bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–07–26
thirteen papers selected by
William Grey, University of York
  1. The NLRC4 Inflammasome Drives Myelodysplastic Syndrome by Linking Epigenetic Reprogramming and Innate Immune Signaling.
  2. JARID2 Inhibition Reprograms Human Hematopoietic Progenitor Cells To Enhance Bone Marrow Transplantation.
  3. Reassessment of Hematopoietic Stem Cell Aging through Metabolic Uncoupling and Mitochondrial Resilience.
  4. Flow-Induced Yap/Taz Signaling Balances Endothelial and Hematopoietic Stem Cell Fates.
  5. Premature senescence impairs hematopoietic stem cell function during sickle cell disease in mice and humans.
  6. Bcl11a orchestrates multilineage integrity in aging hematopoiesis by regulating multipotent progenitor fate decisions.
  7. Ninjurins regulate hematopoietic stem cell amplification through canonical WNT signaling independent of plasma membrane rupture.
  8. LY3410738, a Covalent Inhibitor of Mutant IDH1/2, is Effective in Acute Myeloid Leukemia Preclinical Models.
  9. Synthetic lethality in TP53-mutated AML.
  10. The Nicotinamide Salvage Pathway is a Metabolic Vulnerability of High-Risk MDS Stem Cells.
  11. Measurable Residual Disease and the Unresolved Biology of Leukemic Stem Cells.
  12. SoftHybrid: A Hybrid Imputation Algorithm Optimized for Single-Cell Proteomics Data.
  13. Prior therapy defines mutation profiles in childhood cancer at relapse.
  1. Blood Adv. 2026 Jul 24. pii: bloodadvances.2026020095. [Epub ahead of print]
    The NLRC4 Inflammasome Drives Myelodysplastic Syndrome by Linking Epigenetic Reprogramming and Innate Immune Signaling.
    Chuan Chen, Fan Liu, Tasleem Arif, Na Man, Francesco Tamiro, Daniel Bilbao, Concepcion Martinez Caja, Krystal Hossack, Narges Rostami, Gloria Mas Martin, Stephanie Duffort, Hidehiro Itonaga, Julio Poveda, Jennifer R Chapman, Stephen D Nimer.
      Myelodysplastic syndromes (MDS), which are hematopoietic stem cell malignancies, are often accompanied by signs of chronic inflammation, that can in turn drive the pathogenetic process. The precise mechanisms dysregulating inflammatory and innate immune signaling in MDS hematopoietic stem and progenitor cells (HSPCs) remain under investigation. We report that mice lacking Tet2 developed a hyper-inflammatory state, which can be further fueled by LPS-induced inflammation. This chronic inflammation temporarily promotes the self-renewal and myeloid differentiation of Tet2-deficient HSPCs; however, it ultimately accelerates HSC exhaustion and triggers MDS development in chimeric mouse models. Driving this phenotype was the activation of the NLRC4 inflammasome pathway. Notably, Nlrc4 depletion in Tet2-deficient mice impaired MDS development and improved the survival of these mice. These findings uncover a novel mechanistic basis for the MDS-associated inflammation and provide new targeting opportunities in its management.
    DOI:  https://doi.org/10.1182/bloodadvances.2026020095
  2. Blood Adv. 2026 Jul 22. pii: bloodadvances.2025019220. [Epub ahead of print]
    JARID2 Inhibition Reprograms Human Hematopoietic Progenitor Cells To Enhance Bone Marrow Transplantation.
    Wentao Han, Hassan Bjeije, Hamza Celik, Michael P Rettig, Nancy Issa, Andrew L Young, Yanan Li, Infencia Xavier Raj, Christine R Zhang, Aishwarya Krishnan, Tyler M Parsons, Samantha Burkart, Jason Arand, Wei Yang, Jeffrey A Magee, Grant Challen.
