bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–09–21
nineteen papers selected by
William Grey, University of York
  1. Mitochondrial-activity-driven hematopoietic stem cell fate and lineage choice is first established in the aorta-gonad-mesonephros.
  2. A genome-wide screen identifies Runx2 as a novel regulator of hematopoietic stem cell expansion and T-cell commitment.
  3. JARID2 Inhibition Reprograms Human Hematopoietic Progenitor Cells To Enhance Bone Marrow Transplantation.
  4. An Inflammatory and Quiescent HSC Subpopulation Expands with Age in Humans.
  5. Bone Marrow Adipokine Mediates Hematopoietic Regeneration and Stem Cell Fitness.
  6. Differentiation latency and dormancy signatures define fetal liver hematopoietic stem cells at single-cell resolution.
  7. CRISPR-engineered human GATA2 deficiency model uncovers mitotic dysfunction and premature aging in HSPCs, impairing hematopoietic fitness.
  8. Unlocking hematopoietic stem cell potential: integrative computational approaches for genomic and transcriptomic analysis.
  9. Resolving inter- and intra-patient heterogeneity in NPM1-mutated AML at single-cell resolution.
  10. OGFOD1 enables AML chemo- and nutrient stress resistance by regulating protein synthesis.
  11. Vcam1 in endothelial and stromal cells regulates hematopoietic stem cell contact with the niche.
  12. Unfolded protein response signaling promotes myeloid cell production and cooperates with oncogenic mutation.
  13. Targeting STK17B kinase activates ferroptosis and suppresses drug resistance in multiple myeloma.
  14. Suppression of Rho-associated kinase 1 (ROCK1) promotes human hematopoietic stem cell expansion by attenuating mitochondrial fission.
  15. TYK2 is essential for the therapeutic effect of IFN-α in Jak2V617F-induced murine myeloproliferative neoplasms.
  16. Non-canonical role of ATG4B in PRMT1-mediated DNA repair and leukemia progression.
  17. Hematopoietic stem cell therapy with gene modification to treat sickle cell disease.
  18. MLL/WDR5 complex promotes recruitment of KIF2C to midbody to ensure MT depolymerization and furrow initiation during cytokinesis.
  19. Lentiviral vectors for hematopoietic stem cell gene therapy restore α-globin expression in α-thalassemia red blood cells.
  1. Cell Rep. 2025 Sep 17. pii: S2211-1247(25)01067-8. [Epub ahead of print]44(10): 116296
    Mitochondrial-activity-driven hematopoietic stem cell fate and lineage choice is first established in the aorta-gonad-mesonephros.
    Aishwarya Prakash, Maneesha S Inamdar.
      Mitochondrial metabolism determines bone marrow hematopoietic stem cell (HSC) heterogeneity and influences their repopulation potential, though its embryonic origins remain unclear. We show that during the endothelial-to-hematopoietic transition in the mouse embryo, dynamic changes in mitochondrial activity drive the production of hematopoietic stem and progenitor cells (HSPCs) with differing potencies. Lowering mitochondrial activity in the aorta-gonad-mesonephros (AGM) by pharmacological or genetic means activates Wnt signaling to promote HSPC expansion. Further, mitochondrial membrane potential (MMP) gives rise to functional heterogeneity in HSPCs. In-vitro and in-vivo functional assays and single-cell transcriptomics showed that MMPlow HSPCs in the AGM are myeloid biased, with enhanced differentiation potential, whereas MMPhigh HSPCs are lymphoid biased, with diminished differentiation potential. Mechanistically, low mitochondrial activity in HSPCs upregulates phosphoinositide 3-kinase signaling to promote differentiation. These insights into the initiation of metabolic heterogeneity could be leveraged to isolate the distinct HSPC subsets and to efficiently generate the desired lineages.
    Keywords:  CP: Developmental biology; PI3K signaling; Wnt signaling; cell fate; endothelial to hematopoietic transition; hematopoiesis; hematopoietic stem and progenitor cell; lymphoid; metabolism; mitochondria; myeloid
    DOI:  https://doi.org/10.1016/j.celrep.2025.116296
  2. Blood. 2025 Sep 17. pii: blood.2025029115. [Epub ahead of print]
    A genome-wide screen identifies Runx2 as a novel regulator of hematopoietic stem cell expansion and T-cell commitment.
