ArticleBlood advances2025
Maintenance of hematopoietic stem cells by tyrosine-unphosphorylated STAT5 and JAK inhibition.
Article in Blood advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Severe inflammation and lineage skewing are associated with poor engraftment of engineered hematopoietic stem cells in patients with sickle cell disease.Nature communications · 2025Trial
- Elevated levels of Ube2g1 in hematopoietic stem cells lead to segmental aging of the hematopoietic system.Haematologica · 2026Article
- Parvovirus B19 targets hematopoietic stem cells to disrupt multilineage differentiation and drive pancytopenia.Cell death and differentiation · 2026Article
- Scalable genotyping in fixed transcriptomes resolves clonal heterogeneity via single-cell sequencing.bioRxiv : the preprint server for biology · 2026Article
- Thrombopoietin Receptor MPL in Hematopoiesis and Myeloproliferative Neoplasms: Physiological Roles and Pathogenic Mechanisms.Stem cell reviews and reports · 2026Review
- Human TET2-Mutant Clonal Hematopoiesis Expansion Is Driven by Distinct Inflammatory Signaling Responses in Stem Cells Versus Myeloid Progeny.Blood cancer discovery · 2026Article
- A unified multimodal single-cell framework reveals a discrete state model of hematopoiesis in mice.Nature immunology · 2025Article
- The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice.The Journal of clinical investigation · 2025Article
- CXCL6 Reshapes Lipid Metabolism and Induces Neutrophil Extracellular Trap Formation in Cholangiocarcinoma Progression and Immunotherapy Resistance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
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Authors and funding
26 authors.
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Abstract
abstractAdult hematopoietic stem cells (HSCs) are responsible for the lifelong production of blood and immune cells, a process regulated by extracellular cues, including cytokines. Many cytokines signal through the conserved Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in which tyrosine-phosphorylated STATs (pSTATs) function as transcription factors. STAT5 is a pivotal downstream mediator of several cytokines known to regulate hematopoiesis, but its function in the HSC compartment remains poorly understood. In this study, we show that STAT5-deficient HSCs exhibit an unusual phenotype, including reduced multilineage repopulation and self-renewal, combined with reduced exit from quiescence and increased differentiation. This was driven not only by the loss of canonical pSTAT5 signaling, but also by the loss of distinct transcriptional functions mediated by STAT5 that lack canonical tyrosine phosphorylation (uSTAT5). Consistent with this concept, expression of an unphosphorylatable STAT5 mutant constrained wild-type HSC differentiation, promoted their maintenance, and upregulated transcriptional programs associated with quiescence and stemness. The JAK1/2 inhibitor, ruxolitinib, which increased the uSTAT5:pSTAT5 ratio, had similar effects on murine HSC function; it constrained HSC differentiation and proliferation, promoted HSC maintenance, and upregulated transcriptional programs associated with stemness. Ruxolitinib also enhanced serial replating of normal human hematopoietic stem and progenitor cells (HSPCs), calreticulin-mutant murine HSCs, and HSPCs obtained from patients with myelofibrosis. Our results therefore reveal a previously unrecognized interplay between pSTAT5 and uSTAT5 in the control of HSC function and highlight JAK inhibition as a potential strategy for enhancing HSC function during ex vivo culture. Increased levels of uSTAT5 may also contribute to the failure of JAK inhibitors to eradicate myeloproliferative neoplasms.
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