bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–01–05
eleven papers selected by
William Grey, University of York
  1. Deciphering the effect of UM171 on human hematopoietic progenitor cell fate through clonal analysis.
  2. Reducing functionally defective old HSCs alleviates aging-related phenotypes in old recipient mice.
  3. Bone marrow niches orchestrate stem-cell hierarchy and immune tolerance.
  4. Constitutive activation of the Src-family kinases Fgr and Hck enhances the tumor burden of acute myeloid leukemia cells in immunocompromised mice.
  5. Aberrant activation of adenine nucleotide translocase 3 promotes progression and chemoresistance in multiple myeloma dependent on PINK1 transport.
  6. Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation.
  7. Bone Marrow Endothelial Progenitor Cells remodelling facilitates normal hematopoiesis during Acute Myeloid Leukemia Complete Remission.
  8. The human zinc-binding cysteine proteome.
  9. Peroxiredoxin 6 maintains mitochondrial homeostasis and promotes tumor progression through ROS/JNK/p38 MAPK signaling pathway in multiple myeloma.
  10. LGR4 promotes proliferation and homing via activation of the NF‑κB signaling pathway in multiple myeloma.
  11. Global organelle profiling reveals subcellular localization and remodeling at proteome scale.
  1. Nat Commun. 2025 Jan 02. 16(1): 195
    Deciphering the effect of UM171 on human hematopoietic progenitor cell fate through clonal analysis.
    Patrick Coulombe, Elisa Tomellini, Jalila Chagraoui, Nadine Mayotte, Guy Sauvageau.
      Ex vivo expansion of hematopoietic stem cells (HSC) requires the maintenance of a stemness state while cells are proliferating. This can be achieved via exposure to UM171 which leads to the degradation of chromatin modifiers and prevents the loss of key epigenetic marks. However, the chromatin landscape varies across populations within the hematopoietic system and the effect of UM171 on self-renewal and differentiation potential of different hematopoietic progenitor cells is less characterized. To address this, we use the CellTag barcoding approach to track the fate of individual stem and progenitor cells during in vitro expansion. We show that, in addition to its HSC self-renewing property, UM171 specifically modulates cell fate of a precursor common to erythroid, megakaryocytic, and mast cells in favor of self-renewal and a mast-bias differentiation trajectory. This differentiation bias can be driven by pro-inflammatory signaling pathways that are activated downstream of UM171 and results in an abundant mast cell population that can be transplanted as part of the graft to populate mice tissues in xenotransplantation studies.
    DOI:  https://doi.org/10.1038/s41467-024-55225-7
  2. Cell Res. 2025 Jan 02.
    Reducing functionally defective old HSCs alleviates aging-related phenotypes in old recipient mice.
    Yuting Wang, Wenhao Zhang, Chao Zhang, Hoang Q Tran Van, Takashi Seino, Yi Zhang.
      Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Developing effective anti-aging strategies is of great significance. In this study, we demonstrated that transplantation of young hematopoietic stem cells (HSCs) into old mice can mitigate aging phenotypes, underscoring the crucial role of HSCs in the aging process. Through comprehensive molecular and functional analyses, we identified a subset of HSCs in aged mice that exhibit "younger" molecular profiles and functions, marked by low levels of CD150 expression. Mechanistically, CD150low HSCs from old mice but not their CD150high counterparts can effectively differentiate into downstream lineage cells. Notably, transplantation of old CD150low HSCs attenuates aging phenotypes and prolongs lifespan of elderly mice compared to those transplanted with unselected or CD150high HSCs. Importantly, reducing the dysfunctional CD150high HSCs can alleviate aging phenotypes in old recipient mice. Thus, our study demonstrates the presence of "younger" HSCs in old mice, and that aging-associated functional decline can be mitigated by reducing dysfunctional HSCs.
    DOI:  https://doi.org/10.1038/s41422-024-01057-5
  3. Nature. 2025 Jan 01.
    Bone marrow niches orchestrate stem-cell hierarchy and immune tolerance.
    Kazuhiro Furuhashi, Miwako Kakiuchi, Ryosuke Ueda, Hiroko Oda, Simone Ummarino, Alexander K Ebralidze, Mahmoud A Bassal, Chen Meng, Tatsuyuki Sato, Jing Lyu, Min-Guk Han, Shoichi Maruyama, Yu Watanabe, Yuriko Sawa, Daisuke Kato, Hiroaki Wake, Boris Reizis, John A Frangos, David M Owens, Daniel G Tenen, Ionita C Ghiran, Simon C Robson, Joji Fujisaki.