    Grace A Meaker, Matthew Nicholls, Catherine Chahrour, Ian Hsu, Alastair Smith, Yavor Bozhilov, Maurice Ga Hay Leung, Hugo Vassort, Leonid Olender, Oliver Beaven, Xinran Huang, Elizabeth J Brown, Marlies Vanden Bempt, Hwei Minn Khoo, Joydeep Bhadury, Thomas A Milne, Adam C Wilkinson.
      Self-renewing multipotent hematopoietic stem cells (HSCs) are a rare but important cell population which can reconstitute the entire blood and immune system following transplantation. Due to their rarity, it has been difficult to comprehensively study the mechanisms regulating HSC activity. However, recent improvements in hematopoietic stem and progenitor cell (HSPC) culture methods using polyvinyl alcohol-based media now facilitate large-scale ex vivo HSC expansion. Here we performed a genome-wide CRISPR knockout (KO) screen in primary mouse HSPCs to discover novel regulators of ex vivo expansion. The screen identified Runx2 as a strong negative regulator of HSC expansion, which we validated using ex vivo and in vivo assays. Loss of Runx2 increased the frequency of immunophenotypic HSCs in HSPC cultures by ~3-fold. Following expansion, these Runx2-KO HSCs engrafted at ~5-fold higher levels in transplantation assays. Non-cultured Runx2-KO HSCs also displayed enhanced reconstitution potential, but loss of Runx2 did not alter blood parameters. Notably however, T-cell reconstitution was diminished from Runx2-KO HSCs, and we further validated an additional role for Runx2 in T-cell commitment using ex vivo and in vivo assays. In summary, we have identified a multifaceted role for Runx2 in HSCs, as a negative regulator of HSC self-renewal and as a facilitator of T-cell commitment. These results will contribute understanding transcriptional regulation of hematopoiesis and improve HSC therapies.
    DOI:  https://doi.org/10.1182/blood.2025029115
  3. bioRxiv. 2025 Sep 04. pii: 2025.09.03.672211. [Epub ahead of print]
    JARID2 Inhibition Reprograms Human Hematopoietic Progenitor Cells To Enhance Bone Marrow Transplantation.
    Wentao Han, Hassan Bjeije, Hamza Celik, Michael Rettig, Nancy Issa, Andrew L Young, Yanan Li, Infencia Xavier Raj, Christine R Zhang, Aishwarya Krishnan, Tyler M Parsons, Samantha C Burkart, Jason Arand, Wei Yang, Jeffrey A Magee, Grant A 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 upregulating STAT1 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.
    One Sentence Summary: Genetic inhibition of JARID2 enhances repopulating activity of human hematopoietic stem and progenitor cells in vivo via STAT1 upregulation.
    DOI:  https://doi.org/10.1101/2025.09.03.672211
  4. bioRxiv. 2025 Sep 04. pii: 2025.09.01.673389. [Epub ahead of print]
    An Inflammatory and Quiescent HSC Subpopulation Expands with Age in Humans.
    Ksenia R Safina, Dylan A Kotliar, Michelle Curtis, Jonathan D Good, Chen Weng, Shawn David, Soumya Raychaudhuri, Antonia Kreso, Jennifer Trowbridge, Vijay G Sankaran, Peter van Galen.
      Aging of the blood system impacts systemic health and can be traced to hematopoietic stem cells (HSCs). Despite multiple reports on human HSC aging, a unified map detailing their molecular age-related changes is lacking. We developed a consensus map of gene expression in HSCs by integrating seven single-cell datasets. This map revealed previously unappreciated heterogeneity within the HSC population. It also links inflammatory pathway activation (TNF/NFκB, AP-1) and quiescence within a single gene expression program. This program dominates an inflammatory HSC subpopulation that increases with age, highlighting a potential target for further experimental studies and anti-aging interventions.
    DOI:  https://doi.org/10.1101/2025.09.01.673389
  5. bioRxiv. 2025 Sep 02. pii: 2025.08.28.672647. [Epub ahead of print]
    Bone Marrow Adipokine Mediates Hematopoietic Regeneration and Stem Cell Fitness.
    Parash Prasad, Angelo D'Alessandro, Abhishek K Singh, Yi Zheng, John Manis, Li Chai, Mohd Kamran, Mark Soliman, Ashley M Wellendorf, Leo Mejia, Hongbo R Luo, Sean R Stowell, Shin-Young Park, Martin J Aryee, Mercedes Ricote, Nathan Salomonis, Jose A Cancelas.
