bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–10–25
twenty-two papers selected by
William Grey, University of York
  1. A new reporter strategy reveals a subset of nonmigratory hematopoietic stem cells located in a dynamic bone marrow niche.
  2. Patient-derived neomorphic SEPTIN6 mutations induce hematopoietic stem cell senescence underlying congenital neutropenia and myelodysplasia.
  3. TP53 mutations drive therapy resistance through post-mitochondrial caspase blockade.
  4. Polycomb factor PHF19 affects AML initiation, patient prognosis, and survival.
  5. Vcam1 in endothelial and stromal cells regulates hematopoietic stem cell contact with the niche.
  6. Stathmin 1 regulates mitophagy and non-proliferative cellular function in hematopoietic stem and progenitor cells.
  7. Phase separation of Rbpms sequesters translation elongation machinery to preserve hematopoietic stem cell function.
  8. Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.
  9. Transient ATM inhibition enhances knock-in efficiency in hematopoietic stem cells by attenuating the DNA damage response.
  10. The immunophenotypic landscape of newly diagnosed acute myeloid leukemia: Associations with genotype and outcomes.
  11. Targeting the mitochondrial complex I subunit NDUFS2 potentiates FLT3 inhibition in acute myeloid leukaemia with FLT3 internal tandem duplication.
  12. Targeting lactate-driven protein lactylation overcomes proteasome inhibitor resistance in multiple myeloma.
  13. Arid1a and Arid1b maintain B cell lineage fidelity and constrain myeloid transformation in mice.
  14. Extending single-cell proteomics from HeLa to small primary human immune cells.
  15. A Scalable, Antibody-Free Lipid Nanoparticle Achieves Preferential mRNA Delivery to Human HSPCs In Vivo Without Conditioning.
  16. TET2-driven activation of AGO2 links epigenetic remodeling to myeloid commitment and leukemia.
  17. Proteasome inhibition bidirectionally regulates ferroptosis sensitivity.
  18. Pitavastatin counteracts venetoclax resistance mechanisms including TP53 mutation in acute myeloid leukemia.
  19. Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300.
  20. NRF2 coordinates cystine import and glutathione use to sustain ferroptosis resistance and formaldehyde tolerance in cancer.
  21. The Spatiotemporal Regulation of Glucose Metabolism in Hematopoietic Stem Cells.
  22. BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
  1. Blood. 2026 Oct 19. pii: blood.2025031114. [Epub ahead of print]
    A new reporter strategy reveals a subset of nonmigratory hematopoietic stem cells located in a dynamic bone marrow niche.
    Marine A Secchi, Cera Mai, Qi Liu, Aya M F E Elmeligy, Sara Gonzalez Anton, Aisha Jibril, Thorsten Richter, Jiarui Xu, Dónal O'Carroll, Nicola K Wilson, Konstantinos Kokkaliaris, Kamil R Kranc, Berthold Gottgens, Cristina Lo Celso, Tiago C Luis.
      Interactions of hematopoietic stem cells (HSCs) with the bone marrow microenvironment are critical to regulate stem cell function in homeostasis, emergency hematopoiesis and ageing. The dynamic behavior of endogenous HSCs in their niches has been challenging to study due to the complexity of markers required to define pure HSCs. Multiple recently developed reporter strategies advanced our capacity to identify HSCs in situ. Yet, they provide different levels of HSC enrichment and are frequently not stable in situations of perturbed hematopoiesis, leading to contradictory observations of HSC localization and migratory behavior. Here we employed a new double reporter strategy by combining the Hoxb5-mKO2 and Vwf-GFP reporters, that are stably expressed in homeostasis, stress and ageing. Hoxb5+Vwf+ cells represent a subset of highly pure and potent long-term HSCs with a platelet-biased pattern of differentiation, that are included in the populations identified by other reporter strategies. Intravital microscopy revealed Hoxb5+Vwf+ cells to be non-migratory in homeostasis, ageing, or following acute thrombocytopenia when these cells are actively proliferating, indicating that this non-migratory behavior is independent of cell cycle status. We found Hoxb5+Vwf+ HSCs in perivascular niches with a higher coverage by LepR+ mesenchymal cells but not preferentially located closer to megakaryocytes, when compared to Hoxb5+Vwf- cells. Nevertheless, stress-induced megakaryopoiesis following acute thrombocytopenia bring megakaryocytes into closer proximity of Hoxb5+Vwf+ HSCs, revealing previously unrecognized niche dynamics in HSC regulation during regeneration.
    DOI:  https://doi.org/10.1182/blood.2025031114
  2. JCI Insight. 2026 Oct 22. pii: e209595. [Epub ahead of print]11(20):
    Patient-derived neomorphic SEPTIN6 mutations induce hematopoietic stem cell senescence underlying congenital neutropenia and myelodysplasia.
    Safa F Mohamad, Meaghan McGuinness, Yu Zhou, Xin Jiang, Gabriele Casirati, Adele Mucci, Sara Canovas Nunes, Akiko Shimamura, Pietro Genovese, David A Williams.