      Stem cells reside in specialized microenvironments, termed niches, at several different locations in tissues1-3. The differential functions of heterogeneous stem cells and niches are important given the increasing clinical applications of stem-cell transplantation and immunotherapy. Whether hierarchical structures among stem cells at distinct niches exist and further control aspects of immune tolerance is unknown. Here we describe previously unknown new hierarchical arrangements in haematopoietic stem cells (HSCs) and bone marrow niches that dictate both regenerative potential and immune privilege. High-level nitric oxide-generating (NOhi) HSCs are refractory to immune attack and exhibit delayed albeit robust long-term reconstitution. Such highly immune-privileged, primitive NOhi HSCs co-localize with distinctive capillaries characterized by primary ciliated endothelium and high levels of the immune-checkpoint molecule CD200. These capillaries regulate the regenerative functions of NOhi HSCs through the ciliary protein IFT20 together with CD200, endothelial nitric oxide synthase and autophagy signals, which further mediate immunoprotection. Notably, previously described niche constituents, sinusoidal cells and type-H vessels2-10 co-localize with less immune-privileged and less potent NOlow HSCs. Together, we identify highly immune-privileged, late-rising primitive HSCs and characterize their immunoprotective niches comprising specialized vascular domains. Our results indicate that the niche orchestrates hierarchy in stem cells and immune tolerance, and highlight future immunotherapeutic targets.
    DOI:  https://doi.org/10.1038/s41586-024-08352-6
  4. Sci Rep. 2025 Jan 02. 15(1): 174
    Constitutive activation of the Src-family kinases Fgr and Hck enhances the tumor burden of acute myeloid leukemia cells in immunocompromised mice.
    Sherry T Shu, Li Chen, Giancarlo Gonzalez-Areizaga, Thomas E Smithgall.
      Overexpression of the myeloid Src-family kinases Fgr and Hck has been linked to the development of acute myeloid leukemia (AML). Here we characterized the contribution of active forms of these kinases to AML cell cytokine dependence, inhibitor sensitivity, and AML cell engraftment in vivo. The human TF-1 erythroleukemia cell line was used as a model system as it does not express endogenous Hck or Fgr. To induce constitutive kinase activity, Hck and Fgr were fused to the coiled-coil (CC) oligomerization domain of the breakpoint cluster region protein associated with the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. Expression of CC-Hck or CC-Fgr transformed TF-1 cells to a granulocyte-macrophage colony-stimulating factor (GM-CSF)-independent phenotype that correlated with enhanced phosphorylation of the kinase domain activation loop. Both CC-Hck and CC-Fgr cell populations became sensitized to growth arrest by Src-family kinase inhibitors previously shown to suppress the growth of bone marrow cells from AML patients in vitro and decrease AML cell engraftment in immunocompromised mice. Methionine substitution of the 'gatekeeper' residue (Thr338) also stimulated Hck and Fgr kinase activity and transformed TF-1 cells to GM-CSF independence without CC fusion. TF-1 cells expressing either active form of Hck or Fgr engrafted immunocompromised mice faster and developed more extensive tumors compared to mice engrafted with the parent cell line, resulting in shorter survival. Expression of wild-type Hck also significantly enhanced bone marrow engraftment without an activating mutation. Reverse phase protein array analysis linked active Hck and Fgr to the mammalian target of rapamycin complex-1/p70 S6 ribosomal protein (mTORC-1/S6) kinase and focal adhesion kinase (Fak) signaling pathways. Combining Hck and Fgr inhibitors with existing mTORC-1/S6 kinase or Fak inhibitors may improve clinical responses and reduce the potential for acquired resistance.
    DOI:  https://doi.org/10.1038/s41598-024-83740-6
  5. Int J Biol Sci. 2025 ;21(1): 233-250
    Aberrant activation of adenine nucleotide translocase 3 promotes progression and chemoresistance in multiple myeloma dependent on PINK1 transport.
    Ke Hu, Yue Lai, Jinfeng Zhou, Chaolu Hu, Shushan Guo, Hui Zhang, Guanli Wang, Qikai Zhang, Xuejie Gao, Zhuning Wang, Yujie Liu, Qilin Feng, Hongfei Yi, Yu Peng, Yifei Zhang, Xiaosong Wu, Haiyan Cai, Jumei Shi.