      Bone marrow (BM) hematopoietic stem cells (HSCs) are exquisitely sensitive to cues from the BM microenvironment (ME), which is critical for their engraftment and regeneration following myeloablative stress. Retinoic acid signaling, acting on both HSCs and niche cells, has emerged as a central regulator of this process. Among ME components, BM adipocytes (BMAs), which can comprise up to 45% of BM volume and expand dramatically during the pancytopenic phase after myeloablation, play a previously underappreciated role in hematopoietic recovery. Here, we identify retinoid X receptor (RXR) signaling in BMAs as a key regulator of the adipokine Resistin, which promotes HSC self-renewal and functional fitness by activating NF-κB signaling. Conditional loss of RXR in adiponectin-expressing cells suppressed Resistin production, resulting in reduced NF-κB activity in HSCs, impaired self-renewal, and defective multilineage hematopoietic regeneration. Functionally, in vivo Resistin neutralization impaired hematopoietic reconstitution, whereas supplementation with either monomeric or dimeric Resistin enhanced HSC self-renewal and long-term lympho-hematopoietic reconstitution in an NF-κB-dependent manner. Together, these findings establish BMA-derived Resistin as an RXR-dependent, critical extrinsic regulator of HSC self-renewal and regenerative hematopoiesis, underscoring its essential role in lympho-myeloid reconstitution after myeloablation. Disclosures : The authors declare no relevant conflicts of interest.
    DOI:  https://doi.org/10.1101/2025.08.28.672647
  6. Cell Rep. 2025 Sep 18. pii: S2211-1247(25)01060-5. [Epub ahead of print]44(10): 116289
    Differentiation latency and dormancy signatures define fetal liver hematopoietic stem cells at single-cell resolution.
    Birth Defects Research Laboratory (BDRL),
      Decoding the mechanisms governing the self-renewal of hematopoietic stem cells (HSCs) during their expansion in the fetal liver (FL) could unlock novel therapeutic strategies to expand transplantable HSCs, a long-standing challenge. To explore intrinsic and extrinsic regulation of FL-HSC self-renewal at single-cell resolution, we engineered a culture platform replicating the FL endothelial niche that supports the amplification of serially engraftable HSCs. Leveraging this platform together with single-cell index flow cytometry, live imaging, transplantation assays, and single-cell RNA sequencing, we demonstrate that differentiation latency, cell-division symmetry, and transcriptional signatures of biosynthetic dormancy are distinguishing properties of rare FL-HSCs capable of serial multilineage hematopoietic reconstitution. Our findings support a paradigm in which intrinsic programs and niche-derived signals together facilitate the symmetric self-renewal of FL-HSCs while delaying their active participation in hematopoiesis. Our study also provides a resource for future investigations into intrinsic and extrinsic signaling pathways governing FL-HSC self-renewal.
    Keywords:  CP: Developmental biology; CP: Stem cell research; FL; HSC; cell division symmetry; developmental hematopoiesis; fetal liver; hematopoietic stem cell; microenvironment; niche; self-renewal; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.celrep.2025.116289
  7. Leukemia. 2025 Sep 15.
    CRISPR-engineered human GATA2 deficiency model uncovers mitotic dysfunction and premature aging in HSPCs, impairing hematopoietic fitness.
    Damia Romero-Moya, Eric Torralba-Sales, Cristina Calvo, Oskar Marin-Bejar, Maria Magallon-Mosella, Maximiliano Distefano, Joan Pera, Julio Castaño, Francesca De Giorgio, Jessica Gonzalez, Arnau Iglesias, Clara Berenguer-Balaguer, Marcel Schilling, Mireya Plass, Lorenzo Pasquali, Albert Català, Oscar Molina, Marcin W Wlodarski, Anna Bigas, Alessandra Giorgetti.
      GATA2 deficiency is a monogenic transcriptopathy disorder characterized by bone marrow failure (BMF), immunodeficiency, and a high risk of developing myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Although informative mouse models have been developed, the mechanisms by which GATA2 haploinsufficiency drives disease initiation in humans remain incompletely understood. To address this, we developed a novel humanized model using CRISPR/Cas9 technology to knock-in GATA2-R398W variant in primary cord blood CD34⁺ cells. Additionally, we introduced specific mutations in SETBP1 and ASXL1 to model distinct premalignant stages of GATA2 deficiency. Through clonal competition and serial transplantation assays, we demonstrated that human CD34+ cells harboring the GATA2 mutation exhibit significantly reduced fitness in vivo when compete with wild-type cells. Notably, this fitness disadvantage persists even when GATA2 mutations are combined with oncogenic SETBP1 and ASXL1 drivers, underscoring the dominant, deleterious effect of GATA2 deficiency on hematopoietic stem cell function. Functional in vitro analyses revealed that GATA2-R398W mutation impairs cell proliferation, disrupts cell cycle progression, and induces mitotic defects, which may contribute to hematopoietic stem/progenitor cell loss and impaired self-renewal. Transcriptomic profiles of GATA2-mutant cells revealed that these functional defects are associated with reduced HSC self-renewal capacity and upregulation of the pre-aging phenotype. Our work highlights the feasibility of generating a human GATA2 deficiency model suitable for studying the biological consequences of various GATA2 variants and the generation of a platform to test potential phenotype-rescuing therapeutics.