      Septins are RAS-like GTP-binding proteins involved in cytoskeletal organization and cellular division. We previously described 2 pediatric patients harboring SEPT6 germline mutations (GM1: SEPT6 c.1282T>C and GM2: SEPT6 c.1282T>A) presenting with congenital neutropenia associated with the development of myelodysplastic syndrome. In one patient, an additional somatic mutation (SM: SEPT6 c.43C>T) was detected at a low allelic fraction in the BM. Here, we describe the consequences of these mutations for hematopoiesis. Transgenic expression or gene editing of GM1 or GM2 in human CD34+ cells led to enlarged, multinucleated cells associated with accelerated exhaustion and premature senescence of hematopoietic stem and progenitor cells (HSPCs). Senescence defects were associated with the upregulation of mTOR phosphorylation, and pharmacologic inhibition of the mTOR pathway resulted in rescue of senescence. In parallel, HSPCs exhibited marked mitochondrial abnormalities, including increased expression of OPA-1, a key regulator of mitochondrial fusion, and enhanced oxygen consumption during mitochondrial respiration. Introduction of the SM in cis with GM1 mitigated all observed defects. Collectively, our findings demonstrate a gain-of-function mechanism underlying marrow failure in patients carrying germline SEPT6 mutations and suggest that acquisition of a secondary somatic SEPT6 variant may confer a compensatory effect within hematopoietic cells.
    Keywords:  Hematology; Hematopoietic stem cells; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.209595
  3. Cell Death Dis. 2026 Jul 28. pii: 902. [Epub ahead of print]17(1):
    TP53 mutations drive therapy resistance through post-mitochondrial caspase blockade.
    Ahmed M Mamdouh, Fizza Iftikhar, Elyse A Olesinski, Fang Qi Lim, Shaista Jasdanwala, Yuhan Wang, Yang Mi, Nicole Si En Lin, Daniel Tan En Liang, Md Al Nayem Chowdhury, Nishtha Chitkara, Leah Hogdal, Coleman R Lindsley, Anthony Letai, Koji Itahana, Shruti Bhatt.
      Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a broad spectrum of molecular alterations that influence clinical outcomes. TP53 mutations define one of the most lethal subtypes of AML, driving resistance to nearly all available treatment modalities, including venetoclax plus azacitidine (VenAza). Yet, the molecular basis of this resistance, beyond affecting transactivation of BCL-2 family genes, has remained elusive. Here, we demonstrate that VenAza treatment leads to reduced transcriptional upregulation of the p53 signaling pathway in TP53 mutant/deficient AML compared to wild-type AML. Functionally, TP53 mutant/deficient AML exhibits selective failure in apoptosis induction rather than impaired G1 arrest or senescence. Despite inhibition of pro-apoptotic BAX and selective enrichment for MCL-1 in TP53 mutant isogenic AML cells, compensatory upregulation of BIM preserved functional mitochondrial outer membrane permeabilization (MOMP). TP53 mutant primary AML tumors at baseline also had retained capacity for MOMP. Instead, TP53 mutant AML exhibited disruption in caspase-3/7 activation to evade apoptosis after VenAza therapy - decoupling the mitochondrial and executioner phases of apoptosis. Importantly, this "post-MOMP brake" is not a bystander effect but itself a driver of VenAza and chemotherapy resistance in TP53 mutant/deficient AML. This previously unrecognized mechanistic insight shifts the focus from mitochondrial priming to terminal caspase blockade in TP53 mutant AML and opens the door for urgently needed therapeutic strategies that reignite apoptosis at its execution point.
    DOI:  https://doi.org/10.1038/s41419-026-09087-0
  4. Sci Adv. 2026 Oct 23. 12(43): eaed6757
    Polycomb factor PHF19 affects AML initiation, patient prognosis, and survival.
    Gianni Paolo Gamarra Figueroa, Arantxa Gutierrez, Enrique Blanco, Pedro Vizán, Cecilia Ballaré, Aleksandra Sparavier, Marta Tosto, Saverio Minucci, Lars Velten, Luciano Di Croce.
      Acute myeloid leukemia (AML) is marked by unchecked expansion of undifferentiated myeloid cells. Although oncogenic fusions such as MLL-AF9 can initiate disease, the early steps of leukemogenesis and the role of cell-intrinsic regulators remain unclear. We previously showed that the Polycomb-associated factor Phf19 is required for hematopoietic stem cell (HSC) maintenance and state control in mice and that its loss (Phf19KO) impairs HSC function. To define Phf19's role in transformation, we expressed MLL-AF9 in Phf19KO hematopoietic cells and performed integrated multiomic analyses. Phf19 deletion promoted acquisition of stemlike features and reduced responsiveness to differentiation-inducing AML therapies. Molecular and functional consequences of Phf19 loss paralleled those observed in the datasets of patients with AML. From these data, we derived a prognostic signature-PHFScore-which reveals previously unrecognized AML survival-correlating genes that robustly stratify patients across distinct cellular origins and leukemogenic stages, underscoring Phf19's key role in AML biology and prognosis.
    DOI:  https://doi.org/10.1126/sciadv.aed6757
  5. Development. 2026 Oct 20. pii: dev.205304. [Epub ahead of print]
    Vcam1 in endothelial and stromal cells regulates hematopoietic stem cell contact with the niche.
    Octavia Santis Larrain, Alice Alhaj Kadour, Sobhika Agarwala, Wantong Li, Bradley W Blaser, Michael R Lasarev, Roxana Alexandridis, Julian T Kamanda, Anthony Veltri, Khaliun Enkhbayar, Elliott J Hagedorn, Owen J Tamplin.