      Hematopoietic stem cell transplantation is a common treatment for many blood disorders and can be a life-saving therapy for patients with leukemias, lymphomas and multiple myeloma. Umbilical cord blood (UCB) serves as a valuable source of hematopoietic stem and progenitor cells (HSPCs) for transplantation, particularly for patients lacking a matched donor. However, the limited number of repopulating cells in UCB units restricts its clinical utility. Our prior studies showed that genetic deletion of the polycomb repressive complex 2 (PRC2) co-factor Jarid2 in mouse multipotent progenitors (MPPs) conveyed ectopic self-renewal capacity. Here, we hypothesized that the function of human HSPCs could be enhanced through JARID2 inhibition. In this study, we demonstrate that both constitutive and transient knockdown of JARID2 increases the number and enhances the functionality of human HSPCs both in vitro and in vivo. This phenotype was distinct from inhibition of EZH2 in UCB cells, suggesting the mechanism was independent of PRC2 co-factor activity of JARID2. Mechanistically, JARID2 knockdown promotes a quiescent, long-term self-renewal gene expression program governed by STAT1 upregulation and characterized by an MHC class II immunophenotype. Analogous to mice, these mechanisms conferred HSC-like potential to human MPPs in vivo. Taken together, these findings highlight JARID2 inhibition as a novel and reversible approach to expand functional UCB-derived HSPCs ex vivo, potentially improving access to stem cell transplantation for a wider patient population.
    DOI:  https://doi.org/10.1182/bloodadvances.2025019220
  3. Exp Hematol. 2026 Jul 22. pii: S0301-472X(26)00118-9. [Epub ahead of print] 105485
    Reassessment of Hematopoietic Stem Cell Aging through Metabolic Uncoupling and Mitochondrial Resilience.
    Chong Yang, Keiyo Takubo, Toshio Suda.
      Hematopoietic stem cell (HSC) aging is often described as a gradual loss of stem cell fitness that culminates in impaired blood production, immune dysfunction, and increased susceptibility to hematologic disease. However, recent work suggests that this view is too simple. Rather than a uniform decline, aging appears to remodel the HSC compartment into metabolically and functionally distinct states, including maladaptive trajectories as well as surprisingly resilient subsets. In this review, we argue that HSC aging is best understood through the interplay of mitochondrial regulation, metabolic uncoupling, and niche-derived stress, with particular emphasis on how recent findings revise several longstanding assumptions in the field (Box 1).
    Keywords:  HSC aging; Hematopoietic resilience; Metabolic uncoupling; Mitochondrial metabolism; Niche
    DOI:  https://doi.org/10.1016/j.exphem.2026.105485
  4. bioRxiv. 2026 Jun 23. pii: 2026.06.20.733393. [Epub ahead of print]
    Flow-Induced Yap/Taz Signaling Balances Endothelial and Hematopoietic Stem Cell Fates.
    Wade W Sugden, Stephan George, Zachary C LeBlanc, Morgan T Walcheck, Eleanor Meader, Julia Goldstein, Elizabeth Molnar, Wandi Zhu, Rubul Mout, Christopher Li, Leah Radeke, Zoey Young, Maria Gonzalez di Tillio, Marcelo Falchetti, Mohamad A Najia, Yang Tang, Brittney D Love, Ran Jing, Allison M Tompkins, Olivia Stockard, Caroline Kubaczka, Katharina Kirchhof, Vanessa Lundin, Calum A MacRae, Thorsten M Schlaeger, George Q Daley, Trista E North.
      Mechanical forces from blood flow are essential for production of hematopoietic stem and progenitor cells (HSPCs) during embryogenesis, but the molecular mechanisms by which hemodynamic cues are sensed and orchestrate endothelial-to-hematopoietic (EHT) transition remain incompletely defined. We previously identified YAP mechanotransduction as a key integrator of physical forces with EHT. Here we show that hemodynamic forces can activate YAP signaling via the mechanoresponsive ion channel Piezo1 in human iPSC-derived hemogenic endothelium (HE) and zebrafish embryos. Investigation of the Piezo1/YAP axis revealed shared and unique roles of YAP and its paralogue TAZ in EHT. Mechanistically, we find a requirement for the Tead DNA-binding co-factor in YAP/TAZ-dependent control of HSPC number, and note that TAZ uniquely augments transcriptional output of the hematopoietic master regulator Runx1 via direct protein-protein interactions. By comprehensive scRNA-sequencing of YAP/TAZ gain-of-function (GOF) and yap-deficient cells from zebrafish, we reveal that YAP/TAZ promotes HSC production by positively regulating gene programs for hematopoietic self-renewal, cell cycle, and glycolysis-to-oxidative phosphorylation switching, while preventing reversion to endothelial identity. Importantly, comparison of GOF transcriptomes and functional analyses suggest decoupling of metabolic/proliferative and endothelial gene regulatory modules between YAP and TAZ: while either can functionally compensate for loss of the other in EHT, indiscriminate overactivation of TAZ enhances an endothelial program over pro-hematopoietic fate, ultimately blunting progression of HSPC production. Given that hemodynamic cues are integrated simultaneously by arterial and HE cells in embryonic vessels in which EHT occurs, these findings have strong implications for strategies designed to introduce biomechanical cues to in vitro hematopoietic differentiation systems to drive HSC production.
