bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–07–13
sixteen papers selected by
William Grey, University of York



  1. Front Hematol. 2025 ;pii: 1525132. [Epub ahead of print]4
      Hematopoietic stem cells (HSCs) undergo a functional decline during aging. The intrinsic characteristics of aged HSCs have been well-described and include a strong myeloid bias, an increase in total number, and a decrease in functionality during transplantation. The impact of the aged bone marrow microenvironment, or niche, on HSCs is less well understood. It is critical to understand the changing condition of the niche during aging, and its ability to support HSCs, as this could reveal the very signals and mechanisms needed to improve HSC fitness. Furthermore, heterochronic transplantation provides an approach to test the influence of an aged recipient niche on young donor HSCs, and conversely, of a young recipient niche on aged donor HSCs. Importantly, these experiments demonstrated that donor HSC engraftment is reduced if the recipient niche is aged, and conversely, the young niche can rejuvenate aged donor HSCs. Here we will focus on the interactions between aged HSCs and their microenvironment. We will highlight current controversies, research gaps, and future directions.
    Keywords:  aging; inflammation; microenvironment; niche; stem cells
    DOI:  https://doi.org/10.3389/frhem.2025.1525132
  2. Nat Commun. 2025 Jul 07. 16(1): 6247
      The long-term maintenance of hematopoietic stem cells (HSCs) relies on the regulation of endoplasmic reticulum (ER) stress at a low level, but the underlying mechanism remains poorly understood. Here, we demonstrate that suppression of ER stress improves the functions of HSCs and protects HSCs against ionizing radiation (IR)-induced injury. We identify epithelial membrane protein 1 (EMP1) as a key regulator that mitigates ER stress in HSCs. Emp1 deficiency leads to the accumulation of protein aggregates and elevated ER stress, ultimately resulting in impaired HSC maintenance and self-renewal. Mechanistically, EMP1 is located within the ER and interacts with ceramide synthase 2 (CERS2) to limit the production of a class of sphingolipids, dihydroceramides (dhCers). DhCers accumulate in Emp1-deficient HSCs and induce protein aggregation. Furthermore, Emp1 deficiency renders HSCs more susceptible to IR, while overexpression of Emp1 or inhibition of CERS2 protects HSCs against IR-induced injury. These findings highlight the critical role played by the EMP1-CERS2-dhCers axis in constraining ER stress and preserving HSC potential.
    DOI:  https://doi.org/10.1038/s41467-025-61552-0
  3. Blood. 2025 Jul 10. pii: blood.2024027335. [Epub ahead of print]
      Hematopoietic stem cells (HSCs) are responsible for sustaining hematopoietic system throughout life, and their functional decline contributes to hematological disorders and organismal aging. Understanding the molecular mechanisms that govern HSC function is critical for developing interventions for treating and preventing aging-related diseases. Here, we show that DCAF8, a substrate recognition component of Cullin-RING E3 ubiquitin ligases, is highly expressed in HSCs and undergoes a progressive decline with age. Loss of DCAF8 in mice results in impaired function in HSCs, characterized by increased number yet decreased self-renewal capacity, which associates with cellular senescence and elevated DNA damage. Mechanistically, DCAF8 mediates the degradation of DOCK11, a guanine nucleotide exchange factor for CDC42. In the absence of DCAF8, DOCK11 accumulates, leading to elevated CDC42 activity and consequential loss of polarity of HSCs. Knocking out Dock11 mitigates the senescence, DNA damage, and self-renewal defects of Dcaf8-/- HSCs. This study highlights a critical role of DCAF8 in preventing HSC senescence via the DOCK11-CDC42 axis and suggests potential therapeutic targets for preventing functional decline in HSCs.