      Hematopoietic stem and progenitor cells (HSPCs) are essential for differentiation into all blood cell types. In mammals, the interaction between HSPCs and the fetal liver niche during development is critical for stem cell maturation. Integrin alpha 4 (Itga4) on HSPCs and vascular cell adhesion molecule (Vcam1) on niche cells are critical for HSPC colonization of the fetal liver (FL). Itga4 and Vcam1 also function in the zebrafish equivalent of the FL, the caudal hematopoietic tissue (CHT), however, the specific niche cells that express Vcam1 remain unclear. Using multiple approaches, including fluorescent in situ hybridization, we found Vcam1 is expressed in endothelial cells (ECs) and mesenchymal stromal cells (MSCs), but not macrophages. Time-lapse live imaging of itga4 mutants showed the Itga4-Vcam1 axis is not required for guiding HSPCs into the CHT niche but is required for their retention. Our results show that Itga4 on HSPCs, and Vcam1 on ECs and MSCs, are involved in CHT niche retention.
    Keywords:  Hematopoietic stem cell; Integrin; Microenvironment; Niche; Vcam1; Zebrafish
    DOI:  https://doi.org/10.1242/dev.205304
  6. iScience. 2026 Nov 20. 29(11): 117458
    Stathmin 1 regulates mitophagy and non-proliferative cellular function in hematopoietic stem and progenitor cells.
    Luana Chiquetto, Meg Schuetz, Qian Dong, Mia Warmka, Liana Valin, Ashley Jones, Patrick Hunt, Copper Petermeier, Jie Wang, Nate Roundy, Zev J Greenberg, Wei Yang, Christine R Zhang, Grant A Challen, Cliff J Luke, Robert A J Signer, Wandy L Beatty, Stephen Sykes, Weikai Li, David J Kast, Laura G Schuettpelz.
      Stathmin 1 is a cytoplasmic phosphoprotein that regulates microtubule dynamics. Stathmin 1 expression is a feature of proliferating cells, and it is overexpressed in many cancers, including leukemias. In contrast to its roles in proliferating cells, considerably less is known of stathmin 1 in quiescent cells. Importantly, stathmin 1 is highly expressed in hematopoietic stem and progenitor cells (HSPCs), and herein we found that stathmin 1 loss is associated with altered microtubule architecture and markedly impaired HSPC function. Transcriptomic studies suggested metabolic differences in Stmn1 -/- HSPCs, and further mechanistic studies revealed defective mitochondrial structure and function. Microtubules facilitate autophagosome formation and mitophagy, and indeed we found that this critical mitochondrial quality control process is impaired in Stmn1 -/- HSPCs. Finally, stimulation of autophagy improved Stmn1 -/- HSPC colony-forming ability. Together, these data identify a non-proliferative role for stathmin 1 in the regulation of HSPC mitochondrial quality control and cellular function.
    Keywords:  autophagy; hematopoietic stem cells; metabolism; microtubules; mitophagy; stathmin
    DOI:  https://doi.org/10.1016/j.isci.2026.117458
  7. Cell Stem Cell. 2026 Oct 21. pii: S1934-5909(26)00355-3. [Epub ahead of print]
    Phase separation of Rbpms sequesters translation elongation machinery to preserve hematopoietic stem cell function.
    Le Chang, Mengyao Sun, Lingyan Zhao, Jiahuan He, Sijia Bai, Zhongyang Chen, Siqi Liu, Xinyan Shen, Fanqi Zhou, Yu Rong, Chenxi Han, Yanmin Si, Hualu Zhao, Fang Wang, Yanni Ma, Jia Yu.
      The mechanisms by which hematopoietic stem cells (HSCs) maintain long-term (LT) hematopoietic capacity and transition from quiescence remain incompletely understood, limiting their in vitro expansion and applications. Accumulating evidence underscores the importance of maintaining a low protein synthesis rate for HSC function, yet the underlying mechanisms remain elusive. Here, we identified ribosome-associated proteins specifically enriched in HSCs and multipotent progenitors (MPPs) and found that RNA-binding protein gene with multiple splicing (Rbpms) is required for sustaining low protein synthesis rates in HSCs. Rbpms forms biomolecular condensates that sequester translation elongation factors and protein-folding chaperones from ribosomes, slowing translation elongation and ensuring proper protein folding in HSCs. Rbpms deletion led to accelerated protein synthesis, accumulation of misfolded proteins in HSCs, impaired LT hematopoietic reconstitution capacity, accompanied by aberrant exit from quiescence. Our findings unveil a unique mechanism of translation elongation regulation in HSCs and highlight significance of spatial compartmentalization and translational control in HSCs.
    Keywords:  Rbpms; biomolecular condensates; hematopoietic stem cells; translation elongation
    DOI:  https://doi.org/10.1016/j.stem.2026.09.013
  8. Leukemia. 2026 Oct 23.
    Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.
    Ilias Sinanidis, Panagiotis Tsakiroglou, Benjamin Dubner, Rebecca Foertsch, Julia Gondek, InYoung Choi, Bogdan Paun, Teodora Supeanu, Liang Zhao, Gabriel Ghiaur, W Brian Dalton.
