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Cell Stem Cell. 2017 Oct 5;21(4):489-501.e7. doi: 10.1016/j.stem.2017.08.011. Epub 2017 Sep 28.

Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA; Program in Immunology, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
3
Department of Neurological Surgery, Weill Cornell Medicine, New York, NY 10065, USA.
4
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Department of Pathology, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USA.
6
Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
7
Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA; Program in Immunology, Stanford University, Stanford, CA 94305, USA.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: leviner@mskcc.org.

Abstract

JAK1 is a critical effector of pro-inflammatory cytokine signaling and plays important roles in immune function, while abnormal JAK1 activity has been linked to immunological and neoplastic diseases. Specific functions of JAK1 in the context of hematopoiesis, and specifically within hematopoietic stem cells (HSCs), have not clearly been delineated. Here, we show that conditional Jak1 loss in HSCs reduces their self-renewal and markedly alters lymphoid/myeloid differentiation in vivo. Jak1-deficient HSCs exhibit decreased competitiveness in vivo and are unable to rescue hematopoiesis in the setting of myelosuppression. They exhibit increased quiescence, an inability to enter the cell cycle in response to hematopoietic stress, and a marked reduction in cytokine sensing, including in response to type I interferons and IL-3. Moreover, Jak1 loss is not fully rescued by expression of a constitutively active Jak2 allele. Together, these data highlight an essential role for Jak1 in HSC homeostasis and stress responses.

KEYWORDS:

Jak1; cytokine signaling; hematopoietic stem cells; stress hematopoiesis

PMID:
28965767
PMCID:
PMC5847260
DOI:
10.1016/j.stem.2017.08.011
[Indexed for MEDLINE]
Free PMC Article

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