Jak1 integrates cytokine sensing to regulate hematopoietic stem cell function and stress hematopoiesis Journal Article


Authors: Kleppe, M.; Spitzer, M. H.; Li, S.; Hill, C. E.; Dong, L.; Papalexi, E.; De Groote, S.; Bowman, R. L.; Keller, M.; Koppikar, P.; Rapaport, F. T.; Teruya-Feldstein, J.; Gandara, J.; Mason, C. E.; Nolan, G. P.; Levine, R. L.
Article Title: Jak1 integrates cytokine sensing to regulate hematopoietic stem cell function and stress hematopoiesis
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. Selective JAK1 inhibition has emerged as a potential strategy for treating autoimmune and hematological diseases. Levine and colleagues show that Jak1 integrates multiple cytokine signals in normal and malignant HSCs to regulate their self-renewal and quiescence, highlighting further potential therapeutic benefits and risks of Jak1 inhibition. © 2017 Elsevier Inc.
Keywords: hematopoietic stem cells; jak1; cytokine signaling; stress hematopoiesis
Journal Title: Cell Stem Cell
Volume: 21
Issue: 4
ISSN: 1934-5909
Publisher: Cell Press  
Date Published: 2017-10-05
Start Page: 489
End Page: 501.e7
Language: English
DOI: 10.1016/j.stem.2017.08.011
PROVIDER: scopus
PUBMED: 28965767
PMCID: PMC5847260
DOI/URL:
Notes: Erratum published at DOI: 10.1016/j.stem.2017.12.018 -- Export Date: 1 December 2017 -- Source: Scopus
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MSK Authors
  1. Ross Levine
    782 Levine
  2. Maria Kleppe
    41 Kleppe
  3. Robert L Bowman
    52 Bowman
  4. Matthew D Keller
    26 Keller
  5. Lauren   Dong
    15 Dong
  6. Corinne Elizabeth Hill
    7 Hill