      Serine metabolism is of growing biologic and therapeutic interest in cancer. Upregulation of the serine synthesis pathway (SSP) can fuel tumor growth, and cancers with this phenotype are often sensitive to. SSP inhibitors. In parallel, dietary restriction of serine and glycine (SG) can suppress some cancers, but the determinants of sensitivity to. this approach are poorly understood. This is especially true in acute myeloid leukemia (AML), where serine metabolism has been less explored. We report that a subset of human AML cell lines and primary samples are completely dependent on external serine, known as serine auxotrophy. These leukemias consistently suppressed the SSP enzyme PSAT1, failed to. synthesize serine, responded to. SG restriction in vivo, and were rescued by restoring PSAT1. We also found that SG restriction synergized with venetoclax in serine auxotrophic AML, and that MECOM rearrangement was strongly associated with PSAT1 suppression and serine auxotrophy. These findings define a metabolically distinct AML subtype and nominate it for targeting by SG restriction.
    DOI:  https://doi.org/10.1038/s41375-026-03176-x
  9. Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2531364123
    Transient ATM inhibition enhances knock-in efficiency in hematopoietic stem cells by attenuating the DNA damage response.
    Munkh-Erdene Natsagdorj, Hiromasa Hara, Kohei Iida, Yuji Kashiwakura, Nemekhbayar Baatartsogt, Enkhzaya Ganzorig, Daniele Canarutto, Sandra Pinho, Luigi Naldini, Tsukasa Ohmori, Yutaka Hanazono, Fumio Nakahara.
      Precise genome editing in hematopoietic stem cells (HSCs) holds great potential for treating inherited blood disorders; however, low knock-in (KI) efficiency and loss of functional HSCs after genome editing remain major obstacles. Here, we demonstrate that transient inhibition of Ataxia-Telangiectasia Mutated (ATM) kinase markedly enhanced KI efficiency in mouse HSCs genome-edited with Cas9/ribonucleoprotein (RNP) and AAV donor DNA. Phosphoproteomic and capillary western blot analyses revealed that ATM inhibition suppressed aberrant Cas9-AAV-induced ATM activation and the subsequent DNA damage response, reduced p53-dependent apoptosis, and enhanced survival of KI HSCs. In serial transplantation assays, ATM inhibition preserved long-term engrafting KI HSCs, increasing their frequency from ~0.3 to 40% in secondary recipients, an over 100-fold improvement. Furthermore, in an X-linked severe combined immunodeficient mouse model, ATM inhibition increased KI efficiency and restored T- and B cell differentiation. Comprehensive safety analyses, including long-read nanopore sequencing, amplicon deep sequencing, whole genome sequencing and clonal tracking, did not detect increased genomic alterations, chromosomal abnormalities, or clonal expansion following transient ATM inhibition. Taken together, these findings establish transient ATM inhibition as an effective strategy to enhance KI-mediated genome editing while maintaining the long-term repopulating capacity of HSCs.
    Keywords:  Ataxia-telangiectasia mutated; DNA damage response; genome editing; hematopoietic stem cells; knock-in
    DOI:  https://doi.org/10.1073/pnas.2531364123
  10. iScience. 2026 Nov 20. 29(11): 117762
    The immunophenotypic landscape of newly diagnosed acute myeloid leukemia: Associations with genotype and outcomes.
    Tim R Mocking, Tom Reuvekamp, Lukas H Haaksma, Eirini Papavasileiou, Angèle Kelder, Willemijn J Scholten, Dimitri A Breems, Thomas Fischer, Bjørn T Gjertsen, Laimonas Griškevičius, Gunnar Juliusson, Johan A Maertens, Markus G Manz, Thomas Pabst, Jakob R Passweg, Kimmo Porkka, Jeroen J W M Janssen, Patrycja Gradowska, Bob Löwenberg, Gert J Ossenkoppele, Arjan A van de Loosdrecht, David C de Leeuw, Jacqueline Cloos, Peter J M Valk, Costa Bachas.
      Despite widespread immunophenotyping in acute myeloid leukemia (AML), its immunophenotypic heterogeneity remains incompletely understood. Here, we applied state-of-the-art computational modeling to >50 million single cells from diagnostic bone marrow aspirates of 502 AML patients. Jointly modeling leukemic and non-malignant cells, we identified seven patient clusters with distinct immunophenotypic signatures. These clusters showed strong concordance with recurrent mutations, including NPM1, IDH1/IDH2, CEBPA, and t(8;21)(q22;q22); RUNX1-RUNX1T1 fusions, and enabled accurate prediction of genomic subgroups. Although these immunophenotypic signatures were not associated with therapy responses, loss of HLA-DR expression on leukemic blasts at diagnosis was independently associated with inferior outcomes in patients with chromatin-spliceosome mutations. In addition, we identified an immunophenotypic patient cluster comprising ∼11% of patients characterized by significant bone marrow lymphocyte enrichment where outcomes diverged depending on genetic risk. Together, these findings provide a comprehensive single-cell characterization of AML bone marrow and reveal clinically relevant genotype-phenotype relationships.
    Keywords:  acute myeloid leukemia; flow cytometry; genomics; immunophenotyping; machine learning; patient stratification; unsupervised clustering
    DOI:  https://doi.org/10.1016/j.isci.2026.117762
  11. Leukemia. 2026 Oct 19.
    Targeting the mitochondrial complex I subunit NDUFS2 potentiates FLT3 inhibition in acute myeloid leukaemia with FLT3 internal tandem duplication.