    DOI:  https://doi.org/10.1182/blood.2024027335
  4. Cell Death Dis. 2025 Jul 07. 16(1): 498
      Recent studies have shown that the interaction between acute myeloid leukemia (AML) and bone marrow stromal cells (BMSCs) plays a vital role in the progression of leukemia and the development of drug resistance, while the underlying mechanisms remain inconclusive. In this study, we found that AML patient-derived BMSCs exhibit a hyperinflammatory phenotype. Histone deacetylase 3 (HDAC3) in BMSCs enhances mitochondrial reactive oxygen species (ROS) production by RAB5A-mediated blockade of mitophagy. Furthermore, we confirmed that HDAC3 regulates RAB5A expression through transcription factor YY1. Excessive ROS accelerates the senescence of BMSCs and promotes the secretion of senescence-associated secretory phenotype, creating a hyperinflammatory bone marrow niche, activating the NF-κB pathway in AML cells to promote their survival and drug resistance. The inhibition of HDAC3 in BMSCs reduces the mitochondrial ROS production and thus delays BMSCs senescence. Consequently, HDAC3 inhibition in BMSCs decreases AML proliferation and synergizes with the anti-AML efficacy of venetoclax. Therefore, our study suggests that targeting HDAC3 in BMSCs may be used for the combination therapy of AML by remodeling the AML-supportive niche.
    DOI:  https://doi.org/10.1038/s41419-025-07777-9
  5. Blood. 2025 Jul 11. pii: blood.2025028896. [Epub ahead of print]
      The bone marrow microenvironment is intimately linked to the biology that underpins the development and progression of multiple myeloma. However, the complex cellular and molecular features that form bone marrow niches are poorly defined. Here, we used subcellular spatial transcriptomics to profile the expression of 5,001 genes in human bone marrow in the context of multiple myeloma. Using this approach, we explored the plasma cell and stroma ecosystem in bone marrow trephines from 21 individuals, including 7 with pre-malignant disease and 10 with newly diagnosed multiple myeloma. Using spatial transcriptomics in conjunction with an optimised trephine biobanking methodology, we could resolve major components of the human bone marrow microenvironment and reliably characterise distinct plasma cell populations in samples from healthy, pre-malignant disease and active myeloma. When plasma cells were visualised in the context of location, we detected spatially restricted subpopulations of plasma cells in five of ten newly diagnosed myeloma trephines. Surprisingly, the composition of haematopoietic and stromal microenvironments varied significantly between newly diagnosed myeloma trephines. Furthermore, these differences in microenvironments were also observed within trephines that had spatially restricted plasma cell subpopulations. Thus, these data are not consistent with the hypothesis that a universal bone marrow microenvironment supports the expansion of malignant plasma cells in myeloma. Instead, we propose that myeloma subpopulations form distinct microenvironments and can vary between both patients and spatial location.
    DOI:  https://doi.org/10.1182/blood.2025028896
  6. Haematologica. 2025 Jul 10.
      Metabolic dependencies are emerging as promising therapy targets in cancer, including acute myeloid leukemia (AML). Several metabolic vulnerabilities have been identified in AML cells, including a requirement for balanced sphingolipid metabolism to maintain survival and proliferation. Here we describe a novel function of the RAS superfamily small GTPase ARF6 in maintaining sphingolipid homeostasis in AML. Genetic depletion of ARF6 inhibited the proliferation of AML cell lines and reduced colony formation of primary AML CD34+ cells. Mechanistically, ARF6 promotes conversion of ceramide to sphingomyelin by enhancing sphingomyelin synthase (SGMS1/2) expression, thereby preventing accumulation of cytotoxic ceramide levels. Accordingly, higher expression of ARF6 and its effectors SGMS1/2 in AML patient cells correlates with shorter survival in two independent AML cohorts, with ARF6 exhibiting an adverse prognostic effect independent of European Leukemia Net genetic risk. Small molecule inhibitors of ARF6 suppressed colony formation by primary AML CD34+ cells, but not cord blood CD34+ cells and showed activity in xenograft models. The dependency of AML cells on ARF6 to regulate sphingolipid homeostasis may present a therapeutic opportunity.