    DOI:  https://doi.org/10.1038/s41375-025-02771-8
  8. Front Cell Dev Biol. 2025 ;13 1589823
    Unlocking hematopoietic stem cell potential: integrative computational approaches for genomic and transcriptomic analysis.
    Pawan Kumar Raghav, Basudha Banerjee, Rajni Chadha.
      Hematopoietic stem cells (HSCs) sustain lifelong hematopoiesis through their capacity for self-renewal and multilineage differentiation. However, the isolation and functional characterization of HSCs remain challenging due to their cellular heterogeneity and dynamically regulated transcriptional and epigenetic landscapes. Advances in experimental and computational biology, including single-cell RNA sequencing (scRNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), network inference algorithms, and machine learning, have improved our ability to resolve transcriptional states, trace lineage trajectories, and reconstruct gene regulatory networks (GRN) at single-cell resolution. These approaches enable the discovery of novel HSC subtypes and regulatory factors, and facilitate the integration of multi-omics data to uncover epigenetic and transcriptional mechanisms that drive stem cell fate decisions. Additionally, machine learning models trained on high-throughput datasets provide predictive power for identifying novel enhancers, transcription factors, and therapeutic targets. This review underscores the synergistic role of computational tools in deciphering HSC biology and highlights their potential to improve stem cell therapies and precision treatments for hematologic disorders.
    Keywords:  HSC transplantation; Hematopoietic stem cells (HSCs); computational biology; differentiation; regenerative medicine; self-renewal; single-cell RNA sequencing (scRNA-Seq); stem cell therapy
    DOI:  https://doi.org/10.3389/fcell.2025.1589823
  9. Leukemia. 2025 Sep 15.
    Resolving inter- and intra-patient heterogeneity in NPM1-mutated AML at single-cell resolution.
    E Onur Karakaslar, Eva M Argiro, Nadine E Struckman, Ramin Shirali Hz, Jeppe F Severens, M Willy Honders, Susan L Kloet, Hendrik Veelken, Marcel Jt Reinders, Marieke Griffioen, Erik B van den Akker.
      NPM1-mutated AML is one of the largest entities in international classification systems of myeloid neoplasms, which are based on integrating morphologic and clinical data with genomic data. Previous research, however, indicates that bulk transcriptomics-based subtyping may improve prognostication and therapy guidance. Here, we characterized the heterogeneity in NPM1-mutated AML by performing single-cell RNA-sequencing and spectral flow cytometry on 16 AML belonging to three distinct subtypes previously identified by bulk transcriptomics. Using single-cell expression profiling we generated a comprehensive atlas of NPM1-mutated AML, collectively reconstituting complete myelopoiesis. The three NPM1-mutated transcriptional subtypes showed consistent differences in the proportions of myeloid cell clusters with distinct patterns in lineage commitment and maturational arrest. In all samples, leukemic cells were detected across different myeloid cell clusters, indicating that NPM1-mutated AML are heavily skewed but not fully arrested in myelopoiesis. Same-sample multi-color spectral flow cytometry recapitulated these skewing patterns, indicating that the three NPM1-mutated subtypes can be consistently identified across platforms. Moreover, our analyses highlighted differences in the abundance of rare hematopoietic stem cells suggesting that skewing occurs early in myelopoiesis. To conclude, by harnessing single-cell RNA-sequencing and spectral flow cytometry, we provide a detailed description of three distinct and reproducible patterns in lineage skewing in NPM1-mutated AML that may have potential relevance for prognosis and treatment of patients with NPM1-mutated AML.
    DOI:  https://doi.org/10.1038/s41375-025-02745-w
  10. Cell Metab. 2025 Sep 16. pii: S1550-4131(25)00381-X. [Epub ahead of print]
    OGFOD1 enables AML chemo- and nutrient stress resistance by regulating protein synthesis.