    Xiqin Tong, Guopeng Chen, Yuzhe Pan, Yanling Chen, Yuxin Tan, Hongqiang Jiang, Qian Wang, Linlu Ma, Ruihang Li, Yuxing Liang, Xiaoyan Liu, Fuling Zhou.
      Acute myeloid leukaemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) frequently relapses after FLT3 tyrosine kinase inhibitor (TKI) therapy, highlighting the need to define mechanisms of drug tolerance. Here, we identify the mitochondrial complex I core subunit NDUFS2 as a determinant of FLT3 TKI tolerance in FLT3-ITD AML. A metabolism-focused CRISPR-Cas9 sensitiser screen, integrated with transcriptomic profiling of gilteritinib-resistant cells and primary samples, identified NDUFS2 as upregulated in acquired resistance and preferentially expressed in FLT3-ITD AML. NDUFS2 knockdown impaired complex I activity, oxidative phosphorylation, mitochondrial membrane potential and ATP production, thereby promoting apoptosis and sensitising FLT3-ITD AML cells to gilteritinib. Pharmacologic complex I inhibition with IACS-010759 similarly enhanced gilteritinib activity in FLT3-ITD AML cell lines and primary FLT3-ITD samples, activated AMPK-PERK-ATF4-CHOP stress signalling, promoted apoptosis, and reduced leukaemia burden in a patient-derived xenograft model. Genetic NDUFS2 knockdown also prolonged survival in a xenograft model. A preliminary murine safety assessment showed no overt toxicity under the tested short-term dosing schedule. These findings identify NDUFS2-dependent complex I activity as an adaptive metabolic dependency supporting FLT3 inhibitor tolerance and provide mechanistic insight for further preclinical evaluation.
    DOI:  https://doi.org/10.1038/s41375-026-03170-3
  12. Apoptosis. 2026 Oct 23. pii: 253. [Epub ahead of print]31(11):
    Targeting lactate-driven protein lactylation overcomes proteasome inhibitor resistance in multiple myeloma.
    Guangcan Gao, Qi Li, Chaowei Cheng, Weicheng Zheng, Ran Xue, Xingming Peng, Fuyu Pei, Jianyun Wen, Wenzhuo Zhuang, Bingzong Li.
      Acquired resistance to proteasome inhibitors (PIs) remains a major challenge limiting the long-term efficacy of multiple myeloma (MM) therapy, while the metabolic-epigenetic mechanisms underlying PI resistance remain incompletely defined. Using clinical bone marrow specimens, paired parental and PI-resistant MM cell models, xenografts, and integrated lactylome, CUT&Tag, and RNA-seq profiling, we investigated the role of lactate-associated lactylation in acquired PI resistance. Bone marrow lactate levels, lactate dehydrogenase (LDH) activity, and global protein lactylation were elevated in relapsed/refractory MM and in PI-resistant cell models. Lactylome profiling revealed extensive lactylation remodeling and identified histone H4K12 lactylation (H4K12la) as a prominent resistance-associated epigenetic mark. Integrative prioritization and functional validation identified EP300 as an upstream regulator of H4K12la; EP300 was upregulated in resistant cells, and its depletion reduced H4K12la and partially restored PI sensitivity. Integration of H4K12la CUT&Tag and RNA-seq linked resistance-associated H4K12la remodeling to autophagy/lysosome-related transcriptional programs, with increased H4K12la occupancy at the Cathepsin L (CTSL) promoter accompanied by increased CTSL expression. Pharmacological LDH inhibition with FX-11 reduced H4K12la and CTSL expression. Moreover, combining FX-11 with carfilzomib markedly enhanced antitumor activity in a PI-resistant MM xenograft model without detectable systemic or hematological toxicity during the treatment period. Collectively, these findings define a lactate-EP300-H4K12la-CTSL pathway that contributes to PI resistance and provide a preclinical rationale for combined metabolic and proteasomal inhibition in refractory MM.
    Keywords:  Cathepsin L; Histone H4K12 lactylation; Multiple myeloma; Proteasome inhibitor resistance
    DOI:  https://doi.org/10.1007/s10495-026-02457-1
  13. Exp Hematol. 2026 Oct 23. pii: S0301-472X(26)00589-8. [Epub ahead of print] 105956
    Arid1a and Arid1b maintain B cell lineage fidelity and constrain myeloid transformation in mice.
    Phyo Nay Lin, Sarah M Zimmerman, Joohyung Park, Yoon-A Kang, George P Souroullas.