    DOI:  https://doi.org/10.3324/haematol.2024.286228
  7. Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2421159122
      To uncover substrates mediating the oncogenic activity of WWP1 in acute myeloid leukemia (AML), we performed a proteomic analysis that identified the histone demethylase KDM5B/JARID1B as a candidate target. Of note, JARID1B is indispensable for efficient recruitment of several DNA damage repair factors and for damage resolution, thus negatively influencing the sensitivity of cancer cells to chemo- and radiation therapies. Validation of JARID1B as a substrate of WWP1 revealed a positive regulation of JARID1B half-life by WWP1 through the establishment of K63-linked polyubiquitin chains. As a result, downregulation of JARID1B rising from WWP1 inactivation was associated with higher H3K4me3 enrichment at JARID1B target genes in WWP1-depleted relatively to control AML cells. Integration of RNA-seq and H3K4me3 ChIP-seq data uncovered a highly significant overlap between upregulated gene expression and enriched H3K4me3 peaks after shWWP1 inactivation. We confirmed transcriptional activation of JARID1B targets in WWP1-depleted cells, supporting a role for WWP1 in regulating JARID1B activity. Coherently, upon WWP1 inactivation, we observed a defective recruitment of repair proteins after DNA damage, with subsequent reduced DNA damage repair efficiency and enhanced sensitization of AML cells to the cytotoxic activity of chemotherapeutic drugs. All together, these data identify JARID1B as a bona fide target of WWP1 and imply that WWP1-mediated regulation of JARID1B impacts its ability to modify chromatin and to recruit DNA damage repair factors, thus ultimately affecting chemosensitivity of AML cells.
    Keywords:  DNA repair; acute myeloid leukemia; protein degradation; protein ubiquitination
    DOI:  https://doi.org/10.1073/pnas.2421159122
  8. Blood. 2025 Jul 10. pii: blood.2024027363. [Epub ahead of print]
      The megakaryocytic (MK) specific immunoreceptor G6b-B plays an essential role in MK development. Since germline loss-of-function mutations of G6b-B in man and its deletion in mouse models leads to thrombocytopenia and a myelofibrosis-like clinical phenotype (MF-MPIG6B), we explored the role of G6b-B in patients with MF due to a myeloproliferative neoplasm (MPN) with thrombocytopenia (MPN-MF-T). We demonstrated that MKs generated from mononuclear cells (MNCs) from a patient with MF-MPIG6B as well as patients with MPN-MF-T, failed to express GATA1 and G6B and possessed a protein pattern expression characteristic of MKs primed for inflammation rather than platelet production. MNCs from MPN-MF-T patients also generated fewer MK biased hematopoietic stem cells (HSCs) and greater numbers of small cytoplasmic immature MKs (CD41+CD42-G6B-) as compared to MNCs from non-thrombocytopenic MPN-MF patients (MPN-MF-NT). Plasma levels of TGFβ1 and YKL-40 which were shown to arrest normal MK maturation were elevated in the MF-MPIG6B patient. Although TGFβ1 plasma levels were similarly elevated in MPN-MF-T and MPN-MF-NT patients, TNFα and YKL-40 levels were upregulated to a greater extent in MPN-MF-T than MPN-MF-NT patients. Moreover, we identified a reciprocal positive regulatory loop involving TGFβ1 and YKL-40 in MF MKs. These findings indicate that impaired MK maturation, and reduced G6B expression lead to the predominance of pro-inflammatory MKs which produce factors that further arrest MK development in MF-MPIG6B and MPN-MF-T patients. NCT03895112.
    DOI:  https://doi.org/10.1182/blood.2024027363
  9. Leukemia. 2025 Jul 09.
      Multiple myeloma (MM) cells secrete high levels of immunoglobulin and are therefore addicted to mechanisms that maintain proteome homeostasis (proteostasis). While proteasome inhibitors that target the degradative aspect of proteostasis have proven effective, only limited attempts have been made to target protein secretion. Here we show that the receptor tyrosine kinase LTK is a regulatory node in the proteostasis network that responds to secretory load and helps cells maintain a high secretory output. LTK is a highly similar paralog to ALK and by repurposing existing ALK inhibitors, we demonstrate that targeting LTK causes immunoglobulin retention, ER stress and subsequent apoptosis of primary MM cells, even in patients refractory to proteasome inhibitors. Thus, LTK is a novel therapeutic target in the biosynthetic pathway of proteostasis, with significant potential for MM treatment.
