bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024–02–18
eightteen papers selected by
William Grey, University of York
  1. ER stress and the unfolded protein response in gastrointestinal stem cells and carcinogenesis.
  2. CHCHD2 up-regulation in Huntington disease mediates a compensatory protective response against oxidative stress.
  3. Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth.
  4. The UBE2J2/UBE2K-MARCH5 ubiquitination machinery regulates apoptosis in response to venetoclax in acute myeloid leukemia.
  5. Direct observation of autoubiquitination for an integral membrane ubiquitin ligase in ERAD.
  6. Relationships between protein degradation, cellular senescence, and organismal aging.
  7. Neutrophil Granulopoiesis optimized through Ex vivo Expansion of Hematopoietic Progenitors in Engineered 3D Gelatin Methacrylate Hydrogels.
  8. The HRI branch of the integrated stress response selectively triggers mitophagy.
  9. Selenium reduction of ubiquinone via SQOR suppresses ferroptosis.
  10. A methylation-phosphorylation switch controls EZH2 stability and hematopoiesis.
  11. Stromal Cell Isolation from Hematopoietic Organs.
  12. Bone marrow plasma cells require P2RX4 to sense extracellular ATP.
  13. Bone marrow-inspired hydrogel/graphene composite scaffolds to support in vitro expansion of hematopoietic stem cells.
  14. A system for inducible mitochondria-specific protein degradation in vivo.
  15. Human ASXL1-mutant hematopoiesis is driven by a truncated protein associated with aberrant de-ubiquitination of H2AK119.
  16. IGFBP5 is released by senescent cells and is internalized by healthy cells, promoting their senescence through interaction with retinoic receptors.
  17. Cell competition: emerging signaling and unsolved questions.
  18. Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms.
  1. Cancer Lett. 2024 Feb 13. pii: S0304-3835(24)00071-5. [Epub ahead of print] 216678
    ER stress and the unfolded protein response in gastrointestinal stem cells and carcinogenesis.
    R J de Boer, J F van Lidth de Jeude, J Heijmans.
      Endoplasmic reticulum (ER) stress and the adaptive response that follows, termed the unfolded protein response (UPR), are crucial molecular mechanisms to maintain cellular integrity by safeguarding proper protein synthesis. Next to being important in protein homeostasis, the UPR is intricate in cell fate decisions such as proliferation, differentiation, and stemness. In the intestine, stem cells are critical in governing epithelial homeostasis and they are the cell of origin of gastrointestinal malignancies. In this review, we will discuss the role of ER stress and the UPR in the gastrointestinal tract, focusing on stem cells and carcinogenesis. Insights in mechanisms that connect ER stress and UPR with stemness and carcinogenesis may broaden our understanding in the development of cancer throughout the gastrointestinal tract and how we can exploit these mechanisms to target these malignancies.
    DOI:  https://doi.org/10.1016/j.canlet.2024.216678
  2. Cell Death Dis. 2024 02 10. 15(2): 126
    CHCHD2 up-regulation in Huntington disease mediates a compensatory protective response against oxidative stress.
    Xuanzhuo Liu, Fang Wang, Xinman Fan, Mingyi Chen, Xiaoxin Xu, Qiuhong Xu, Huili Zhu, Anding Xu, Mahmoud A Pouladi, Xiaohong Xu.
      Huntington disease (HD) is a neurodegenerative disease caused by the abnormal expansion of a polyglutamine tract resulting from a mutation in the HTT gene. Oxidative stress has been identified as a significant contributing factor to the development of HD and other neurodegenerative diseases, and targeting anti-oxidative stress has emerged as a potential therapeutic approach. CHCHD2 is a mitochondria-related protein involved in regulating cell migration, anti-oxidative stress, and anti-apoptosis. Although CHCHD2 is highly expressed in HD cells, its specific role in the pathogenesis of HD remains uncertain. We postulate that the up-regulation of CHCHD2 in HD models represents a compensatory protective response against mitochondrial dysfunction and oxidative stress associated with HD. To investigate this hypothesis, we employed HD mouse striatal cells and human induced pluripotent stem cells (hiPSCs) as models to examine the effects of CHCHD2 overexpression (CHCHD2-OE) or knockdown (CHCHD2-KD) on the HD phenotype. Our findings demonstrate that CHCHD2 is crucial for maintaining cell survival in both HD mouse striatal cells and hiPSCs-derived neurons. Our study demonstrates that CHCHD2 up-regulation in HD serves as a compensatory protective response against oxidative stress, suggesting a potential anti-oxidative strategy for the treatment of HD.