      Chromatin remodeling by mammalian SWI/SNF complexes is essential for hematopoietic lineage specification and differentiation. Although the canonical BAF subunits ARID1A and ARID1B are recurrently altered in B-cell malignancies, their overlapping and stage-specific functions during B-cell development remain incompletely understood. Here, we used CD19-Cre-mediated deletion of Arid1a and Arid1b to define their roles in B-cell development and hematopoietic transformation in vivo. Loss of either Arid1a or Arid1b impaired B-cell differentiation, reduced immature and recirculating B-cell output, and compromised germinal center responses following antigen challenge, with more pronounced defects following combined deletion. Unexpectedly, combined Arid1a/Arid1b loss resulted in a lethal, transplantable myeloid leukemia rather than a B-cell malignancy. CD19-Cre lineage tracing and allele-recombination analysis identified a subset of multipotent progenitors carrying CD19-Cre activity, while combined deletion was associated with selective MPP3 expansion and impaired myelo-erythroid colony-forming capacity. Transcriptional profiling of Arid1a/Arid1b-deficient MPP2/3 cells revealed loss of HSPC- and lymphoid-associated programs together with aberrant activation of erythroid and megakaryocyte-erythroid transcriptional states, without acquisition of a conventional mature myeloid program. These findings reveal overlapping functions of ARID1A and ARID1B in B-cell development and support a broader role for canonical BAF complexes in maintaining hematopoietic lineage fidelity and constraining malignant transformation.
    Keywords:  ARID1A; ARID1B; B cell development; BAF; MPPs; Myeloid leukemia; SWI/SNF; lineage fidelity; multipotent progenitors
    DOI:  https://doi.org/10.1016/j.exphem.2026.105956
  14. Nat Commun. 2026 09 19. pii: 10985. [Epub ahead of print]17(1):
    Extending single-cell proteomics from HeLa to small primary human immune cells.
    Ivo A Hendriks, Sara C Buch-Larsen, Martin Rykær, Maico Y Lechner, Anders H Kverneland, Tabiwang N Arrey, Daniel Hermanson, Eugen Damoc, Jesper V Olsen.
      Single-cell proteomics (SCP) holds the promise of decoding cellular heterogeneity at the functional level, yet achieving deep and reproducible proteome coverage from individual cells has remained a formidable challenge. Here, we establish a high-sensitivity, label-free SCP platform that extends current depth and reproducibility. By integrating optimized low-input sample processing, refined liquid chromatography, and the Orbitrap Astral Zoom mass spectrometer, our approach routinely quantifies up to 7000 proteins per individual HeLa cell at over 100 samples-per-day (SPD), capturing thousands of low-abundance proteins that eluded prior SCP studies. Applied to very small human peripheral blood mononuclear cells (PBMCs), we identify up to 4000 proteins per cell, including key markers that distinguish monocytes, T cells, and activated lymphocytes within heterogeneous populations, underscoring that single-cell proteomics can now directly elucidate clinically relevant primary samples with both depth and precision.
    DOI:  https://doi.org/10.1038/s41467-026-77675-x
  15. Mol Ther. 2026 Oct 23. pii: S1525-0016(26)00881-6. [Epub ahead of print]
    A Scalable, Antibody-Free Lipid Nanoparticle Achieves Preferential mRNA Delivery to Human HSPCs In Vivo Without Conditioning.
    Eunyoung Kim, Ryan Zenhausern, Shivani Kapadia, Sylvanie Johnson, Skylar Cho, Joanne Choi, Kernyu Park, Edgard Diaz, Ananda R Podilapu, Ramachandran Kuppan, James E Dahlman, Hyejin Kim, Janghee Woo.
      Systemic nucleic acid delivery to hematopoietic stem and progenitor cells (HSPCs) remains a major barrier to in vivo gene therapy due to hepatic sequestration of lipid nanoparticles (LNPs). Here, we report a scalable, ligand-free HSPC-tropic LNP enabling efficient mRNA delivery to human HSPCs in vivo without conditioning. In humanized NBSGW mice, the LNP preferentially delivered mRNA to human HSPCs and early myeloid progenitors, with limited delivery to lymphoid and non-hematopoietic cells. Single-cell transcriptomic and multiomic analyses revealed no broad transcriptional perturbation associated with delivery. Compared with the SM-102 LNP, the HSPC-tropic LNP achieved greater mRNA delivery to human HSPCs, while exhibiting substantially reduced hepatic delivery. The LNP also enabled functional delivery of Cas9 mRNA and β2M-targeting sgRNA to human CD34+ HSPCs, resulting in efficient gene editing and reduced β2M expression. These findings establish a ligand-free platform for functional RNA delivery and genome engineering in human HSPCs.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.10.024
  16. Sci Adv. 2026 Oct 23. 12(43): eaee5701
    TET2-driven activation of AGO2 links epigenetic remodeling to myeloid commitment and leukemia.
    Aleksey Lazarenkov, Gemma Valcárcel, Alba Martinez, Clara Berenguer, Anna V López-Rubio, Mireia Obiols, Claudia Fontanet, Ana Barba, Juan José Rodríguez-Sevilla, Gregoire Stik, Irmela Jeremias, Pablo Menendez, José Luis Sardina.
      DNA methylation dynamics shape hematopoietic differentiation and leukemogenesis, yet how the dioxygenase TET2-frequently mutated in myeloid malignancies-directs lineage-specific regulatory programs remains unclear. Here, we integrated DNA methylation, chromatin accessibility, three-dimensional (3D) genome architecture, transcriptional profiling, and TET2 chromatin occupancy to define TET2-dependent control of human myeloid commitment. We found that TET2-bound regulatory regions gain short- and long-range chromatin interactions and that a distinct subset of distal, enhancer-enriched sites undergoes TET2-driven demethylation and activation. Among these, we identified and functionally validated an AGO2 myeloid-specific intragenic enhancer that is frequently hypermethylated in patients with TET2-mutant acute myeloid leukemia. AGO2 expression stratifies patient survival, and AGO2 depletion abrogates leukemic engraftment in vivo. These findings uncover a TET2-AGO2 regulatory axis that integrates epigenetic remodeling, 3D genome reorganization, and leukemic fitness, and they highlight AGO2 as a potential biomarker and therapeutic target in myeloid leukemia.