    DOI:  https://doi.org/10.1038/s41375-025-02682-8
  10. Leukemia. 2025 Jul 09.
      Acute myeloid leukemia with mutations in TP53 (TP53mut AML) is fatal with a median survival of 6 months. RNA sequencing on purified AML patient samples showed that TP53mut AML had higher expression of mevalonate pathway genes. Using novel, isogenic TP53mut AML cell lines and primary samples, we determined that TP53mut AML resistance to AML chemotherapy cytarabine (AraC) correlated with increased mevalonate pathway activity, a lower induction of reactive oxygen species (ROS), and a mitochondrial response with increased mitochondrial mass and oxidative phosphorylation. Pretreatment with the statin class of mevalonate pathway inhibitors reversed these effects and chemosensitized TP53mut AML. The geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway was required for TP53mut AML chemoresistance. In addition to its role in mitochondria biogenesis, we identified a novel function of GGPP in regulating glutathione for management of AraC-induced ROS. However, statins alone were inadequate to fully reverse chemoresistance in vivo and in a retrospective study of 364 TP53mut AML patients who received chemotherapy concurrently with a statin. Finally, we identified clinical settings and strategies to successfully target the mevalonate pathway, particularly to address the unmet need of TP53mut AML.
    DOI:  https://doi.org/10.1038/s41375-025-02668-6
  11. PLoS Genet. 2025 Jul 07. 21(7): e1011773
      Mitochondria perform essential metabolic functions and respond rapidly to changes in metabolic and stress conditions. As the majority of mitochondrial proteins are nuclear-encoded, intricate post-transcriptional regulation is crucial to enable mitochondria to adapt to changing cellular demands. The eukaryotic Clustered mitochondria protein family has emerged as an important regulator of mitochondrial function during metabolic shifts. Here, we show that the Drosophila melanogaster and Saccharomyces cerevisiae Clu/Clu1 proteins form dynamic, membraneless, mRNA-containing granules adjacent to mitochondria in response to metabolic changes. Yeast Clu1 regulates the translation of a subset of nuclear-encoded mitochondrial proteins by interacting with their mRNAs while these are engaged in translation. We further show that Clu1 regulates translation by interacting with polysomes, independently of whether it is in a diffuse or granular state. Our results demonstrate remarkable functional conservation with other members of the Clustered mitochondria protein family and suggest that Clu/Clu1 granules isolate and concentrate ribosomes engaged in translating their mRNA targets, thus, integrating metabolic signals with the regulation of mitochondrial protein synthesis.
    DOI:  https://doi.org/10.1371/journal.pgen.1011773
  12. Sci Adv. 2025 Jul 11. 11(28): eadw4871
      Given the graft-versus-leukemia effect observed with allogeneic hematopoietic stem cell transplantation in refractory or relapsed acute myeloid leukemia (AML), immunotherapies have been explored in nontransplant settings. We applied a multiomic approach to examine bone marrow interactions in patients with AML treated with pembrolizumab and decitabine. Using extensively trained nuclear and membrane segmentation models, we achieved precise transcript assignment and deep learning-based image analysis. To address read-depth limitations, we integrated single-cell RNA sequencing with single-cell spatial transcriptomics from the same sample. Quantifying cell-cell distances at the edge level enabled more accurate tumor microenvironment analysis, revealing global and local immune cell enrichment near leukemia cells postpembrolizumab treatment, potentially linked to clinical response. Furthermore, ligand-receptor analysis indicated potential alterations in specific signaling pathways between leukemia and immune cells following immunotherapy treatment. These findings provide insights into immune interactions in AML and may inform therapeutic strategies.
    DOI:  https://doi.org/10.1126/sciadv.adw4871
  13. Transplant Cell Ther. 2025 Jul;pii: S2666-6367(25)01231-X. [Epub ahead of print]31(7): 405-406
      
    DOI:  https://doi.org/10.1016/j.jtct.2025.06.008
  14. Science. 2025 Jul 10. 389(6756): 157-162
      Maintenance of mitochondrial redox homeostasis is of fundamental importance to cellular health. Mitochondria harbor a host of intrinsic antioxidant defenses, but the contribution of extrinsic, nonmitochondrial antioxidant mechanisms is less well understood. We found a direct role for peroxisomes in maintaining mitochondrial redox homeostasis through contact-mediated reactive oxygen species (ROS) transfer. We found that ACBD5 and PTPIP51 form a contact between peroxisomes and mitochondria. The percentage of these contacts increased during mitochondrial oxidative stress and helped to maintain mitochondrial health through the transfer of mitochondrial ROS to the peroxisome lumen. Our findings reveal a multiorganelle layer of mitochondrial antioxidant defense-suggesting a direct mechanism by which peroxisomes contribute to mitochondrial health-and broaden the scope of known membrane contact site functions.
    DOI:  https://doi.org/10.1126/science.adn2804