      Chemoresistance is an important factor in multiple myeloma (MM) relapse and overall survival. However, the mechanism underlying resistance remains unclear. In this study, we identified adenine nucleotide translocase 3 (ANT3) as a novel biomarker and therapeutic target for MM progression and resistance to the proteasome inhibitor bortezomib (BTZ). The oncogenic functions of ANT3 in MM were verified using MM sensitive/drug-resistant cells, bone marrow tissues from patients with MM, orthotopic MM model, and subcutaneous tumor model. ANT3 knockdown impaired MM cell proliferation owing to a lack of cellular ATP levels, causing cell cycle arrest in the G0/G1 phase. Moreover, our study showed that ANT3 leads to BTZ resistance by promoting mitophagy. Notably, ANT3-mediated mitophagy is independent of its biological function as an ADP/ATP translocase. Mechanistically, ANT3 interacts with mitochondrial inner and outer membrane transporters, including Timm22 and Tomm20, thus restricting PINK1 import to the inner membrane of mitochondria. In this case, PINK1 is stabilized in the outer membrane of the mitochondria and recruits Parkin, resulting in mitophagy. Furthermore, targeted intervention with ANT3 combined with BTZ limited the growth of BTZ-resistant myeloma in vivo. This study identified ANT3 as a novel biomarker and therapeutic target for MM.
    Keywords:  Adenine nucleotide translocase 3; Bortezomib resistance; Mitophagy; Multiple myeloma
    DOI:  https://doi.org/10.7150/ijbs.101850
  6. J Exp Clin Cancer Res. 2024 Dec 30. 43(1): 335
    Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation.
    Jessy Sirera, Saharnaz Sarlak, Manon Teisseire, Alexandrine Carminati, Victoria J Nicolini, Coline Savy, Patrick Brest, Thierry Juel, Christophe Bontoux, Marcel Deckert, Mickael Ohanna, Sandy Giuliano, Maeva Dufies, Gilles Pages, Frederic Luciano.
       BACKGROUND: Multiple Myeloma (MM) is the second most common hematological malignancy, characterized by the accumulation of monoclonal plasmocytes in the bone marrow. Despite advancements with proteasome inhibitors, immunomodulatory agents, and CD38-targeting antibodies, MM remains largely incurable due to resistant clones and frequent relapses. The success of the proteasome inhibitor bortezomib (BTZ) in MM treatment highlights the critical role of the ubiquitin-proteasome system (UPS) in this disease. Deubiquitinases (DUBs), which regulate protein stability, interactions, and localization by removing ubiquitin modifications, have emerged as promising therapeutic targets in various cancers, including MM.
    METHODS: Through a comprehensive loss-of-function screen, we identified USP39 as a critical survival factor for MM cells. Gene Set Enrichment Analysis (GSEA) was employed to correlate USP39 mRNA levels with clinical outcomes in MM patients. USP39 protein expression was evaluated via immunohistochemistry (IHC) on bone marrow samples from MM patients and healthy controls. The impact of USP39 knockdown via SiRNA was assessed through in vitro assays measuring cellular metabolism, clonogenic capacity, cell cycle progression, apoptosis, and sensitivity to BTZ. Co-immunoprecipitation and deubiquitination assays were conducted to elucidate the interaction and regulation of ZEB1 by USP39. Finally, in vitro and in vivo zebrafish experiments were used to characterize the biological consequences of ZEB1 regulation by USP39.
    RESULTS: Our study found that elevated USP39 mRNA levels are directly associated with shorter survival in MM patients. USP39 protein expression is significantly higher in MM patient plasmocytes compared to healthy individuals. USP39 knockdown inhibits clonogenic capacity, induces cell cycle arrest, triggers apoptosis, and overcomes BTZ resistance. Gain-of-function assays revealed that USP39 stabilizes the transcription factor ZEB1, enhancing the proliferation and the trans-migratory potential of MM cells.
    CONCLUSIONS: Our findings highlight the critical role of the deubiquitinase USP39, suggesting that the USP39/ZEB1 axis could serve as a potential diagnostic marker and therapeutic target in MM.
    Keywords:  Deubiquitinase; Migration; Multiple myeloma; USP39; ZEB1
    DOI:  https://doi.org/10.1186/s13046-024-03241-2
  7. Nat Commun. 2024 Dec 30. 15(1): 10832
    Bone Marrow Endothelial Progenitor Cells remodelling facilitates normal hematopoiesis during Acute Myeloid Leukemia Complete Remission.
    Tong Xing, Li-Juan Hu, Hong-Yan Zhao, Chen-Yuan Li, Zhen-Kun Wang, Meng-Zhu Shen, Zhong-Shi Lyu, Jing Wang, Yu Wang, Hao Jiang, Qian Jiang, Ying-Jun Chang, Xiao-Hui Zhang, Yuan Kong, Xiao-Jun Huang.