    DOI:  https://doi.org/10.1126/sciadv.aee5701
  17. Cell Chem Biol. 2026 Oct 21. pii: S2451-9456(26)00369-7. [Epub ahead of print]
    Proteasome inhibition bidirectionally regulates ferroptosis sensitivity.
    Magdalena B Murray, Rishi Upadhyay, Krystina J Szylo, Aastha Gautam, Judith Goncalves, Giovanni Forcina, Ananya Vinayak, Onn Brandman, Scott J Dixon.
      Ferroptosis is a non-apoptotic cell death mechanism whose fundamental regulation continues to be elucidated. The proteasome is an essential multiprotein complex important for protein turnover. How proteasome function regulates ferroptosis is difficult to study given that proteasome inhibition causes apoptosis. Here, we isolated the effects of proteasome inhibition on ferroptosis by combining small molecule cell death inducers, pathway-specific cell death inhibitors, and direct cell death imaging. We find that proteasome inhibition enhances sensitivity to ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition while simultaneously promoting resistance to ferroptosis induced by system xc- inhibition. Sensitization to GPX4 inhibition requires protein synthesis but not the apoptosis execution machinery and is opposed by the activating transcription factor 4 (ATF4) stress response pathway. These findings establish proteasome-mediated protein turnover as a context-dependent regulator of ferroptosis and identify protein synthesis and ATF4 as key determinants of GPX4 inhibitor sensitivity.
    Keywords:  ATF4; Necrosis; cancer; iron metabolism; lipid peroxidation; oxidative stress; protein synthesis; ubiquitination
    DOI:  https://doi.org/10.1016/j.chembiol.2026.09.020
  18. Blood Neoplasia. 2026 Nov;3(4): 100296
    Pitavastatin counteracts venetoclax resistance mechanisms including TP53 mutation in acute myeloid leukemia.
    Roberta Buono, Dennis Juarez, Madhuri Paul, Sarah J Skuli, Ian B Wong, Ishita Tarnekar, Zhili Ying, Izabelle Marie F Le, Wen-Pin Chen, Min Zhang, Gerald Wertheim, A'ishah Bakayoko, Marisa Kruidenier, Dequina A Nicholas, Pankaj Gupta, Said M Sebti, Marina Konopleva, Angela G Fleischman, Cholsoon Jang, Martin Carroll, David A Fruman.
      The B-cell lymphoma 2 inhibitor venetoclax has therapeutic activity in several hematological malignancies. In acute myeloid leukemia (AML), venetoclax combined with hypomethylating agents is the standard of care for patients unfit for intensive chemotherapy, but intrinsic and acquired resistance are common. Loss of p53 function is strongly associated with venetoclax resistance, and adding venetoclax to 5-azacitidine provides no overall survival benefit in TP53-mutant AML. Other frequent mechanisms of venetoclax resistance in AML include FLT3 mutations, myeloid cell leukemia 1 (MCL-1) upregulation, and altered mitochondrial metabolism. However, it has been challenging to develop agents that target these mechanisms directly and combinatorially. Here, we report that pitavastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, promotes apoptosis and overcomes several venetoclax resistance mechanisms in human AML cells. At clinically achievable concentrations, pitavastatin treatment has potent cytotoxic activity in cells with mutations in TP53 or FLT3, including primary cells resistant to venetoclax and 5-azacitidine. The apoptotic mechanism involves p53-independent PUMA upregulation and reduced MCL-1 expression. Pitavastatin also suppresses mitochondrial gene expression, oxidative metabolism, and MYC/E2F-driven transcription. These results provide a mechanistic rationale for clinical trials adding pitavastatin to AML regimens to prevent or overcome venetoclax resistance with TP53 mutations and other high-risk features.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100296
  19. J Exp Med. 2026 Nov 02. pii: e20251898. [Epub ahead of print]223(11):
    Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300.
    Ian M Delahunty, Stephanie Nance, Yang Zhang, Francois Lamoureux, Qi Liu, William C Wright, K Elaine Ritter, Noha A M Shendy, Bénédicte Brounais-Le Roye, Sandra J Kietlinska, Mohammad A Mohammad Nezhady, Yuan Feng, Barbara De Kegel, Matthew G Rees, Mustafa Kocak, Ashish B George, Meifen Lu, Anoop M Kavirayani, Bo Wang, Yanling Liu, Paris E A Prinsen, Yousef Khashana, Vernon Justice Ebegboni, Melissa M Ronan, Jennifer A Roth, E Alejandro Sweet-Cordero, Lillian M Guenther, Paul Geeleher, Xiaotu Ma, Benjamin Ory, Jun Qi, Brian J Abraham, Adam D Durbin.