    DOI:  https://doi.org/10.1038/s41419-024-06523-x
  3. Nat Commun. 2024 Feb 14. 15(1): 1359
    Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth.
    Sophie G Kellaway, Sandeep Potluri, Peter Keane, Helen J Blair, Luke Ames, Alice Worker, Paulynn S Chin, Anetta Ptasinska, Polina K Derevyanko, Assunta Adamo, Daniel J L Coleman, Naeem Khan, Salam A Assi, Anja Krippner-Heidenreich, Manoj Raghavan, Peter N Cockerill, Olaf Heidenreich, Constanze Bonifer.
      Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.
    DOI:  https://doi.org/10.1038/s41467-024-45691-4
  4. Leukemia. 2024 Feb 16.
    The UBE2J2/UBE2K-MARCH5 ubiquitination machinery regulates apoptosis in response to venetoclax in acute myeloid leukemia.
    Shan Lin, Constanze Schneider, Angela H Su, Gabriela Alexe, David E Root, Kimberly Stegmaier.
      
    DOI:  https://doi.org/10.1038/s41375-024-02178-x
  5. Nat Commun. 2024 Feb 13. 15(1): 1340
    Direct observation of autoubiquitination for an integral membrane ubiquitin ligase in ERAD.
    Basila Moochickal Assainar, Kaushik Ragunathan, Ryan D Baldridge.
      The endoplasmic reticulum associated degradation (ERAD) pathway regulates protein quality control at the endoplasmic reticulum. ERAD of lumenal and membrane proteins requires a conserved E3 ubiquitin ligase, called Hrd1. We do not understand the molecular configurations of Hrd1 that enable autoubiquitination and the subsequent retrotranslocation of misfolded protein substrates from the ER to the cytosol. Here, we have established a generalizable, single-molecule platform that enables high-efficiency labeling, stoichiometry determination, and functional assays for any integral membrane protein. Using this approach, we directly count Hrd1 proteins reconstituted into individual proteoliposomes. We report that Hrd1 assembles in different oligomeric configurations with mostly monomers and dimers detected at limiting dilution. By correlating oligomeric states with ubiquitination in vitro, we conclude that Hrd1 monomers are inefficient in autoubiquitination while dimers efficiently assemble polyubiquitin chains. Therefore, our results reveal the minimal composition of a Hrd1 oligomer that is capable of autoubiquitination. Our methods are broadly applicable to studying other complex membrane protein functions using reconstituted bilayer systems.
    DOI:  https://doi.org/10.1038/s41467-024-45541-3
  6. J Biochem. 2024 Feb 13. pii: mvae016. [Epub ahead of print]
    Relationships between protein degradation, cellular senescence, and organismal aging.
    Jun Hamazaki, Shigeo Murata.
      Aging is a major risk factor for many diseases. Recent studies have shown that age-related disruption of proteostasis leads to the accumulation of abnormal proteins and that dysfunction of the two major intracellular proteolytic pathways, the ubiquitin-proteasome pathway, and the autophagy-lysosome pathway, is largely responsible for this process. Conversely, it has been shown that activation of these proteolytic pathways may contribute to lifespan extension and suppression of pathological conditions, making it a promising intervention for anti-aging. This review provides an overview of the important role of intracellular protein degradation in aging and summarizes how the disruption of proteostasis is involved in age-related diseases.
    Keywords:  aging; autophagy; proteasome; proteostasis; senescence
    DOI:  https://doi.org/10.1093/jb/mvae016
  7. Adv Healthc Mater. 2024 Feb 12. e2301966
    Neutrophil Granulopoiesis optimized through Ex vivo Expansion of Hematopoietic Progenitors in Engineered 3D Gelatin Methacrylate Hydrogels.
    Evan Cirves, Alex Vargas, Erika E Wheeler, J Kent Leach, Scott I Simon, Tomas Gonzalez-Fernandez.