      Although acute myeloid leukemia (AML) affects hematopoietic stem cell (HSC)-supportive microenvironment, it is largely unknown whether leukemia-modified bone marrow (BM) microenvironment can be remodeled to support normal hematopoiesis after complete remission (CR). As a key element of BM microenvironment, endothelial progenitor cells (EPCs) provide a feasible way to investigate BM microenvironment remodeling. Here, we find reduced and dysfunctional BM EPCs in AML patients, characterized by impaired angiogenesis and high ROS levels, could be partially remodeled after CR and improved by N-acetyl-L-cysteine (NAC). Importantly, HSC-supporting ability of BM EPCs is partially recovered, whereas leukemia-supporting ability is decreased in CR patients. Mechanistically, the transcriptome characteristics of leukemia-modified BM EPCs return to near-normal after CR. In a classic AML mouse and chemotherapy model, BM vasculature and normal hematopoiesis are reversed after CR. In summary, we provide further insights into how leukemia-modified BM microenvironment can be remodeled to support normal hematopoiesis after CR, which can be further improved by NAC.
    DOI:  https://doi.org/10.1038/s41467-024-55051-x
  8. Cell. 2024 Dec 26. pii: S0092-8674(24)01341-2. [Epub ahead of print]
    The human zinc-binding cysteine proteome.
    Nils Burger, Melanie J Mittenbühler, Haopeng Xiao, Sanghee Shin, Shelley M Wei, Erik K Henze, Sebastian Schindler, Sepideh Mehravar, David M Wood, Jonathan J Petrocelli, Yizhi Sun, Hans-Georg Sprenger, Pedro Latorre-Muro, Amanda L Smythers, Luiz H M Bozi, Narek Darabedian, Yingde Zhu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Jianwei Che, Edward T Chouchani.
      Zinc is an essential micronutrient that regulates a wide range of physiological processes, most often through zinc binding to protein cysteine residues. Despite being critical for modulation of protein function, the cysteine sites in the majority of the human proteome that are subject to zinc binding remain undefined. Here, we develop ZnCPT, a deep and quantitative mapping of the zinc-binding cysteine proteome. We define 6,173 zinc-binding cysteines, uncovering protein families across major domains of biology that are subject to constitutive or inducible zinc binding. ZnCPT enables systematic discovery of zinc-regulated structural, enzymatic, and allosteric functional domains. On this basis, we identify 52 cancer genetic dependencies subject to zinc binding and nominate malignancies sensitive to zinc-induced cytotoxicity. We discover a mechanism of zinc regulation over glutathione reductase (GSR), which drives cell death in GSR-dependent lung cancers. We provide ZnCPT as a resource for understanding mechanisms of zinc regulation of protein function.
    Keywords:  GSR; cancer; cysteine proteomics; glutathione reductase; zinc; zinc-binding proteome
    DOI:  https://doi.org/10.1016/j.cell.2024.11.025
  9. Sci Rep. 2025 Jan 02. 15(1): 70
    Peroxiredoxin 6 maintains mitochondrial homeostasis and promotes tumor progression through ROS/JNK/p38 MAPK signaling pathway in multiple myeloma.
    Dandan Gao, Yang Lv, Fei Hong, Dong Wu, Ting Wang, Gongzhizi Gao, Zujie Lin, Ruoyu Yang, Jinsong Hu, Aili He, Pengyu Zhang.
      Peroxiredoxin 6 (PRDX6) is one of the Peroxiredoxin family members with only 1-Cys, using glutathione as the electron donor to reduce peroxides in cells. PRDX6 has been frequently studied and its expression was associated with poor prognosis in many tumors. However, the expression of PRDX6 in multiple myeloma (MM) and its relevance with MM remain unclear. In our study, we found that PRDX6 was overexpressed in MM patients. Its high expression was inversely correlated with prognosis but positively correlated with the levels of β2-microglobulin (B2M), lactate dehydrogenase (LDH), and International Staging System (ISS) stage of MM patients. Further, the deficiency of PRDX6 promoted MM cell lines (RPMI 8226, MM.1S, and U266) apoptosis significantly. Mechanically, PRDX6 serves as an anti-oxidative enzyme, and its deficiency led to over-accumulation of reactive oxygen species (ROS), resulting in oxidative stress, following the activation of MAPK signaling pathway, which manifested as phosphorylation of JNK and p38. Then, the expression of BAX and Bcl2 was imbalance, and the cascade cleavage of PARP and caspase 3 was increased, ultimately triggering cell apoptosis. In addition, oxidative stress decreased mitochondrial membrane potential (MMP), reduced gene expression levels of oxidative phosphorylation (OXPHOS), and increased in the density of mitochondrial crumpling, leading to mitochondrial structural abnormalities and dysfunction. Furthermore, PRDX6 deficiency combined with bortezomib induced a robust anti-tumor effect in MM cell lines. Finally, in vivo experiments also showed that the deficiency of PRDX6 inhibited tumor growth of tumor-bearing mice. Collectively, PRDX6 protects MM cells from oxidative damage and maintains mitochondrial homeostasis. And targeting PRDX6 is an attractive strategy to enhance the anti-tumor effect of bortezomib in MM.