    DOI:  https://doi.org/10.64898/2026.06.20.733393
  5. Sci Transl Med. 2026 Jul 22. 18(859): eadv0628
    Premature senescence impairs hematopoietic stem cell function during sickle cell disease in mice and humans.
    Aditya Barve, Preeti Dabas, Adam Cornwell, Pramika Sriram, Alex Kopyov, Mattieu Zhai, Emilia Kooienga, Zakiya Kelley, James Johnson, Jacquelyn A Myers, Esther A Obeng, Guolian Kang, Yunusa Olufadi, Terri Cain, Lindsay Talbot, David Spence, Mauricio Cortes, Samuel A Miller, Dirk Loeffler, Akshay Sharma, Shannon McKinney-Freeman.
      Sickle cell disease (SCD) is a blood disorder affecting millions worldwide. Emerging evidence reveals that SCD pathophysiology increases the risk of myeloid malignancies and hematopoietic stem cell (HSC) dysfunction, likely because of chronic stress on bone marrow. To investigate this further, we interrogated bone marrow hematopoietic stem and progenitor cells (HSPCs) from mice and individuals with SCD and observed molecular signatures of chronic cellular stress including oxidative stress, DNA damage, and hallmarks of senescence. Consistent with these findings, SCD HSPCs displayed transcriptomic dysregulation of senescence-associated molecular programs and diminished mitogen response with prolonged cell cycle kinetics during time-lapse live cell imaging. SCD mice displayed a marked loss of immunophenotypic bone marrow HSPCs by flow cytometry and functional blood repopulating HSPCs in transplantation studies, whereas human SCD bone marrow HSPCs exhibited poor ex vivo hematopoietic colony-forming ability, and these phenotypes were reversed after senescence-targeting therapy with either ABT-263 (navitoclax) or the combination of dasatinib and quercetin. Thus, treatment with senescence-targeting therapy improves bone marrow HSPC function in vivo in mice and ex vivo in cells from individuals with SCD and could represent a possible strategy to improve HSPC health, promote manufacture of high-quality bespoke clinical products, and potentially enhance the safety of potentially curative gene therapies using autologous HSPCs from individuals with SCD.
    DOI:  https://doi.org/10.1126/scitranslmed.adv0628
  6. Cell Rep. 2026 Jul 20. pii: S2211-1247(26)00794-1. [Epub ahead of print]45(7): 117716
    Bcl11a orchestrates multilineage integrity in aging hematopoiesis by regulating multipotent progenitor fate decisions.
    Linlin Zhang, Xiang Xu, Jing Wang, Xinyu Cui, Cui Wang, Yong Yu.
      Aging hematopoiesis exhibits progressive myeloid skewing and impaired lymphopoiesis, driving age-related blood disorders. We show that multipotent progenitors (MPPs) mediate this lineage imbalance. Aging expands myeloid-biased MPP3 cells while functionally compromising MPP4 lymphoid potential, collectively skewing hematopoietic output toward the myeloid lineage. We identify Bcl11a as a dosage-sensitive regulator of MPP fate: Bcl11a suppresses Fer to restrain premature myeloid differentiation in MPP3, while activating the Irf8-Ebf1 axis to license lymphoid specification. Strikingly, sustained Bcl11a elevation from development preserves balanced lineage output into old age, reverses age-associated transcriptional alterations, and restores multilineage reconstitution capacity. These findings establish Bcl11a as a key molecular guardian of progenitor integrity during aging and underscore MPPs as a critical cellular nexus where transcriptional control translates into lineage fate decisions.