      Neutrophils are the first line of defense of the innate immune system. In response to methicillin resistant Staphylococcus aureus infection in skin, hematopoietic stem and progenitor cells (HSPCs) traffic to wounds and undergo extramedullary granulopoiesis, which produces neutrophils necessary to resolve infection. This prompted engineering a gelatin methacrylate (GelMA) hydrogel that encapsulates HSPCs within a matrix amenable to subcutaneous delivery. We studied the influence of hydrogel mechanical properties to produce an artificial niche for granulocyte-monocyte progenitors (GMPs) to efficiently expand into functional neutrophils that can populate infected tissue. Lin-cKIT+ HSPCs, harvested from LysM-EGFP neutrophil reporter mice, were encapsulated in GelMA hydrogels of varying polymer concentration and UV-crosslinked to produce HSPC-laden gel of specific stiffness and mesh sizes. Softer 5% GelMA gels yielded the most viable progenitors and effective cell-matrix interactions. Compared to suspension culture, 5% GelMA resulted in a two-fold expansion of mature neutrophils that retain antimicrobial functions including degranulation, phagocytosis, and ROS production. When implanted dermally in C57BL/6J mice, luciferase-expressing neutrophils expanded in GelMA hydrogels were visualized at the site of implantation for over 5 days. We demonstrate the potential of GelMA as an artificial niche for delivering HSPCs directly to the site of skin infection to promote local granulopoiesis. This article is protected by copyright. All rights reserved.
    Keywords:  Extramedullary granulopoiesis; Gelatin Methacrylate (GelMA); Hematopoietic stem and progenitor cells (HSPCs); Neutrophils
    DOI:  https://doi.org/10.1002/adhm.202301966
  8. Mol Cell. 2024 Feb 06. pii: S1097-2765(24)00052-2. [Epub ahead of print]
    The HRI branch of the integrated stress response selectively triggers mitophagy.
    Yogaditya Chakrabarty, Zheng Yang, Hsiuchen Chen, David C Chan.
      To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.
    Keywords:  autophagy; integrated stress response; iron metabolism; mitochondria; mitophagy; organelle quality control
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.016
  9. Nat Metab. 2024 Feb 13.
    Selenium reduction of ubiquinone via SQOR suppresses ferroptosis.
    Namgyu Lee, Sung Jin Park, Mike Lange, Tenzin Tseyang, Mihir B Doshi, Tae Yong Kim, Yoseb Song, Dong In Kim, Paul L Greer, James A Olzmann, Jessica B Spinelli, Dohoon Kim.
      The canonical biological function of selenium is in the production of selenocysteine residues of selenoproteins, and this forms the basis for its role as an essential antioxidant and cytoprotective micronutrient. Here we demonstrate that, via its metabolic intermediate hydrogen selenide, selenium reduces ubiquinone in the mitochondria through catalysis by sulfide quinone oxidoreductase. Through this mechanism, selenium rapidly protects against lipid peroxidation and ferroptosis in a timescale that precedes selenoprotein production, doing so even when selenoprotein production has been eliminated. Our findings identify a regulatory mechanism against ferroptosis that implicates sulfide quinone oxidoreductase and expands our understanding of selenium in biology.
    DOI:  https://doi.org/10.1038/s42255-024-00974-4
  10. Elife. 2024 Feb 12. pii: e86168. [Epub ahead of print]13
    A methylation-phosphorylation switch controls EZH2 stability and hematopoiesis.
    Pengfei Guo, Rebecca C Lim, Keshari Rajawasam, Tiffany Trinh, Hong Sun, Hui Zhang.
      The Polycomb Repressive Complex 2 (PRC2) methylates H3K27 to regulate development and cell fate by transcriptional silencing. Alteration of PRC2 is associated with various cancers. Here, we show that mouse Kdm1a deletion causes dramatic reduction of PRC2 proteins, whereas mouse null mutation of L3mbtl3 or Dcaf5 results in PRC2 accumulation and increased H3K27 trimethylation. The catalytic subunit of PRC2, EZH2, is methylated at lysine 20 (K20), promoting EZH2 proteolysis by L3MBTL3 and the CLR4DCAF5 ubiquitin ligase. KDM1A (LSD1) demethylates the methylated K20 to stabilize EZH2. K20 methylation is inhibited by AKT-mediated phosphorylation of serine 21 in EZH2. Mouse Ezh2K20R/K20R mutants develop hepatosplenomegaly associated with high GFI1B expression, and Ezh2K20R/K20R mutant bone marrows expand hematopoietic stem cells and downstream hematopoietic populations. Our studies reveal that EZH2 is regulated by methylation-dependent proteolysis, which is negatively controlled by AKT-mediated S21 phosphorylation to establish a methylation-phosphorylation switch to control the PRC2 activity and hematopoiesis.
