bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–06–28
seven papers selected by
William Grey, University of York
  1. Niche-targeted therapy via YAP/TAZ activation enhances hematopoietic regeneration.
  2. FGF18 mediates fibroblast-leukemia crosstalk to promote acute myeloid leukemia progression.
  3. Translational Regulation of Sf1 Integrates Alternative Splicing and Hematopoietic Stem Cell Fate.
  4. Proteome profiling reveals NQO2 activity contributing to proteasome inhibitor resistance in multiple myeloma cell lines.
  5. Galectin-1 Fuels Monocyte Hyperinflammation and Represents a Novel Therapeutic Target in Myeloproliferative Neoplasms.
  6. Plasticity under pressure: biology and detection of lineage switch in acute leukemia.
  7. Nrf2-mediated epigenetic priming of osmoprotective genes enhances cellular adaptation to hyperosmotic stress.
  1. Blood. 2026 Jun 22. pii: blood.2025030831. [Epub ahead of print]
    Niche-targeted therapy via YAP/TAZ activation enhances hematopoietic regeneration.
    Shun Uemura, Masayuki Yamashita, Takako Yokomizo-Nakano, Ayako Aihara, Takumi Iwawaki, Shuhei Koide, Yaeko Nakajima-Takagi, Motohiko Oshima, Yoshiki Omatsu, Yuki Matsumoto, Yoshiaki Kubota, Bahityar Rahmutulla, Atsushi Kaneda, Miki Nishio, Akira Suzuki, Takashi Nagasawa, Kenta Kagaya, Taito Nishino, Atsushi Iwama.
      The distinctive milieu of the bone marrow (BM), known as the BM niche, supports hematopoietic stem cells (HSCs) and serves as a foundation for hematopoietic regeneration. Myeloablative stress disrupts not only hematopoietic stem and progenitor cells but also essential BM niche components, including endothelial cells (ECs) and mesenchymal stromal cells (MSCs); disruption of the latter impairs efficient hematopoietic recovery. However, therapeutic strategies targeting niche restoration remain largely underdeveloped. Here, we demonstrate that the Hippo pathway effectors YAP/TAZ are critical for enabling ECs and MSCs to respond to BM injury, and that YAP/TAZ activation accelerates BM niche recovery, thereby promoting hematopoietic regeneration. We found that YAP/TAZ are rapidly activated in both MSCs and ECs following myeloablative stress, maintaining MSC multipotency and orchestrating vascular remodeling. Mechanistically, YAP/TAZ function as transcriptional hubs in MSCs, regulating key transcriptional factors such as Ebf1 and Ebf3. This regulation preserves MSC identity by preventing osteogenic and fibrogenic differentiation while promoting the expression of hematopoietic factors such as Cxcl12 and angiogenic factors. In addition, YAP/TAZ signaling in MSCs and ECs appeared to coordinately remodel sinusoidal vessels following BM injury. These YAP/TAZ-mediated niche responses are essential for HSC retention and hematopoietic regeneration following diverse myelosuppressive therapies. Notably, pharmacological activation of YAP/TAZ enhances BM niche reorganization and augments hematopoietic regeneration following myeloablative therapies. These findings establish YAP/TAZ as central regulators of BM niche resilience, providing a rationale for niche-targeted therapeutic strategies to enhance hematopoietic regeneration.
    DOI:  https://doi.org/10.1182/blood.2025030831
  2. Blood. 2026 Jun 26. pii: blood.2026033125. [Epub ahead of print]
    FGF18 mediates fibroblast-leukemia crosstalk to promote acute myeloid leukemia progression.
    Wuju Zhang, Zhixin Ye, Xuan Zhou, Pengfei Xiong, Yating Pan, Jielei Qiu, Meifang Li, Jingling Shen, Yuhua Li, 姚 Lu, Yiran Chen, Xiaochun Bai, Xiaoling Xie.