    Christina Mayerhofer, Dan Li, Trine Kristiansen, Ernst Mayerhofer, Azeem Sharda, Giulia Schiroli, Karin Gustafsson, Lingli He, Michael Mazzola, Sam Keyes, Anna Kiem, Eve Crompton, Yanxin Xu, Sovannarith Korm, Zhixun Dou, Charles Vidoudez, Peter G Miller, Nick van Gastel, Timothy A Graubert, David T Scadden.
      Acute myeloid leukemia (AML) commonly relapses after initial chemotherapy response. We assessed metabolic adaptations in chemoresistant cells in vivo before overt relapse, identifying altered branched-chain amino acid (BCAA) levels in patient-derived xenografts (PDXs) and immunophenotypically identified leukemia stem cells from AML patients. Notably, this was associated with increased BCAA transporter expression with low BCAA catabolism. Restricting BCAAs further reduced chemoresistant AML cells, but relapse still occurred. Among the persisting cells, we found an unexpected increase in protein production. This was accompanied by elevated translation of 2-oxoglutarate- and iron-dependent oxygenase 1 (OGFOD1), a known ribosomal dioxygenase that adjusts the fidelity of tRNA anticodon pairing with coding mRNA. We found that OGFOD1 upregulates protein synthesis in AML, driving disease aggressiveness. Inhibiting OGFOD1 impaired translation processing, decreased protein synthesis and improved animal survival even with chemoresistant AML while sparing normal hematopoiesis. Leukemic cells can therefore persist despite the stress of chemotherapy and nutrient deprivation through adaptive control of translation. Targeting OGFOD1 may offer a distinctive, translation-modifying means of reducing the chemopersisting cells that drive relapse.
    Keywords:  BCAA; OGFOD1; Ribo-seq; acute myeloid leukemia; chemoresistance; metabolism; protein biosynthesis; ribosome pausing; translation accuracy
    DOI:  https://doi.org/10.1016/j.cmet.2025.08.008
  11. bioRxiv. 2025 Sep 04. pii: 2025.08.30.673252. [Epub ahead of print]
    Vcam1 in endothelial and stromal cells regulates hematopoietic stem cell contact with the niche.
    Octavia Santis Larrain, Alice Alhaj Kadour, Sobhika Agarwala, Wantong Li, Bradley W Blaser, Michael R Lasarev, Roxana Alexandridis, Anthony Veltri, Khaliun Enkhbayar, Elliott J Hagedorn, Owen J Tamplin.
      Hematopoietic stem and progenitor cells (HSPCs) are essential for differentiation into all blood cell types. In mammals, the interaction between HSPCs and the fetal liver niche during development is critical for stem cell maturation. Integrin alpha 4 (Itga4) on HSPCs and vascular cell adhesion molecule (Vcam1) on niche cells are critical for HSPC colonization of the fetal liver (FL). Itga4 and Vcam1 also function in the zebrafish equivalent of the FL, the caudal hematopoietic tissue (CHT), however, the specific niche cells that express Vcam1 remain unclear. Using multiple approaches, including fluorescent in situ hybridization, we found Vcam1 is expressed in endothelial cells (ECs) and mesenchymal stromal cells (MSCs), but not macrophages. Time-lapse live imaging of itga4 mutants showed the Itga4-Vcam1 axis is required for HSPC retention in the CHT niche, but not homing or lodgment. Our results show that Itga4 on HSPCs and Vcam1 on ECs and MSCs are involved in retention in the CHT niche.
    Summary: Blood stem cell interaction with the niche microenvironment during development is critical for establishing a robust stem cell pool into adulthood. This study determines the niche cell types that present Vcam1 in the embryo and allow interaction with blood stem cells.
    DOI:  https://doi.org/10.1101/2025.08.30.673252
  12. bioRxiv. 2025 Sep 08. pii: 2025.09.07.674755. [Epub ahead of print]
    Unfolded protein response signaling promotes myeloid cell production and cooperates with oncogenic mutation.
    Hyunjoo Choi, Sang-Eun Jung, Hyojung Paik, Maggie J Cox, Stephen T Oh, Yoon-A Kang.