    Keywords:  biochemistry; cancer biology; chemical biology; mouse
    DOI:  https://doi.org/10.7554/eLife.86168
  11. J Vis Exp. 2024 Jan 26.
    Stromal Cell Isolation from Hematopoietic Organs.
    Trine Kristiansen, Christina Mayerhofer, Karin Gustafsson, David T Scadden.
      Single-cell sequencing has enabled the mapping of heterogeneous cell populations in the stroma of hematopoietic organs. These methodologies provide a lens through which to study previously unresolved heterogeneity at steady state, as well as changes in cell type representation induced by extrinsic stresses or during aging. Here, we present step-wise protocols for the isolation of high-quality stromal cell populations from murine and human thymus, as well as murine bone and bone marrow. Cells isolated through these protocols are suitable for generating high-quality single-cell multiomics datasets. The impacts of sample digestion, hematopoietic lineage depletion, FACS analysis/sorting, and how these factors influence compatibility with single-cell sequencing are discussed here. With examples of FACS profiles indicating successful and inefficient dissociation and downstream stromal cell yields in post-sequencing analysis, recognizable pointers for users are provided. Considering the specific requirements of stromal cells is crucial for acquiring high-quality and reproducible results that can advance knowledge in the field.
    DOI:  https://doi.org/10.3791/66231
  12. Nature. 2024 Feb 14.
    Bone marrow plasma cells require P2RX4 to sense extracellular ATP.
    Masaki Ishikawa, Zainul S Hasanali, Yongge Zhao, Arundhoti Das, Marieke Lavaert, Carly J Roman, Jennifer Londregan, David Allman, Avinash Bhandoola.
      Plasma cells produce large quantities of antibodies and so play essential roles in immune protection1. Plasma cells, including a long-lived subset, reside in the bone marrow where they depend on poorly defined microenvironment-linked survival signals1. We show that bone marrow plasma cells use the ligand-gated purinergic ion channel P2RX4 to sense extracellular ATP released by bone marrow osteoblasts through the gap-junction protein pannexin 3 (PANX3). Mutation of Panx3 or P2rx4 each caused decreased serum antibodies and selective loss of bone marrow plasma cells. Compared to their wild-type counterparts, PANX3-null osteoblasts secreted less extracellular ATP and failed to support plasma cells in vitro. The P2RX4-specific inhibitor 5-BDBD abrogated the impact of extracellular ATP on bone marrow plasma cells in vitro, depleted bone marrow plasma cells in vivo and reduced pre-induced antigen-specific serum antibody titre with little posttreatment rebound. P2RX4 blockade also reduced autoantibody titre and kidney disease in two mouse models of humoral autoimmunity. P2RX4 promotes plasma cell survival by regulating endoplasmic reticulum homeostasis, as short-term P2RX4 blockade caused accumulation of endoplasmic reticulum stress-associated regulatory proteins including ATF4 and B-lineage mutation of the pro-apoptotic ATF4 target Chop prevented bone marrow plasma cell demise on P2RX4 inhibition. Thus, generating mature protective and pathogenic plasma cells requires P2RX4 signalling controlled by PANX3-regulated extracellular ATP release from bone marrow niche cells.
    DOI:  https://doi.org/10.1038/s41586-024-07047-2
  13. J Mater Chem B. 2024 Feb 12.
    Bone marrow-inspired hydrogel/graphene composite scaffolds to support in vitro expansion of hematopoietic stem cells.
    Jing Hong, Zhanchi Zhu, Leisha Cui, Zhaojun Wang, Ying Hao, Xiaopeng Tian, Guosheng Cheng.