      Non‑hematopoietic stromal cells are essential regulators of hematopoiesis; however, their contribution to leukemogenesis and immune dysfunction remains poorly defined. Here, we identified fibroblast‑derived fibroblast growth factor 18 (FGF18) as a novel stromal cytokine that reprograms leukemia-immune interactions. Single-cell RNA sequencing of the bone marrow (BM) niche during acute myeloid leukemia (AML) revealed the upregulation of Fgf18 in stromal fibroblasts. Administration of recombinant FGF18 accelerated AML progression, whereas fibroblast-specific Fgf18 depletion markedly delayed disease development and improved the survival of mice. We performed a pooled CRISPR-Cas9 screen in AML cells and identified FGFR3 signaling as a critical mediator of leukemic fitness in the FGF18‑rich microenvironment. Genetic loss of Fgfr3 in AML cells recapitulated the effects of FGF18 deficiency and limited leukemic expansion in vivo. Mechanistically, FGF18 binds to its receptor, FGFR3, on AML cells, activating the AKT-mTOR signaling pathway and inducing interleukin (IL)-6 production. IL‑6 acts autocrinely to reinforce leukemic signaling and paracrinely to activate fibroblast JAK-STAT3 signaling, thereby amplifying stromal fibroblast FGF18 expression and forming a feed‑forward loop that suppresses CD8⁺ T‑cell effector function and weakens anti‑leukemic immunity. Clinically, elevated FGF18 expression correlates with poor prognosis in AML patients. To therapeutically target this malignant crosstalk, we generated an FGF18‑neutralizing antibody that disrupted the stromal-leukemia feedback loop, restored CD8⁺ T cell effector function, and synergized with anti-PD-1 therapy to elicit durable anti‑leukemic immunity in vivo. Collectively, these findings identify FGF18-dependent stromal-leukemia crosstalk that drives AML progression and immune dysfunction, highlighting FGF18 neutralization as a potential therapeutic strategy.
    DOI:  https://doi.org/10.1182/blood.2026033125
  3. Blood. 2026 Jun 23. pii: blood.2025032484. [Epub ahead of print]
    Translational Regulation of Sf1 Integrates Alternative Splicing and Hematopoietic Stem Cell Fate.
    Vladyslava Liudkovska, Martyna Ciołek, Daniel Grygorowicz, Ankita Kumari, Sandra Irena Binias, Jan Mikołajczyk, Anna M Lenkiewicz, Anna Konturek-Ciesla, Agata Szade, Bartosz Wojtas, Remigiusz Serwa, Tomasz W Turowski, David Bryder, Krzysztof Szade, Maciej Ciesla.
      The transition of hematopoietic stem cells (HSCs) from quiescence to lineage commitment requires precise post-transcriptional control, yet the contribution of mRNA isoform regulation remains poorly defined. Here, we identify a translationally controlled splicing program that contributes to HSC fate decisions. Using activity-based signatures of 305 splicing regulators, we uncover widespread post-transcriptional modulation of the spliceosome in stem and progenitor cells. The branch-point recognition factor Sf1 emerges as a key node, regulated by a conserved structured 5' UTR that cooperates with the RNA-binding protein Igf2bp2 to control its translation. Disrupting this cis-trans module reduces Sf1 protein synthesis and skews differentiation toward stem and erythroid programs. Mechanistically, Sf1-dependent alternative splicing remodels 5' UTRs of hematopoietic and DNA damage response genes, altering their translation and modulating DNA damage resolution. Together, these findings reveal an unrecognized translational layer controlling spliceosome activity and link RNA regulons, alternative splicing, and HSC fate determination.
    DOI:  https://doi.org/10.1182/blood.2025032484
  4. Mol Cell Proteomics. 2026 Jun 26. pii: S1535-9476(26)00111-8. [Epub ahead of print] 101615
    Proteome profiling reveals NQO2 activity contributing to proteasome inhibitor resistance in multiple myeloma cell lines.
    Chien-Yun Lee, Seungbin Han, Larissa Haertle, Umair Munawar, Cornelia Vogt, Johanna Streubel, Andrej Besse, Lenka Besse, Christoph Driessen, Hermann Einsele, Johannes Waldschmidt, Martin Kortüm, Bernhard Kuster.
