bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–10–26
eight papers selected by
William Grey, University of York
  1. Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors.
  2. P-selectin overexpression impairs hematopoietic stem cell homeostasis via inflammatory receptor-mediated proliferation and differentiation.
  3. The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.
  4. The combination of venetoclax with dimethyl fumarate synergistically induces apoptosis in AML cells by disrupting mitochondrial integrity through ROS accumulation.
  5. A unified multimodal single-cell framework reveals a discrete state model of hematopoiesis in mice.
  6. Cell cycle regulator MYBL2 is a distinct vulnerability in acute myeloid leukemia.
  7. Coupling of stemness maintenance with cell cycle control in stem cells.
  8. Global comparative structural analysis of responses to protein phosphorylation.
  1. Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2509412122
    Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors.
    Kutay Karatepe, Bruna Mafra de Faria, Jian Zhang, Xinyue Chen, Hugo Pinto, Dmitry Fyodorov, Esen Sefik, Michael A Willcockson, Richard A Flavell, Arthur I Skoultchi, Shangqin Guo.
      Myeloid-biased differentiation of multipotent hematopoietic stem and progenitor cells (HSPCs) occurs with aging or exhaustion. The molecular mechanism(s) responsible for this fate bias remain unclear. Here, we report that linker histone regulates HSPC fate choice at the lymphoid versus myeloid bifurcation. Linker histones package nucleosomes and compact chromatin. HSPCs expressing a doxycycline (dox)-inducible H1.0 transgene favor the lymphoid fate, display strengthened nucleosome organization, and reduced chromatin accessibility at subsets of genomic regions. The genomic regions showing reduced chromatin accessibility host many known marker genes of myeloid-biased HSCs. The transcription factor Hlf is located in one of the most differentially closed regions, whose chromatin accessibility and gene expression are reduced in H1.0high HSPCs. Failure to reduce Hlf expression in multipotential HSPCs abrogates the H1.0-endowed lymphoid potential. Furthermore, HSPCs display aspartyl protease-dependent H1.0 decreases, especially in response to interferon alpha (IFNα). Aspartyl protease inhibitors preserve endogenous H1.0 levels and promote the lymphoid fate of wild type HSPCs. Thus, our work elucidates a molecular scenario of how myeloid bias arises and uncovers a point of intervention for correcting myeloid skewed hematopoiesis.
    Keywords:  inflammation; linker histone; myeloid bias
    DOI:  https://doi.org/10.1073/pnas.2509412122
  2. Cell Death Dis. 2025 Oct 21. 16(1): 745
    P-selectin overexpression impairs hematopoietic stem cell homeostasis via inflammatory receptor-mediated proliferation and differentiation.
    Wei He, Huandi Qiu, Yunyu Feng, Qiang Qiu, Li Zheng, Cong Pan, Xue Cui, Yuanyuan Sun, Bochuan Wang, Yiguo Hu.
      Hematopoietic stem cells (HSC) sustain lifelong blood and immune system homeostasis. This study identifies P-selectin as a pivotal regulator of HSC function under aging and inflammatory stress. We observed pronounced Selp upregulation in aged HSC and inflammatory contexts, which drives excessive proliferation and differentiation while depleting their long-term self-renewal capacity. Using tissue-specific Selp overexpression models, we demonstrate that chronic Selp elevation disrupts HSC polarity, promotes oxidative stress accumulation, and induces genomic instability. Over time, sustained Selp expression leading to LT-HSC exhaustion and impaired hematopoietic reconstitution. Single-cell transcriptomics revealed that Selp enforces a pro-inflammatory transcriptional program in HSC, hyperactivating IFN-γ and PI3K-AKT-MOTR signaling pathways. Mechanistically, P-selectin directly interacted with IFNγR1 on the HSC surface, which driving activation of JAK1-STAT1 and PI3K-AKT-mTOR signaling axes. Notably, Selp overexpression suppresses the pathogenic capacity of leukemia stem cells (LSC), highlighting potential therapeutic implications. Our findings established P-selectin as a molecular nexus linking chronic inflammation and aging to hematopoietic decline, with dual therapeutic implications: targeting P-selectin may mitigate age-related hematopoietic dysfunction while offering a strategy to selectively impair LSC activity in malignancies.
    DOI:  https://doi.org/10.1038/s41419-025-08050-9
  3. Blood. 2025 Oct 20. pii: blood.2024026749. [Epub ahead of print]
    The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.
    Kentson Lam, Yoon Joon Kim, Evelyn Li-Ting Tan, Carlo Miguel Ong, Andrea Zoey Liu, Fanny Jiahua Zhou, Mary Jean Sunshine, Bernadette Chua, Silvia Vicenzi, Katelyn Zhining Chen, Helena Yu, Pierce Ford, Jie-Hua Zhou, Yuning Hong, Eric J Bennett, Leslie A Crews, Edward D Ball, Robert Signer.