      Hematopoietic stem cell (HSC) expansion offers a key strategy to address the source limitation and donor shortages of HSCs for the treatment of various blood disorders. Specific remodeling of the complex bone marrow microenvironment that contributes to efficient in vitro expansion of HSCs remains challenging. Here, inspired by the regions with different stiffness levels in the bone marrow niche, a three dimensional (3D) bone marrow-mimicking composite scaffold created based on gelatin-hyaluronic acid (Gel-HA) hydrogels and graphene foams (GFs) was engineered to support the in vitro expansion of HSCs. The composite scaffold was prepared by forming a photo-cross-linked Gel-HA hydrogel surrounding the GF. The "soft" Gel-HA hydrogel and "stiff" GF replicate the structure and stiffness of the vascular niche and endosteal niche in the bone marrow, respectively. Furthermore, HSCs cultured in the Gel-HA/GF scaffold proliferated well and retained the CD34+CD38- immunophenotype and pluripotency, suggesting that the Gel-HA/GF composite scaffold supported the in vitro expansion of HSCs, maintaining the primitive phenotype and the ability to differentiate into functional blood cells. Thus, the hydrogel/graphene composite scaffold offers a means of facilitating HSC expansion through structurally and mechanically mimicking bone marrow niches, demonstrating great promise for HSC transplantation.
    DOI:  https://doi.org/10.1039/d3tb02448b
  14. Nat Commun. 2024 Feb 16. 15(1): 1454
    A system for inducible mitochondria-specific protein degradation in vivo.
    Swastika Sanyal, Anna Kouznetsova, Lena Ström, Camilla Björkegren.
      Targeted protein degradation systems developed for eukaryotes employ cytoplasmic machineries to perform proteolysis. This has prevented mitochondria-specific analysis of proteins that localize to multiple locations, for example, the mitochondria and the nucleus. Here, we present an inducible mitochondria-specific protein degradation system in Saccharomyces cerevisiae based on the Mesoplasma florum Lon (mf-Lon) protease and its corresponding ssrA tag (called PDT). We show that mitochondrially targeted mf-Lon protease efficiently and selectively degrades a PDT-tagged reporter protein localized to the mitochondrial matrix. The degradation can be induced by depleting adenine from the medium, and tuned by altering the promoter strength of the MF-LON gene. We furthermore demonstrate that mf-Lon specifically degrades endogenous, PDT-tagged mitochondrial proteins. Finally, we show that mf-Lon-dependent PDT degradation can also be achieved in human mitochondria. In summary, this system provides an efficient tool to selectively analyze the mitochondrial function of dually localized proteins.
    DOI:  https://doi.org/10.1038/s41467-024-45819-6
  15. Blood Cancer Discov. 2024 Feb 15.
    Human ASXL1-mutant hematopoiesis is driven by a truncated protein associated with aberrant de-ubiquitination of H2AK119.
    Thomas Kohnke, Kevin A Nuno, Catherine C Alder, Eric J Gars, Paul Phan, Amy C Fan, Ravindra Majeti.
      Mutations in additional sex combs like 1 (ASXL1) confer poor prognosis both in myeloid malignancies and in pre-malignant clonal hematopoiesis (CH). However, the mechanisms by which these mutations contribute to disease initiation remain unresolved and mutation-specific targeting has remained elusive. To address this, we developed a human disease model that recapitulates the disease trajectory from ASXL1-mutant CH to lethal myeloid malignancy. We demonstrate that mutations in ASXL1 lead to the expression of a functional, truncated protein and determine that truncated ASXL1 leads to global redistribution of the repressive chromatin mark H2AK119Ub, increased transposase-accessible chromatin, and activation of both myeloid and stem cell gene expression programs. Finally, we demonstrate that H2AK119Ub levels are tied to truncated ASXL1 expression levels and leverage this observation to demonstrate that inhibition of the PRC1 complex might be an ASXL1-mutant specific therapeutic vulnerability both in pre-malignant CH and myeloid malignancy.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0235
  16. Cell Commun Signal. 2024 Feb 13. 22(1): 122
    IGFBP5 is released by senescent cells and is internalized by healthy cells, promoting their senescence through interaction with retinoic receptors.
    Nicola Alessio, Domenico Aprile, Gianfranco Peluso, Valeria Mazzone, Deanira Patrone, Giovanni Di Bernardo, Umberto Galderisi.