      Proteasome inhibitors (PIs) are frontline therapies for multiple myeloma (MM). Although MM patients initially respond to PIs, resistance frequently emerges. While all PIs nominally target the same proteasomal catalytic subunit (PSMB5), the extent to which resistance mechanisms are the same or different among different PIs or between patients is poorly understood. To address this, we performed proteome and phosphoproteome profiling of 12 MM cell line models, comprising four parental lines (AMO-1, ARH77, L363, and RPMI8226) paired with lines that acquired resistance to bortezomib (BTZ) or carfilzomib (CFZ). Over 7,000 proteins and up to 10,000 phosphopeptides were identified per cell line, enabling a comprehensive comparative analysis of shared and cell line-specific resistance signatures at the protein level. Data analysis revealed surprisingly few changes in the phosphoproteome but substantial reprogramming of the proteome in most models. Beyond known adaptations such as the overexpression of the PI target PSMB5 and the drug efflux transporter ABCB1, we identified the oxidoreductases NQO1 and NQO2 as significantly upregulated proteins under chronic proteotoxic stress across several models. Pharmacological follow up in PI resistant AMO-1 cells showed that NQO2 inhibition by imatinib fully restored CFZ sensitivity, validating NQO2 as a contributor to resistance formation in this model system.
    Keywords:  ABCB1; Multiple Myeloma; NQO1; NQO2; Phosphoproteomics; Proteasome Inhibitor Resistance; Quantitative Proteomics
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101615
  5. Blood. 2026 Jun 23. pii: blood.2025032631. [Epub ahead of print]
    Galectin-1 Fuels Monocyte Hyperinflammation and Represents a Novel Therapeutic Target in Myeloproliferative Neoplasms.
    Fan He, Shuyang Lin, Tim Kong, Daniel A C Fisher, Alexander B Kim, Varun Ramesh, Molly Brakhane, Christopher T Letson, Matias Grodzielski, Maggie J Cox, Mary C Fulbright, Yan Xiong, LaYow Yu, Yanbo Yu, Katrina J Ashworth, Joshua Siner, Andrew Engeler, Angelo B A Laranjeira, Stephen M Sykes, Jorge Di Paola, Stephen T Oh.
      Dysregulation of galectins and global protein glycosylation have been reported in various cancers, but their role in myeloproliferative neoplasms (MPNs) have remained incompletely understood. We performed single-cell RNA sequencing (scRNA-seq) which revealed significant enrichment of galectin genes in MPN monocytes. Cell-cell communication analysis predicted monocytes as a pivotal mediator of cell interactions and galectin signaling as a robust input/output pathway for monocytes. We identified elevated expression of galectin-1 (Gal-1, LGALS1) in monocytes from both human MPN samples and mouse models. Mass cytometry (CyTOF) profiling of MPN blood samples demonstrated that recombinant galectin-1 (rGal-1) significantly increased levels of multiple inflammatory cytokines in monocytes without affecting other cell types. Incubation of CD14+ monocytes from MPN patients with rGal-1 led to markedly increased transcription and secretion of inflammatory cytokines. Mechanistically, we uncovered crosstalk between the TLR4 and Gal-1 signaling pathways, as evidenced by protein 3D modeling and co-immunoprecipitation. Notably, TLR4 inhibition abrogated Gal-1 mediated proinflammatory effects in monocytes. We further identified NF-κB-dependent signaling as a key downstream effector of Gal-1, as reporter assays demonstrated rGal-1 mediated activation of NF-κB signaling in a TLR4-dependent manner. We corroborated these findings in vivo in a murine model driven by MPLW515L in which genetic abrogation of Lgals1 ameliorated key MPN disease features, including leukocytosis and splenomegaly. Additionally, Gal-1 inhibition suppressed carrageenan-induced thrombosis and inflammation in vivo. In summary, we identify Gal-1 enrichment in MPN monocytes as a driver of monocyte-mediated inflammation through TLR4 and NF-κB activation and uncover a novel therapeutic avenue for MPNs.