    Keywords:  Bcl11a; CP: stem cell research; aging; hematopoiesis; immune reconstitution; lineage fate; multipotent progenitors
    DOI:  https://doi.org/10.1016/j.celrep.2026.117716
  7. Nat Commun. 2026 Jul 21.
    Ninjurins regulate hematopoietic stem cell amplification through canonical WNT signaling independent of plasma membrane rupture.
    Juan M Lozano-Gil, Annamaria Pedoto, Lola Rodríguez-Ruiz, Francisca Alcaraz-Pérez, Diana García-Moreno, María L Cayuela, Alicia Martínez-López, Sylwia D Tyrkalska, Victoriano Mulero.
      Ninjurin-1 (NINJ1), a protein required for plasma membrane rupture (PMR) during inflammasome-mediated cell death, has no known role in hematopoiesis. Here, using zebrafish and human hematopoietic stem/progenitor cells (HSPCs), we identify an evolutionarily conserved, PMR-independent function of Ninjurins in HSPC development. Ninj1 deficiency reduced HSPC, neutrophil and erythrocyte numbers, whereas PMR-deficient Ninj1 mutants demonstrated that this function is independent of PMR. Ninj1 deficiency also impaired immune cell recruitment and increased susceptibility to bacterial infection. Mechanistically, Ninj1 and Ninj2 cooperatively promoted early HSPC amplification through canonical WNT signaling. Pharmacological and genetic activation of WNT signaling rescued hematopoietic defects in Ninjurin-deficient larvae, whereas inhibition of WNT abolished the effects of Ninj1 gain of function. Human CD34⁺ HSPCs showed reduced expansion and impaired WNT signaling following NINJ1/2 deficiency, demonstrating conservation of this pathway. These findings identify Ninjurins as regulators of HSPC expansion with potential applications in regenerative medicine.
    DOI:  https://doi.org/10.1038/s41467-026-75917-6
  8. Blood Cancer Discov. 2026 Jul 23.
    LY3410738, a Covalent Inhibitor of Mutant IDH1/2, is Effective in Acute Myeloid Leukemia Preclinical Models.
    Nathan A Brooks, Anna Skwarska, Vivian Salama, Mark H Bender, Lisa Kays, Robin I DeWalt, Bryan Perria, Deepti Thete, Jason R Manro, Rachel Cavitt, Rebecca Leon, Sandra Gomez, Raquel Torres, John M Strelow, Paul Milligan, Kate Newell, Kenneth D Roth, Jean-Emmanuel Sarry, Steven M Chan, Danalyn Manglicmot Lagutan, Richard Romero, Stephen Antonysamy, Robert L Johnson, Xueqian Gong, Renato A Bauer, Timothy P Burkholder, Patric J Hahn, Zoran Rankovic, Serge L Boulet, Courtney D DiNardo, Marina Konopleva, Raymond Gilmour.
      Acute myeloid leukemia (AML) is an aggressive blood disorder characterized by rapid growth of poorly differentiated myeloid cells. Gain-of-function mutations in isocitrate dehydrogenases (IDHs) are detected in ~20% of AML and ~80% of secondary gliomas. Mutant IDH1/2 isoenzymes acquire neomorphic activity to produce 2-hydroxyglutarate (2-HG) oncometabolite, resulting in hypermethylated DNA and histones, altered gene expression, and blocked differentiation of hematopoietic progenitors. Here, we presented preclinical development of LY3410738, an oral, dual IDH1/2 inhibitor with potential to penetrate the blood-brain barrier. LY3410738 covalently inhibited mutated-IDH1/2, reduced 2-HG levels at low nanomolar concentrations in human AML and glioma models, and demonstrated efficacy in AML patient-derived xenografts (PDXs) in vivo, inducing myeloid differentiation. LY3410738 retained in vitro activity in cancer models with acquired secondary IDH1/2 mutations conferring resistance to ivosidenib and enasidenib. LY3410738 synergized and was well tolerated with standard-of-care regimens such as cytarabine, azacitidine, venetoclax, or midostaurin in IDH1/2-mutated AML PDXs.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0379
  9. Blood Adv. 2026 Jul 22. pii: bloodadvances.2026021344. [Epub ahead of print]
    Synthetic lethality in TP53-mutated AML.