      Unfolded protein response (UPR) is an evolutionally conserved adaptive mechanism that promotes protein homeostasis under endoplasmic reticulum (ER) stress. UPR signaling has numerous functions in metabolism, cancer, immunology, and neurodegenerative diseases. Recent studies also showed that UPR signaling has important roles in hematopoietic stem and progenitor cell biology. However, whether UPR signaling regulates hematopoietic lineage fate decision remains elusive. Here, we found that FcγR - MPP3 generates erythroid lineage and Jak2 V617F mutation leads to overproduction of erythroid cells by expanding FcγR - MPP3. We showed that UPR signaling increases myeloid cell production through promoting FcγR - MPP3 transition to granulocyte/macrophage progenitor (GMP) producing FcγR + MPP3. Under a disease condition, UPR signaling cooperates with Jak2 V617F mutation and exacerbates disease phenotype as increasing red blood cells in a mouse model of polycythemia vera (PV). Activation of UPR signaling also increased myeloid output in healthy donor bone marrow MPP cells while skewing the output towards erythroid lineage in PV patient bone marrow MPP cells. Together, our results identify a novel function of UPR signaling in hematopoietic lineage specification and provide critical insights into targeting UPR signaling in hematological malignancies.
    Highlights: UPR signaling promotes myeloid cell production. UPR signaling collaborates with Jak2 V617F mutation and increases red blood cell production.
    DOI:  https://doi.org/10.1101/2025.09.07.674755
  13. Blood. 2025 Sep 12. pii: blood.2025029950. [Epub ahead of print]
    Targeting STK17B kinase activates ferroptosis and suppresses drug resistance in multiple myeloma.
    Zhibo Yan, Zhannan Han, Yihui Wang, Maja Beus, Yu Zhang, Alfredo Picado, Carrow I Wells, Jian Wu, Loren B Weidenhammer, Karla M Pires, Elizabeth A Leibold, Liang Liu, David M Gooden, Ivan Spasojevic, Erik Soderblom, Yubin Kang, Lawrence H Boise, Timothy M Willson, Mikhail A Nikiforov.
      The progression of multiple myeloma (MM), an incurable malignancy of plasma cells, is often associated with the suppression of ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation. The mechanisms underlying this suppression remain largely unknown. Here, we identified STK17B kinase as a critical suppressor of ferroptosis in MM. Elevated levels of STK17B are associated with poor overall survival in MM patients and STK17B expression is significantly higher in relapsed vs newly diagnosed MM cases. We found that inhibiting STK17B in MM cells increased the labile iron pool, enhanced lipid peroxidation, and sensitized cells to conventional anti-MM therapies. Notably, an orally available, in-house-generated STK17B inhibitor induced ferroptosis and significantly reduced tumor growth in MM xenograft mouse models. Mechanistically, proximity labeling assay combined with the phospho-proteomic analysis identified two major regulators of iron uptake and transport as direct targets of STK17B: iron-responsive element binding protein 2 (IREB2) and heat shock protein family B member 1 (HSPB1). We demonstrated that STK17B phosphorylates critical regulatory sites on IREB2 (S157) and HSPB1 (S15), thereby modulating the balance between IREB2 and HSPB1 downstream effectors, pro-ferropototic transferrin receptor and anti-ferroptotic ferritin heavy chain proteins. Furthermore, we demonstrated that STK17B indirectly maintains activating phosphorylation of STAT3, a ferroptosis suppressor and a major driver of MM pathobiology. Our findings uncovered a clinically relevant and targetable STK17B-pIREB2S157/pHSPB1S15 signaling axis that suppresses ferroptosis and contributes to drug resistance in MM.
    DOI:  https://doi.org/10.1182/blood.2025029950
  14. Leukemia. 2025 Sep 16.
    Suppression of Rho-associated kinase 1 (ROCK1) promotes human hematopoietic stem cell expansion by attenuating mitochondrial fission.
    Xuepeng Wang, Baskar Ramdas, Ramesh Kumar, Ji Zhang, Reuben Kapur.
      
    DOI:  https://doi.org/10.1038/s41375-025-02770-9
  15. Blood Neoplasia. 2025 Aug;2(3): 100087
    TYK2 is essential for the therapeutic effect of IFN-α in Jak2V617F-induced murine myeloproliferative neoplasms.
    Yuki Tahira, Kotaro Shide, Takuro Kameda, Taisuke Uchida, Ayako Kamiunten, Keiichi Akizuki, Yoko Kubuki, Masayoshi Karasawa, Ryoma Ikeda, Kengo Matsumoto, Jie Bai, Minoru Terashima, Koji Kato, Tomofumi Uto, Tomohiro Fukaya, Shuya Mitoma, Katsuaki Sato, Yudai Uehira, Hiroaki Ueno, Goro Sashida, Hideki Yamaguchi, Kazuya Shimoda.