    DOI:  https://doi.org/10.1182/blood.2025032631
  6. Leukemia. 2026 Jun 26.
    Plasticity under pressure: biology and detection of lineage switch in acute leukemia.
    Alexandra E Kovach, Yang-Yang Ding, Adam J Lamble, Kathrin Bernt, Simon Bomken, Lisa E Brodersen, Barbara Buldini, Dana Delgado Colon, Tim H H Coorens, Rula Green Gladden, Zhaohui Gu, Shimin Hu, Elad Jacoby, Derek Janssens, Jason H Kurzer, Ester Mejstrikova, Sunil S Raikar, Susan R Rheingold, Sara K Silbert, Kai Tan, Constance M Yuan, Hao-Wei Wang, Sara Ghorashian, Nirali N Shah, Kara L Davis.
      Relapsed acute leukemia can be difficult to salvage. An uncommon but increasingly recognized and aggressive mechanism of relapse involves lineage switch. In lineage switch, the immunophenotype of the leukemia at relapse differs from the immunophenotype at initial diagnosis, with the underlying genetic driver(s) conserved, confirming a clonal relationship. Lineage switch is most common-and was first recognized-in B-cell acute lymphoblastic leukemia with KMT2A rearrangement, which often relapses as acute myeloid leukemia. In an era where antigen-targeted therapies, including chimeric antigen receptor T-cells and bispecific T-cell engagers, are increasingly utilized and thus apply selective antigen pressure, this may increase the incidence of lineage switch across different leukemia subtypes. Patients with lineage switch have dismal outcomes and optimal therapies remain unknown, thus there is a large unmet need to better understand the biology, define the diagnosis, and determine the therapeutic approaches to lineage switch. Here, we address these needs providing a review of the current biology of lineage switch, the relationship to different genetic subtypes and present definitions and recommendations for immunophenotypic and molecular monitoring.
    DOI:  https://doi.org/10.1038/s41375-026-03020-2
  7. J Biol Chem. 2026 Jun 22. pii: S0021-9258(26)02150-2. [Epub ahead of print] 113278
    Nrf2-mediated epigenetic priming of osmoprotective genes enhances cellular adaptation to hyperosmotic stress.
    Yi Lu, Na Li, Xudan Dou, Ziling Zhang, Yongxuan Su, Xueting Li, Jing Wang, Weiping Tian, Shao-Kai Sun, Lirong Zhang, Yupeng Chen, Zhiheng Liu.
      Hyperosmotic stress triggers a complex adaptive response that enables cells to maintain homeostasis and survive osmotic perturbations. However, the molecular mechanisms that coordinate transcriptional and epigenetic programs in response to osmotic stress remain poorly defined. Here, through an unbiased chemical screen, we identify activation of nuclear factor erythroid 2 - related factor 2 (Nrf2) as a potent enhancer of cell survival under hyperosmotic stress. Mechanistically, Nrf2 does not function as a sustained transcriptional activator of osmoprotective genes during stress. Instead, Nrf2 establishes a primed chromatin state prior to osmotic challenge, characterized by increased enrichment of activation-associated histone modifications at osmoprotective loci. This epigenetic priming enables enhanced recruitment of NFAT5 upon hyperosmotic stimulation, thereby amplifying osmoprotective gene transcription. Disruption of Nrf2 abolishes chromatin activation, NFAT5 binding, and transcriptional induction of osmoprotective genes, whereas pharmacological Nrf2 activation restores these processes and improves cell survival. In a model of dehydration-induced hyperosmotic stress, renal cell death was markedly increased in Nrf2-deficient mice, while Nrf2 activation promoted the expression of osmoprotective genes and conferred tissue protection. Together, our findings identify Nrf2 as an epigenetic priming factor that licenses NFAT5 - dependent transcription under hyperosmotic stress, revealing a previously unrecognized chromatin-based mechanism that enhances cellular adaptation to osmotic challenges.
    Keywords:  NFAT5; Nrf2; hyperosmotic stress; kidney; osmoprotective genes
    DOI:  https://doi.org/10.1016/j.jbc.2026.113278
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