Maintenance of haematopoietic stem cells by tyrosine-unphosphorylated STAT5 and JAK inhibition - STAT5 deficient HSPCs (LK)
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ABSTRACT:
PROVIDER: PRJNA926999 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23209537.fastq.gz | Fastqsanger.gz | |||
| SRR23209538.fastq.gz | Fastqsanger.gz | |||
| SRR23209539.fastq.gz | Fastqsanger.gz | |||
| SRR23209540.fastq.gz | Fastqsanger.gz | |||
| SRR23209541.fastq.gz | Fastqsanger.gz |
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Project description:Adult haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood and immune cells and must respond to extracellular cues including cytokines. The JAK/STAT pathway is a highly conserved pathway, activated by many cytokines, in which tyrosine-phosphorylated STATs (pSTATs) function as transcription factors. STAT5 is a pivotal downstream mediator of several cytokines known to regulate haematopoiesis but its function in the HSC compartment remains poorly understood. Here we show that STAT5-deficient HSCs exhibited an unusual phenotype - reduced multi-lineage repopulation and self-renewal combined with reduced cell cycle entry and increased differentiation. This reflected not only loss of a canonical pSTAT5 transcriptional program but also loss of distinct functions mediated by tyrosine-unphosphorylated STAT5 (uSTAT5). Consistent with this concept expression of an unphosphorylatable STAT5B mutant constrained HSC differentiation, promoted HSC maintenance and upregulated transcriptional programs associated with quiescence and stemness. Moreover, treatment with a JAK1/2 inhibitor (ruxolitinib) increased the uSTAT5:pSTAT5 ratio, constrained HSC differentiation and proliferation and promoted HSC maintenance, thus phenocopying uSTAT5B overexpression. Our results therefore reveal a previously unrecognized interplay between pSTAT5 and uSTAT5 in the control of HSC function. In addition the demonstration that JAK inhibition promotes HSC maintenance has implications for gene therapy using HSCs and may contribute to the failure of JAK inhibitors to eradicate myeloproliferative neoplasms.
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Project description:Adult haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood and immune cells and must respond to extracellular cues including cytokines. The JAK/STAT pathway is a highly conserved pathway, activated by many cytokines, in which tyrosine-phosphorylated STATs (pSTATs) function as transcription factors. STAT5 is a pivotal downstream mediator of several cytokines known to regulate haematopoiesis but its function in the HSC compartment remains poorly understood. Here we show that STAT5-deficient HSCs exhibited an unusual phenotype - reduced multi-lineage repopulation and self-renewal combined with reduced cell cycle entry and increased differentiation. This reflected not only loss of a canonical pSTAT5 transcriptional program but also loss of distinct functions mediated by tyrosine-unphosphorylated STAT5 (uSTAT5). Consistent with this concept expression of an unphosphorylatable STAT5B mutant constrained HSC differentiation, promoted HSC maintenance and upregulated transcriptional programs associated with quiescence and stemness. Moreover, treatment with a JAK1/2 inhibitor (ruxolitinib) increased the uSTAT5:pSTAT5 ratio, constrained HSC differentiation and proliferation and promoted HSC maintenance, thus phenocopying uSTAT5B overexpression. Our results therefore reveal a previously unrecognized interplay between pSTAT5 and uSTAT5 in the control of HSC function. In addition the demonstration that JAK inhibition promotes HSC maintenance has implications for gene therapy using HSCs and may contribute to the failure of JAK inhibitors to eradicate myeloproliferative neoplasms.
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Project description:Adult hematopoietic stem cells (HSCs) are responsible for the lifelong production of blood and immune cells and must respond to extracellular cues including cytokines. The JAK/STAT pathway is a highly conserved pathway, activated by many cytokines, 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. Here we show that STAT5-deficient HSCs exhibited an unusual phenotype - reduced multi-lineage repopulation and self-renewal combined with reduced cell cycle entry and increased differentiation. This reflected not only loss of a canonical pSTAT5 transcriptional program but also loss of distinct functions mediated by tyrosine-unphosphorylated STAT5 (uSTAT5). Consistent with this concept expression of an unphosphorylatable STAT5B mutant constrained HSC differentiation, promoted HSC maintenance and upregulated transcriptional programs associated with quiescence and stemness. Moreover, treatment with a JAK1/2 inhibitor (ruxolitinib) increased the uSTAT5:pSTAT5 ratio, constrained HSC differentiation and proliferation and promoted HSC maintenance, thus phenocopying uSTAT5B overexpression. Our results therefore reveal a previously unrecognized interplay between pSTAT5 and uSTAT5 in the control of HSC function. In addition the demonstration that JAK inhibition promotes HSC maintenance has implications for gene therapy using HSCs and may contribute to the failure of JAK inhibitors to eradicate myeloproliferative neoplasms.
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Project description:Maintenance of hematopoietic stem cells by tyrosine-unphosphorylated STAT5 and JAK inhibition
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Project description:The regulation of protein function by reversible oxidation is increasingly recognized as a key mechanism for the control of cellular signalling, modulating crucial biological processes such cell differentiation. In this scenario, the NADPH oxidases must occupy a prominent position. Our results show that haematopoietic stem and progenitor cells (HSPCs) express three p22phox-dependent NADPH oxidases members (Nox1, Nox2 and Nox4). By deleting the p22phox coding gene (Cyba), here we have analysed the importance of this family of enzymes during in vivo haematopoiesis. Cyba-/- mice show a myeloid bias in detriment of B-cells differentiation, and an enrichment of HSPCs populations. By means of haematopoietic transplant experiments we have also tried to dissect the specific role of the NADPH oxidases. While the absence of Nox1 or Nox2 provides an advantage of reconstitution, the lack of Nox4 rendered the opposite result, what suggests a functional specificity among the different NADPH oxidases. Regarding signalling pathways, the activation of AKT and STAT5 is hampered in Cyba-/- cells, the later due to the downregulation of STAT5 protein. This is in line with the diminished response to IL-7 shown by our results, what could explain defective B-cells development observed in Cyba-/- mice, supporting the requirement of NADPH oxidase activity for terminal B-cell differentiation.
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