      Interferon-α (IFN-α) exhibits antiviral and antiproliferative effects on normal and neoplastic cells. Intracellular signaling of IFN-α is mediated by tyrosine kinase 2 (TYK2) and janus kinase 1 (JAK1), followed by signal transducers and activators of transcription (STATs). TYK2 is redundant for the antiviral effect of IFN-α; however, the requirements for antiproliferative effects are unknown. We assessed the role of TYK2 in the effects of IFN-α in myeloproliferative neoplasm (MPN) model mice. Jak2V617F transgenic mice develop MPNs resembling human primary myelofibrosis, and ropeginterferon-α-2b ameliorated their features. However, these IFN-α effects were absent in Jak2V617F;Tyk2 -/- mice. In mixed wild-type (WT)/Jak2V617F chimeric mice, IFN-α treatment induces Jak2V617F hematopoietic stem cells (HSCs) to enter the cell cycle and skew their differentiation into the megakaryocyte lineage, decreasing the number of Jak2V617F HSCs. The effects of IFN-α on Jak2V617F HSCs were not observed in mixed WT/Jak2V617F;Tyk2 -/- mice, indicating that TYK2 is essential for the effects of IFN-α on both Jak2V617F progenitors and HSCs. The mechanism of IFN-α in Jak2V617F HSCs and progenitors differed: genes regulating the cell cycle were enriched in IFN-α-stimulated Jak2V617F HSCs, but not in Jak2V617F progenitors; genes regulating antiproliferation were enriched in IFN-α-stimulated Jak2V617F progenitors but not in Jak2V617F HSCs. The major IFN-α signaling molecule activated by JAKs is STAT1, which is essential for the antiviral effect. Most effects of IFN-α on Jak2V617F cells were preserved in Jak2V617F;Stat1 -/- mice but to a moderate degree compared with Jak2V617F mice. Our study reveals essential roles of TYK2 for the preferential suppressive effect of IFN-α on Jak2V617F progenitors and HSCs.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100087
  16. Autophagy. 2025 Sep 19.
    Non-canonical role of ATG4B in PRMT1-mediated DNA repair and leukemia progression.
    Zhenkun Wang, Yuting Fu, Shuyi Lin, Yuanyuan Zhou, Qiongdan Gao, YanHong Xiao, Zhenyu Ju, Bo Liu.
      Accumulating evidence indicates that many ATG (autophagy related) proteins perform non-canonical functions beyond their canonical roles in autophagy, particularly when they localize to subcellular compartments outside the cytoplasm. Although the autophagic functions of ATG4B (autophagy related 4B, cysteine peptidase) are well established, its potential non-canonical roles, especially under metabolic stress, remain largely unexplored. In our recent study, we show that energy deprivation induces autophagy-independent nuclear translocation of ATG4B. In the nucleus, ATG4B interacts with and cleaves PRMT1 (protein arginine methyltransferase 1), thereby reducing PRMT1-mediated methylation of the DNA-repair nuclease MRE11 and consequently impairing DNA repair. Notably, ATG4B is significantly upregulated in acute myeloid leukemia (AML) and shows prominent nuclear accumulation. Genetic knockdown or pharmacological inhibition of ATG4B in AML cells restores DNA repair capacity, activates the cell-cycle checkpoint kinase CHEK1/CHK1, attenuates malignant progression, and ultimately delays leukemia progression. These findings reveal an autophagy-independent role for nuclear ATG4B that links metabolic stress to the suppression of DNA repair and identify ATG4B as a potential therapeutic target in AML.
    Keywords:  ATG4B; DNA repair; PRMT1; energy metabolism; leukemia
    DOI:  https://doi.org/10.1080/15548627.2025.2564225
  17. Stem Cells Transl Med. 2025 Sep 11. pii: szaf042. [Epub ahead of print]14(9):
    Hematopoietic stem cell therapy with gene modification to treat sickle cell disease.
    Julia Ball, Avery Bradley, Anh Le, John F Tisdale, Naoya Uchida.