      Cells that are exposed to harmful genetic damage, either from internal or external sources, may undergo senescence if they are unable to repair their DNA. Senescence, characterized by a state of irreversible growth arrest, can spread to neighboring cells through a process known as the senescence-associated secretory phenotype (SASP). This phenomenon contributes to both aging and the development of cancer. The SASP comprises a variety of factors that regulate numerous functions, including the induction of secondary senescence, modulation of immune system activity, remodeling of the extracellular matrix, alteration of tissue structure, and promotion of cancer progression. Identifying key factors within the SASP is crucial for understanding the underlying mechanisms of senescence and developing effective strategies to counteract cellular senescence. Our research has specifically focused on investigating the role of IGFBP5, a component of the SASP observed in various experimental models and conditions.Through our studies, we have demonstrated that IGFBP5 actively contributes to promoting senescence and can induce senescence in neighboring cells. We have gained valuable insights into the mechanisms through which IGFBP5 exerts its pro-senescence effects. These mechanisms include its release following genotoxic stress, involvement in signaling pathways mediated by reactive oxygen species and prostaglandins, internalization via specialized structures called caveolae, and interaction with a specific protein known as RARα. By uncovering these mechanisms, we have advanced our understanding of the intricate role of IGFBP5 in the senescence process. The significance of IGFBP5 as a pro-aging factor stems from an in vivo study we conducted on patients undergoing Computer Tomography analysis. In these patients, we observed an elevation in circulating IGFBP5 levels in response to radiation-induced organismal stress.Globally, our findings highlight the potential of IGFBP5 as a promising therapeutic target for age-related diseases and cancer.
    Keywords:  IGFBP; Mesenchymal stromal cells; SASP; Secretome; Senescence
    DOI:  https://doi.org/10.1186/s12964-024-01469-1
  17. FEBS Lett. 2024 Feb 13.
    Cell competition: emerging signaling and unsolved questions.
    Rina Nagata, Tatsushi Igaki.
      Multicellular communities have an intrinsic mechanism that optimizes their structure and function via cell-cell communication. One of the driving forces for such self-organization of the multicellular system is cell competition, the elimination of viable unfit or deleterious cells via cell-cell interaction. Studies in Drosophila and mammals have identified multiple mechanisms of cell competition caused by different types of mutations or cellular changes. Intriguingly, recent studies have found that different types of "losers" of cell competition commonly show reduced protein synthesis. In Drosophila, the reduction in protein synthesis levels in loser cells is caused by phosphorylation of the translation initiation factor eIF2α via a bZip transcription factor Xrp1. Given that a variety of cellular stresses converge on eIF2α phosphorylation and thus global inhibition of protein synthesis, cell competition may be a machinery that optimizes multicellular fitness by removing stressed cells. In this review, we summarize and discuss emerging signaling mechanisms and critical unsolved questions, as well as the role of protein synthesis in cell competition.
    Keywords:  Drosophila; TOR signaling; autophagy; cell competition; cell death; eIF2α; protein synthesis
    DOI:  https://doi.org/10.1002/1873-3468.14822
  18. Exp Hematol. 2024 Feb 08. pii: S0301-472X(24)00037-7. [Epub ahead of print] 104178
    Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms.
    Taylor B Collins, Angelo B A Laranjeira, Tim Kong, Mary C Fulbright, Daniel A C Fisher, Christopher M Sturgeon, Luis F Z Batista, Stephen T Oh.
      Myeloproliferative neoplasms (MPN) are driven by hyperactivation of JAK-STAT signaling but can demonstrate skewed hematopoiesis upon acquisition of additional somatic mutations. Here, using primary MPN samples and engineered embryonic stem cells, we demonstrate that mutations in JAK2 induce a significant increase in erythroid colony formation, whereas mutations in additional sex combs-like 1 (ASXL1) led to erythroid colony defect. RNA-sequencing revealed upregulation of protein arginine methyltransferase 6 (PRMT6) induced by mutant ASXL1. Furthermore, genetic perturbation of PRMT6 exacerbated MPN disease burden including leukemic engraftment and splenomegaly in patient-derived xenograft models, highlighting a novel tumor-suppressive function of PRMT6. However, augmented erythroid potential and bone marrow human CD71+ cells following PRMT6 knockdown were reserved only to primary MPN samples harboring ASXL1 mutations. Lastly, treatment of CD34+ hematopoietic/stem progenitor cells with PRMT6 inhibitor, EPZ020411 induced expression of genes involved in heme metabolism, hemoglobin, and erythropoiesis. These findings highlight interactions between JAK2 and ASXL1 mutations and a unique erythroid regulatory network in the context of mutant ASXL1.
    Keywords:  ASXL1; Erythrocytosis; JAK2; Myeloproliferative neoplasms; PRMT6
    DOI:  https://doi.org/10.1016/j.exphem.2024.104178
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