      Oncogenic growth places great strain and dependence on protein homeostasis (proteostasis). This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for treatment of other cancers at tolerable doses, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and increased autophagic flux to preserve proteostasis. Genetic inactivation of HSF1 sensitized AML cells to proteasome inhibition, marked by accumulation of unfolded protein, activation of the PERK-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival and significant slowing of disease progression and extension of survival in vivo. Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed human AML cells, and significantly reduced AML burden and extended survival in vivo. Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and colony formation, and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, compared to normal hematopoietic stem/progenitor cells. Combined autophagy/proteasome inhibition activated a terminal integrated stress response, which was surprisingly driven by Protein kinase R (PKR). These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.
    DOI:  https://doi.org/10.1182/blood.2024026749
  4. Cell Death Dis. 2025 Oct 21. 16(1): 750
    The combination of venetoclax with dimethyl fumarate synergistically induces apoptosis in AML cells by disrupting mitochondrial integrity through ROS accumulation.
    Shin-Ichiro Kawaguchi, Kazuya Sato, Junko Izawa, Norihito Takayama, Hiroko Hayakawa, Kaoru Tominaga, Hitoshi Endo, Tom Kouki, Nobuhiko Ohno, Yoshinobu Kanda.
      Leukemia cells are consistently subjected to higher oxidative stress than normal cells. To mitigate reactive oxygen species (ROS) overload, which can trigger various forms of cell death, leukemia cells employ a robust antioxidant defense system and maintain redox homeostasis. Recent evidence suggests that dimethyl fumarate (DMF), a derivative of fumarate, inactivates the antioxidant glutathione (GSH), thereby inducing oxidative stress and metabolic dysfunction, eventually leading to cell death in cancer cells. In this study, we observed that DMF decreases the GSH/oxidated GSH ratio and increases intracellular ROS levels, the extent of which is closely correlated with cell death, in acute myeloid leukemia (AML) cell lines. DMF reduced the mitochondrial membrane potential and oxidative phosphorylation (OXPHOS), effects that were almost fully restored by the antioxidant N-acetylcysteine, suggesting that these responses are ROS-dependent. Electron microscopy and inhibition assays revealed that apoptosis, rather than necroptosis or ferroptosis, is the predominant form of cell death of AML cells following DMF treatment. Notably, the combination of DMF and the BCL-2 selective BH3-mimetic venetoclax induced marked cell death in AML cells, including venetoclax-refractory　BCL-2 low expressing U937 and acquired venetoclax-resistant MOLM-14 cells. This combination also caused greater mitochondrial depolarization and a more profound reduction in OXPHOS activity than either agent alone. Collectively, our findings indicate that DMF exerts potent anti-leukemia activity in AML cells and sensitizes cells to venetoclax treatment by synergistically disrupting mitochondrial integrity through ROS accumulation.
    DOI:  https://doi.org/10.1038/s41419-025-08040-x
  5. Nat Immunol. 2025 Oct 22.
    A unified multimodal single-cell framework reveals a discrete state model of hematopoiesis in mice.
    Kyle Ferchen, Xuan Zhang, Kairavee Thakkar, Guangyuan Li, David Bernardicius, Sidharth Sen, Priyanka Rawat, Andre Olsson, Sierra N Bennett, Crystal Potter, Fred D Finkelman, Josh Croteau, Samantha Morris, Harinder Singh, Nathan Salomonis, H Leighton Grimes.
      Large-scale, unbiased single-cell genomics studies of complex developmental compartments, such as hematopoiesis, have inferred novel cell states and trajectories; however, further characterization has been hampered by difficulty isolating cells corresponding to discrete genomic states. To address this, we present a framework that integrates multimodal single-cell analyses (RNA, surface protein and chromatin) with high-dimensional flow cytometry and enables semiautomated enrichment and functional characterization of diverse cell states. Our approach combines transcription factor expression with chromatin activity to uncover hierarchical gene regulatory networks driving these states. We delineated and isolated rare bone marrow Lin-Sca-CD117+CD27+ multilineage cell states ('MultiLin'), validated predicted lineage trajectories and mapped differentiation potentials. Additionally, we used transcription factor activity on chromatin to trace and isolate multilineage progenitors undergoing multipotent to oligopotent lineage restriction. In the proposed model of steady-state hematopoiesis, discrete states governed developmental trajectories. This framework provides a scalable solution for isolating and characterizing novel cell states across different biological systems.
    DOI:  https://doi.org/10.1038/s41590-025-02307-3
  6. Cell Death Discov. 2025 Oct 20. 11(1): 470
    Cell cycle regulator MYBL2 is a distinct vulnerability in acute myeloid leukemia.
    Sandra Küchler, Silke Brilloff, Silvia Schäfer, Elahe Rahimian, Vida Kufrin, Shraddha S Peri, Julian Musa, Thomas G P Grünewald, Denis M Schewe, Claudia R Ball, Martin Bornhäuser, Hanno Glimm, Marius Bill, Alexander A Wurm.
      Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the accumulation of myeloid blasts in the bone marrow. Despite the availability of potential curative treatments, patients frequently experience unfavorable outcomes. One crucial aspect contributing to relapse is the plasticity of leukemic clones, which enables them to switch between active proliferation and dormancy. The adaptability of AML underscores the need for novel therapies targeting AML-specific proteins. To address this, genome-wide CRISPR screens can be utilized to identify cancer entity-specific vulnerabilities. Leveraging publicly available functional genomics datasets and comparing AML with non-AML cancer cell lines, we identified a significant dependency on the cell cycle-regulating gene MYBL2 in AML. We describe MYBL2 as a key driver of AML cell growth and proliferation, highlighting its established role as a cell cycle regulator. Also, our findings uncover its previously unrecognized function as an inhibitor of cellular senescence. A knockdown of MYBL2 induces cell cycle arrest in the G2/M phase with subsequent induction of apoptosis in vitro, and reduces leukemic burden in a patient-derived xenograft (PDX) model in vivo. Interestingly, some AML cells evade apoptosis and enter a senescent-like phenotype upon MYBL2-knockdown, which is reversible upon re-expression of MYBL2. Finally, analyses of clinical data from two publicly available patient cohorts demonstrate a lower probability of survival in patients with higher MYBL2 expression, further hinting at the potential relevance of MYBL2 in AML. In conclusion, our findings demonstrate the essential role of MYBL2 in AML, governing the balance between cell proliferation, cell survival and senescence, ultimately influencing the fate of AML cells.
    DOI:  https://doi.org/10.1038/s41420-025-02810-4
  7. Front Cell Dev Biol. 2025 ;13 1693489
    Coupling of stemness maintenance with cell cycle control in stem cells.
    Xia Huang, Yujie Wang, Qiushuang Li, Xinyi Li, Congcong Wang.
      Stem cells are undifferentiated cells characterized by their self-renewal capacity and pluripotency. The multipotent differentiation potential of stem cells grants them significant promise in clinical therapies for tissue injury and organ regeneration. Therefore, the molecular mechanisms underlying the maintenance of stem cell self-renewal and pluripotency have been a major focus of research in the field. In recent years, increasing evidence suggests that cell cycle is not only a central driver of cell division but also participate in controlling stem cell self-renewal and differentiation fate through various pathways. Stem cells, especially embryonic stem cells (ESCs), exhibit unique cell cycle features, with a notably short overall cycle duration, a significantly shortened G1 phase, and a prolonged S phase. This rapid cell cycle not only results in increased cell numbers but is also closely associated with the maintenance of their self-renewal capacity. Pluripotency states (such as naïve, formative, and primed) are tightly linked to specific cell cycle patterns, and this association exhibits species specificity. Elucidating the molecular mechanisms coupling the cell cycle with stemness maintenance is of great significance for the clinical application of stem cells. This review focuses on the cell cycle regulatory network centered around Cyclins and their inhibitors in stem cells, as well as the molecular mechanisms by which core pluripotency factors and cell cycle proteins influence stem cell fate determination. We discuss signaling pathways such as Jak1/Stat3, PI3K/Akt, and Hippo/YAP, and the role of epigenetic regulation, particularly histone modifications, in modulating the expression of differentiation-related and cell cycle-associated genes. Additionally, a brief overview is provided of the unique glycolytic metabolic mode and one-carbon metabolism in stem cells, along with their relationship with epigenetic modifications and rapid proliferative characteristics. Moreover, we analyze the regulatory functions of cell cycle regulators such as Cyclins and checkpoint protein p53 in somatic cell reprogramming and the fate determination of adult stem cells including neural and hematopoietic stem cells (HSCs). Practical strategies based on cell cycle regulation are discussed, along with prospects and challenges for their applications in regenerative medicine.
    Keywords:  Cyclin; Jak1/Stat3 pathway; Metabolism; adult stem cells; cyclin-dependent kinases; epigenetic modification; pluripotent stem cells; somatic cell reprogramming
    DOI:  https://doi.org/10.3389/fcell.2025.1693489
  8. Nat Commun. 2025 Oct 24. 16(1): 9407
    Global comparative structural analysis of responses to protein phosphorylation.
    Miguel Correa Marrero, Victor Hugo Mello, Pablo Sartori, Pedro Beltrao.
      Post-translational modifications (PTMs), particularly protein phosphorylation, are key regulators of cellular processes, impacting numerous aspects of protein activity. Despite widespread phosphorylation of eukaryotic proteomes, the function of most phosphosites remains unknown. Elucidating the structural mechanisms underlying phosphorylation is crucial for understanding its regulatory roles. Here, we present a comparative structural analysis of phosphorylated and non-phosphorylated proteins taken from the Protein Data Bank (PDB). Our study systematically evaluates how phosphorylation affects backbone conformation, protein dynamics, and mechanical strain. We found that phosphorylation commonly induces small, stabilizing conformational changes through conformational selection and frequently modulates local residue fluctuations, influencing overall protein motion. Notably, a small but significant subset of phosphosites shows mechanical coupling with functional sites, aligning with the domino model of allosteric signal transduction. This work provides a foundation for studying phosphorylation and other PTMs in their structural context, which will guide the rational design of synthetic phosphosites and enable the engineering of PTM-driven regulatory circuits in synthetic biology.
    DOI:  https://doi.org/10.1038/s41467-025-64116-4
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