    Jeremy T Baeten, Daniel C Link.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2026021344
  10. Blood Cancer Discov. 2026 Jul 21.
    The Nicotinamide Salvage Pathway is a Metabolic Vulnerability of High-Risk MDS Stem Cells.
    Sweta B Patel, Daniel R Moskop, Steven Moreira, Stephanie Gipson, Colin C Anderson, Alexandra Crook, Maxwell McCabe, Daniel Stephenson, Hannah E Terry, Andrew Kent, Tracy N Young, Anna E Krug, Connon I Thomas, Caitlin Price, Monica Ransom, Regan Miller, Ana Vujovic, Mohammad Minhajuddin, Mark J Althoff, The Cuijbp Consortium, Anthony J Saviola, Brett M Stevens, Robert S Welner, Ekaterina L Andrianova, Andrei V Gudkov, Anza Darehshouri, Julie A Reisz, Travis Nemkov, Angelo D'Alessandro, Austin E Gillen, Daniel A Pollyea, Craig T Jordan, Eric M Pietras.
      High-risk myelodysplastic syndrome (HR-MDS) is a malignant clonal disorder originating in hematopoietic stem and progenitor cells (HSPCs). The current standard of care for HR-MDS patients has a poor response, thus necessitating exploration of vulnerabilities of HR-MDS HSPCs for better clinical outcomes. We demonstrate that compared to healthy HSPCs, HR-MDS HSPCs have significant upregulation of metabolic proteins leading to increased oxygen consumption, suggesting an increased metabolic rate. Corroboratively, compared to healthy HSPCs, HR-MDS HSPCs have increased abundance of NADH dehydrogenases, which are crucial for energy production. Therefore, we investigated whether HR-MDS HSPCs are functionally reliant on NAMPT, the rate-limiting enzyme in the nicotinamide salvage pathway of NAD anabolism. NAMPT inhibition reduced the oxygen-consuming capacity of HR-MDS-HSPCs compared to healthy. Importantly, NAMPT inhibition significantly impaired function, increased cell death, and reduced disease burden specifically of HR-MDS HSPCs. Collectively, our data suggests that NAMPT is a promising therapeutic target to eradicate HR-MDS HSPCs.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0498
  11. Stem Cell Rev Rep. 2026 Jul 25.
    Measurable Residual Disease and the Unresolved Biology of Leukemic Stem Cells.
    Deepa Bhartiya, Nitu Jha, Shruti Dutta, Anish Tripathi, Ashish Tripathi.
      Measurable residual disease (MRD) testing has transformed the management of hematologic cancers by enabling detection of residual malignant cells after therapy. Current approaches rely on qPCR and next-generation sequencing to monitor leukemia-associated somatic mutations, while multiparameter flow cytometry identifies aberrant leukemic immunophenotypes. Although these methods provide valuable prognostic and therapeutic information, MRD negativity remains an imperfect surrogate for cure. Most MRD platforms evaluate CD45+, rapidly dividing leukemic populations and fail to detect quiescent cells that may survive cytotoxic therapies which efficiently target proliferating hematopoietic cells. Relapse frequently occurs despite deep molecular remission, suggesting persistence of rare leukemic stem cells (LSCs) that are intrinsically resistant to chemotherapy and targeted therapies. The paradox of relapse despite molecular remission could be explained by the presence of very small embryonic-like stem cells (VSELs) which are pluripotent, quiescent stem cells sitting at the top of cellular hierarchy in multiple adult tissues including bone marrow. A pluripotent VSEL divides through asymmetrical cell division to give rise to two cells of different sizes and fates, smaller cell is to self-renew while the bigger is lineage-restricted and tissue-committed progenitor which undergoes extensive epigenetic changes, divides rapidly and undergoes clonal expansion before further differentiation. Dysfunctions of VSELs initiate both solid and hematologic cancers. Based on this view, somatic mutations monitored during MRD assessment possibly represent downstream consequences of clonal expansion rather than the initiating drivers of disease persistence. Thus, exclusive monitoring of somatic mutations and CD45 + leukemic populations possibly overlook rare, small-sized, CD45- VSELs that contribute to therapeutic resistance and relapse.
