalonate pathway impaired oxidative phosphorylation, lowered the NAD⁺/NADH ratio, suppressed serine and aspartate biosynthesis, and activated the GCN2-eIF2α-ATF4 amino acid deprivation response. The resulting depletion of serine-derived glycine and one-carbon units, together with reduced aspartate availability, limited purine and pyrimidine biosynthesis. Genetic and pharmacological disruption of ubiquinone synthesis recapitulated the metabolic defects, whereas expression of the bacterial NADH oxidase LbNOX restored the NAD⁺/NADH ratio and reversed the metabolic and growth defects induced by statin treatment. Importantly, impairment of NAD⁺ regeneration reduced PHGDH-dependent de novo serine synthesis, thereby sensitizing neuroblastoma cells to PHGDH inhibition. Accordingly, simvastatin enhanced the anti-proliferative effects of the PHGDH inhibitor NCT-503 in vitro and exhibited elevated anti-tumor activity in combination with NCT-503 in neuroblastoma xenograft models. Together, these findings establish ubiquinone-dependent NAD⁺ regeneration as a key mechanism linking the mevalonate pathway to amino acid and nucleotide biosynthesis and provide a mechanistic rationale for combined targeting of the mevalonate pathway and serine biosynthesis in cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1063
  28. Nat Genet. 2026 Oct 01.
    Reactivation of the embryonic ζ-globin gene ameliorates severe forms of α-thalassemia.
    Siyu Liu, Ayesha Ejaz, Andrew J King, Aude-Anais Olijnik, Jacqueline Sloane-Stanley, Caroline Scott, Ali Amid, Daniel Biggs, Benjamin Davies, Jennifer Eglinton, Gabriella Martyn, Merlin Crossley, Christian Babbs, Mira T Kassouf, Douglas R Higgs.
      Hemoglobinopathies are the most common inherited anemias worldwide. While most carriers are asymptomatic or mildly affected, severe forms of α-thalassemia, including severe hemoglobin H (HbH) disease and surviving individuals with Hb Bart's hydrops fetalis syndrome (BHFS), require lifelong transfusion support or stem cell transplantation. Reactivating the silenced embryonic α-like globin (ζ-globin) gene is a promising approach for treating these diseases. Here we identify the key cis-regulatory elements responsible for silencing the ζ-globin gene in definitive erythroid cells and subsequently develop gene-editing strategies that reactivate ζ-globin expression to therapeutically relevant levels. In a preclinical mouse model of BHFS, we show that this strategy rescues the otherwise prenatal lethal condition until late in development (E17.5). Using primary erythroid cells derived from patients with HbH disease and BHFS, we show that these approaches reactivate ζ-globin expression to levels exceeding those achieved in the mouse model, producing therapeutic levels of α-like globin.
    DOI:  https://doi.org/10.1038/s41588-026-02770-0
  29. Cell. 2026 Sep 28. pii: S0092-8674(26)01073-1. [Epub ahead of print]
    Opposing functions of gut immunomodulatory metabolites on CAR-T therapy.
    Markus Perl, Severin Guetter, Dhyani Shah, Simon Holzinger, Luisa Becker, Misbah Tariq, Phillipp Menauer, Simon Delahais, Gloria Lutzny-Geier, Julian N Scherer, Sascha Göttert, Konstantin Herfeld, Paul Heinrich, Klaus Georg Kreitmeier, Claudia Gebhard, Wolfgang Herr, Marcel P Trefny, Janina Doerr, Saba Sameri, Dennis C Harrer, Kai Ziegler-Martin, Sarah Staudt, Leo Hansmann, Matthias Edinger, Daniel Wolff, Daniela Weber, Elisabeth Meedt, Alexander Denk, Andre Gessner, Ernst Holler, Tobias Wertheimer, Klaus Neuhaus, Tingting Zheng, David M Cordas Dos Santos, Sebastian Theurich, Melanie Schirmer, Karin Kleigrewe, Jonas Schluter, Marcel van den Brink, Michael Schmitt, Markus Feuerer, Christoph Heuser-Loy, Jeremy Baldwin, Luca Gattinoni, Michael Rehli, Michael Hudecek, Camille Bigenwald, Laurence Zitvogel, Marion Subklewe, Viktoria Blumenberg, Maria-Luisa Schubert, Christoph Stein-Thoeringer, Maik Luu, Sebastian Kobold, Matthias A Fante, Erik Thiele Orberg, Hendrik Poeck.
      Chimeric antigen receptor (CAR)-T cell therapy has transformed hematological cancer treatment, yet nearly half of patients still relapse or progress. Increasing evidence implicates the gut microbiome and antibiotic exposure as key modulators of clinical outcomes. In a cohort of 129 patients across three German centers, shotgun metagenomics and targeted mass spectrometry revealed that reduced short-chain fatty acids, particularly valeric acid, prior to CAR-T cell therapy correlated with increased risk of disease progression. Conversely, high levels of indole metabolites, including indole-3-carboxaldehyde and indole-3-acetic acid as well as the branched-chain fatty acid isovaleric acid, were linked to adverse outcomes. Functional validation in human and murine CAR-T cell models demonstrated that valeric acid supplementation enhanced, while indole-3-carboxaldehyde and isovaleric acid impaired, CAR-T cell efficacy. These findings reveal the opposing roles of immunomodulatory metabolites on CAR-T cell therapy, carrying significant implications for the design of metabolite-guided, microbiome-based therapeutics.
    Keywords:  BCFA; IMM; SCFA; cancer; cancer immunotherapy; indoles
    DOI:  https://doi.org/10.1016/j.cell.2026.09.004
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