      Hematopoietic stem cells (HSCs) reconstitute blood cells throughout life. DNA-level correction of HSCs allows for a one-time cure of genetic diseases, including sickle cell disease (SCD). Sickle cell disease is one of the most common single-gene disorders; therefore, SCD is a prime candidate for gene therapy. Several drug therapies are available for SCD, including hydroxyurea, which is the first-line choice despite requiring lifelong administration. Allogeneic HSC transplantation is a one-time, curative treatment for SCD with limited availability of histocompatible donors. Therefore, autologous HSC gene therapy was developed using patients' own HSCs with lentiviral gene addition/silencing and clustered regularly interspaced short palindromic repeats gene editing, making gene therapy applicable to most patients. However, the established method of HSC gene therapy requires costly and complex ex vivo HSC culture. Therefore, in vivo HSC gene therapy is being developed to treat SCD, envisioning a single-injection HSC-targeted gene delivery system. This review discusses various therapeutic methods to treat SCD, the development of HSC gene therapy, and clinical gene therapy trials in SCD, ranging from FDA-approved to novel in vivo gene therapy.
    Keywords:  gene editing; gene therapy; hematopoietic stem cells; in vivo delivery; lentiviral vector; sickle cell disease
    DOI:  https://doi.org/10.1093/stcltm/szaf042
  18. J Cell Sci. 2025 Sep 17. pii: jcs.263622. [Epub ahead of print]
    MLL/WDR5 complex promotes recruitment of KIF2C to midbody to ensure MT depolymerization and furrow initiation during cytokinesis.
    Avishek Kataria, Neeraja Hemalatha, Akash Chinchole, Shweta Tyagi.
      Mixed-lineage leukemia (MLL) protein is a well-characterised epigenetic regulator whose non-canonical activities remain underappreciated. MLL has been shown to localize on the midbody and loss of this protein leads to binucleation. However, the critical role of the MLL complex in midbody formation remains underexplored. Here, we further characterize the localization of MLL and its associated protein WDR5 to the midbody. Loss of MLL/WDR5 results in defective midbody formation, which displays a wide midzone-like microtubule structure, along with chromosome bridges, resulting in binucleated cells. We show that MLL and WDR5 interact with kinesin 13 motor-KIF2C, and target it to the midbody. The depolymerase activity of KIF2C promotes correct localization of centralspindlin complex, compaction of midzone MTs, and finally, timely furrow initiation. Thus, we identify a previously unrecognized role for MLL and KIF2C in cytokinesis regulation. Together with earlier findings, this implicates them in the regulation of actin-microtubule cytoskeleton interface-pathways frequently altered in oncogenesis.
    Keywords:  Binucleation; Furrow initiation; KIF2C; MLL; MT depolymerase; Midbody
    DOI:  https://doi.org/10.1242/jcs.263622
  19. Cell Rep Med. 2025 Sep 17. pii: S2666-3791(25)00435-5. [Epub ahead of print] 102362
    Lentiviral vectors for hematopoietic stem cell gene therapy restore α-globin expression in α-thalassemia red blood cells.
    Eva E R Segura, Kevyn Hart, Beatriz Campo Fernandez, Devin Brown, Kevin Tam, Andrea Gutierrez Garcia, Eva Seigneurbieux, Karen Li, Carol Mulumba, Emma Blakely, Katelyn Masiuk, Roshani Sinha, Devesh Sharma, John Everett, Matthew Hogenauer, M Kyle Cromer, Frederic Bushman, Tippi C MacKenzie, Donald B Kohn.
      Alpha thalassemia major (ATM) is an inherited blood disorder caused by the absence of all four α-globin genes (HBA2/1), resulting in severe anemia and lifelong transfusion dependence. While allogeneic hematopoietic stem cell transplantation (HSCT) offers a potential cure, donor availability remains limited. We present a gene therapy approach for autologous HSCT using lentiviral vectors (LVs) to deliver HBA2 under the regulation of optimized β-globin locus control region (LCR) enhancers, restoring α-globin expression in red blood cells. The best-performing LVs, erythroid vector-alpha (EV-α) and EV-α-UV, achieved up to 100% transduction efficiency in human hematopoietic stem and progenitor cells (HSPCs), optimal vector copy numbers, and safe integration profiles. ATM-derived HSPCs from three donors treated with these LVs yielded α/β-globin mRNA and chain ratios within the therapeutic range (∼0.5+), and restored hemoglobin levels by 50%-100%. These findings establish the safety and clinical potential of EV-α and EV-α-UV as a promising autologous stem cell gene therapy for ATM.
    Keywords:  alpha globin; alpha thalassemia major; anemia; autologous; beta-globin LCR; gene therapy; hematopoietic stem cell; hemoglobin level; lentiviral vectors; red blood cells
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102362
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