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

Maria Kleppe, Matthew H. Spitzer, Sheng Li, Corinne E. Hill, Lauren Dong, Efthymia Papalexi, Sofie De Groote, Robert L. Bowman, Matthew Keller, Priya Koppikar, Franck T. Rapaport, Julie Teruya-Feldstein, Jorge Gandara, Christopher E. Mason, Garry P. Nolan, Ross L. Levine

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


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.

Original languageEnglish
Pages (from-to)489-501.e7
JournalCell Stem Cell
Issue number4
StatePublished - 5 Oct 2017


  • Jak1
  • cytokine signaling
  • hematopoietic stem cells
  • stress hematopoiesis


Dive into the research topics of 'Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis'. Together they form a unique fingerprint.

Cite this