    Keywords:  AML; CML; HSCs; LSCs; Leukemia; MRD; Relapse; VSELs
    DOI:  https://doi.org/10.1007/s12015-026-11195-5
  12. J Proteome Res. 2026 Jul 22.
    SoftHybrid: A Hybrid Imputation Algorithm Optimized for Single-Cell Proteomics Data.
    Yixin Shi, Simon Davis, Philip D Charles, Stephen Taylor, Eszter Dombi, Georgina Berridge, Daniel Ebner, Roman Fischer.
      Missing values (MVs) remain a significant barrier to reliable proteomics analysis, particularly in single-cell proteomics, where small amounts of starting material and limits in detection drive missing-not-at-random (MNAR) sparsity. Existing imputation methods typically target either missing-at-random (MAR) or MNAR mechanisms, resulting in a trade-off between replicate consistency and preservation of biological variation, and are largely designed for bulk data. Here, we introduce SoftHybrid, a data-driven imputation framework that jointly models missingness and protein abundance to estimate the probability of MNAR, enabling continuous weighting between MAR- and MNAR-oriented strategies. SoftHybrid requires no external priors (cell type labels, group annotations, predefined missingness assumptions, etc.), enabling fully unsupervised applications. Across ground truth benchmarks and real single-cell proteomics data sets, SoftHybrid outperforms existing methods at low input and matches or exceeds their performance at the minibulk level. By preserving the proteomic structure and abundance accuracy, it enhances the recovery of biologically meaningful signals. SoftHybrid is implemented as an R package and is freely available at GitHub.
    Keywords:  benchmarking; imputation; label-free proteomics; missing values; single-cell proteomics
    DOI:  https://doi.org/10.1021/acs.jproteome.5c01221
  13. Nature. 2026 Jul 22.
    Prior therapy defines mutation profiles in childhood cancer at relapse.
    Mehdi Layeghifard, Marcos Díaz-Gay, Erik N Bergstrom, Mathepan J Mahendralingam, Nicholas Light, Sasha Blay, Joshua O Nash, Nathaniel D Anderson, Jessica N Au, Scott Davidson, Pedro L Ballester, Timmy Wen, Syed Kashif Daud, Lisa-Monique Edward, S M Ashiqul Islam, Azhar Khandekar, Burçak Otlu, Ledia Brunga, Rawan Hammad, Shimaa Nassif, Nirav H Thacker, Tara Feltham, Noemi A Fuentes-Bolanos, Marie Wong-Erasmus, Max F Levine, Katherine E Miller, Neerav N Shukla, Michael D Kinnaman, Dominik Glodzik, Carol Portwine, Sabrina Millson, Alexandra P Zorzi, Mariam Mikhail, Conrad V Fernandez, Laura Wheaton, Gunes Gundem, Andrew L Kung, Uri Tabori, Chelsea Mayoh, Elli Papaemmanuil, Mark J Cowley, David Malkin, Anita Villani, Ludmil B Alexandrov, Adam Shlien.
      Children with cancer develop many short- and long-term side-effects of treatment1, but the amount of DNA damage associated with chemotherapy exposure is unclear2. Here we used mutational signatures to measure this damage using whole-genome-sequenced tumours from a multi-institutional cohort for which therapy dose and total exposure were uniformly collected3-5. Chemotherapy and radiotherapy were the only exogenous mutagens in relapsed childhood tumours and were often the dominant source of DNA alteration. Compared with treatment-naive tumours, post-therapy cancers carried nearly three times the number of private signatures, and two times the total burden of somatic mutations. Further, the mutagenic effects of different chemotherapies varied. Platinum-based therapies, for which we more than doubled the number of associated signatures, led to the highest number of variants in most patients. Using therapy exposure dates to track when therapy-associated mutations become detectable, we defined a minimum threshold for platinum-associated mutations to emerge. Remarkably, more than one-third of tumours treated with platinum drugs displayed detectable platinum signatures within one year. This work provides genomic evidence for the critical mutagenic effects of chemotherapy in childhood cancer, as a specific driver of tumour evolution. These data highlight opportunities for treatment de-escalation and the future possibility of tracking resistant clones before expansion.
    DOI:  https://doi.org/10.1038/s41586-026-10803-1
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