    Keywords:  Apoptosis; Bortezomib; Mitochondrial homeostasis; Multiple myeloma; Reactive oxygen species
    DOI:  https://doi.org/10.1038/s41598-024-84021-y
  10. Int J Oncol. 2025 Feb;pii: 12. [Epub ahead of print]66(2):
    LGR4 promotes proliferation and homing via activation of the NF‑κB signaling pathway in multiple myeloma.
    Nihan He, Qin Yang, Zhengjiang Li, Jiaojiao Guo, Chunmei Kuang, Yinghong Zhu, Xing Liu, Xun Chen, Fangming Shi, Xiangling Feng, Gang An, Guoping Zhang, Wen Zhou.
      Multiple myeloma (MM) is a plasma cell malignancy characterized by clonal proliferation in the bone marrow (BM). Previously, it was reported that G‑protein‑coupled receptor 4 (LGR4) contributed to early hematopoiesis and was associated with poor prognosis in patients with MM. However, the mechanism of cell homing and migration, which is critical for MM progression, remains unclear. In the present study, cell counting, cell cycle and BrdU assays were performed to evaluate cell proliferation. Transwell assay and Xenograft mouse models were performed to evaluate cell migration and homing ability both in vitro and in vivo. I was found that overexpression of LGR4 promotes MM cell adhesion, migration and homing to BM both in vitro, while exacerbating osteolytic bone destruction in vivo. However, the LGR4 knockdown displayed the opposite effect. Further mechanistic studies demonstrated that LGR4 activated the nuclear factor kappa B (NF‑κB) signaling pathway and migration‑related adhesion molecule, thus promoting MM cell homing. Moreover, inhibiting the NF‑κB pathway was found to suppress MM cell homing. These findings identify LGR4 as a critical regulator of myeloma cell migration, homing and tumorigenesis, offering a potential therapeutic strategy for MM treatment.
    Keywords:  LGR4; cell homing; multiple myeloma
    DOI:  https://doi.org/10.3892/ijo.2025.5718
  11. Cell. 2024 Dec 26. pii: S0092-8674(24)01344-8. [Epub ahead of print]
    Global organelle profiling reveals subcellular localization and remodeling at proteome scale.
    Marco Y Hein, Duo Peng, Verina Todorova, Frank McCarthy, Kibeom Kim, Chad Liu, Laura Savy, Camille Januel, Rodrigo Baltazar-Nunez, Madhurya Sekhar, Shivanshi Vaid, Sophie Bax, Madhuri Vangipuram, James Burgess, Leila Njoya, Eileen Wang, Ivan E Ivanov, Janie R Byrum, Soorya Pradeep, Carlos G Gonzalez, Yttria Aniseia, Joseph S Creery, Aidan H McMorrow, Sara Sunshine, Serena Yeung-Levy, Brian C DeFelice, Shalin B Mehta, Daniel N Itzhak, Joshua E Elias, Manuel D Leonetti.
      Defining the subcellular distribution of all human proteins and their remodeling across cellular states remains a central goal in cell biology. Here, we present a high-resolution strategy to map subcellular organization using organelle immunocapture coupled to mass spectrometry. We apply this workflow to a cell-wide collection of membranous and membraneless compartments. A graph-based analysis assigns the subcellular localization of over 7,600 proteins, defines spatial networks, and uncovers interconnections between cellular compartments. Our approach can be deployed to comprehensively profile proteome remodeling during cellular perturbation. By characterizing the cellular landscape following HCoV-OC43 viral infection, we discover that many proteins are regulated by changes in their spatial distribution rather than by changes in abundance. Our results establish that proteome-wide analysis of subcellular remodeling provides key insights for elucidating cellular responses, uncovering an essential role for ferroptosis in OC43 infection. Our dataset can be explored at organelles.czbiohub.org.
    Keywords:  CRISPR; HCoV-OC43 coronavirus; cell biology; ferroptosis; k-NN graph; mass spectrometry; native organelle IP; protein localization; spatial proteomics; subcellular remodeling; viral infection
    DOI:  https://doi.org/10.1016/j.cell.2024.11.028
This page is being maintained by Thomas Krichel. It was last updated on 2025‒01‒14 at 9:58.