      Cancers depend on transcriptional control to maintain the malignant cell state. EP300 and CBP are paralogous master epigenetic enzymes that control normal and malignant transcription. Using a cancer-wide integrative chemical-genetic analysis, we demonstrate enhanced dependency on EP300, compared with CBP, in cell lines from most cancer lineages, including lethal osteosarcoma (OS). Using a selective EP300 degrader (JQAD1), we identify that a genetically defined subgroup of OS with dysregulation of the PI3K-AKT-mTOR pathway is genetically and chemically sensitive to loss of EP300. Activated AKT promotes sensitivity to JQAD1, driven by relocalization of EP300, CBP and H3K27ac to genetic subtype-enriched dependency loci. AKT inhibition combines with JQAD1 to synergistically suppress the growth of AKT-dysregulated OS cells in vitro and in orthotopic xenografts. These observations extend across >850 cancer cell lines, where synergy is predicted by elevated protein synthetic rates. These findings reveal determinants of EP300 degrader function in OS and provide a foundation for co-targeting EP300 and AKT in cancers with enhanced protein translation.
    DOI:  https://doi.org/10.1084/jem.20251898
  20. Sci Adv. 2026 Oct 23. 12(43): eaea1431
    NRF2 coordinates cystine import and glutathione use to sustain ferroptosis resistance and formaldehyde tolerance in cancer.
    Agustín E Morellato, Natividad Alquezar-Artieda, Alejandro Guerrero-Maldonado, Rajinder Singh, Lilla Beja, Carla Umansky, Laura Perich-Pallaruelo, Mireia Pellicer, Paula Fernandez-Deu, Nicolas Aira, Nour Bourached-Silva, Uciel Chorostecki, Donald J L Jones, Gaël Roué, Richard J Hopkinson, Lucas B Pontel.
      Cancer cells must balance detoxification of reactive metabolic by-products while preserving redox homeostasis, but how this trade-off is managed remains unclear. The Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor-erythroid 2-related factor 2 (NRF2) pathway, a key regulator of antioxidant defenses, is frequently hyperactivated in cancer. Formaldehyde, a genotoxic one-carbon by-product, is typically detoxified via glutathione (GSH), which is also essential for suppressing ferroptotic cell death. Here, we show that NRF2 promotes formaldehyde tolerance through up-regulation of the cystine transporter SLC7A11, enabling a protective mechanism that is largely independent of GSH, which remains necessary for ferroptosis resistance. In NRF2-active cells, formaldehyde reacts with cysteine to form a thiazolidine conjugate, and the combination of formaldehyde stress and SLC7A11 inhibition activates the integrated stress response, suppresses global protein synthesis, and markedly compromises cell viability. Together, these findings reveal that NRF2 coordinates ferroptosis resistance and formaldehyde tolerance, exposing a cancer vulnerability through combined inhibition of cystine uptake and GSH synthesis.
    DOI:  https://doi.org/10.1126/sciadv.aea1431
  21. Biochemistry. 2026 Sep 15. 65(18): 2785-2797
    The Spatiotemporal Regulation of Glucose Metabolism in Hematopoietic Stem Cells.
    Aoxue Wang, Yaqiong Chen, Hailing Li, Zhuo Zhang, Yuzheng Zhao.
      Hematopoietic stem cell fate decisions are tightly coupled to dynamic changes in glucose metabolism, which are precisely orchestrated across both the spatial and temporal dimensions during differentiation. Tracking the metabolic dynamics is crucial for understanding fate decisions of hematopoietic stem cells and facilitating their efficient expansion for therapeutic applications. Genetically encoded fluorescent biosensors have emerged as powerful tools to monitor glucose metabolism in living hematopoietic stem and precursor cells with high spatiotemporal resolution, enabling the in situ, real-time analysis of cellular metabolic heterogeneity at single-cell resolution and the analysis of the regulatory mechanisms underlying hematopoietic functions. The insights revealed by biosensors are often difficult to attain with conventional bulk or end point assays. This review underscores the unique advantages and growing promise of genetically encoded sensors in decoding the metabolic regulation of HSC differentiation, while critically examining current challenges toward their broader application in stem cell biology.
    DOI:  https://doi.org/10.1021/acs.biochem.6c00155
  22. Science. 2026 Oct 22. 394(6822): eaea2181
    BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
    Shaoyuan Yang, Hyungjin Kim, Guanghong Liao, Na Ta, Ho-Chou Tu, Shriram Ramani, Chih-Yu Chen, Zih-Yu Li, Nobuhiro Tanno, James J Hsieh, Emily H Cheng.
      The apoptotic regulators BAX and BAK, once activated, form homo-oligomers to trigger mitochondrial outer membrane permeabilization (MOMP), activating the apoptosome and caspases. Activation of BAX-BAK without apoptosome activation triggers sustained efflux of mitochondrial DNA (mtDNA) and caspase-independent cell death. However, the molecular basis of mtDNA efflux remains unclear. We purified a macromolecular complex comprising BAK, BAX, activator BH3-only molecules, voltage-dependent anion channels 1 and 2 (VDAC1 and VDAC2), and prohibitins that released mtDNA from mitoplasts. BAX-BAK activation resulted in VDAC closure, mitochondrial calcium influx, and mtDNA efflux. Loss of VDAC1, VDAC2, or prohibitins prevented BAX-BAK activation-induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome c and mtDNA efflux by distinct BAX-BAK complexes.
    DOI:  https://doi.org/10.1126/science.aea2181
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