Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells

Hajime Akada, Saeko Akada, Robert E. Hutchison, Kazuhito Sakamoto, Kay Uwe Wagner, Golam Mohi

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Jak2, a member of the Janus kinase family of nonreceptor protein tyrosine kinases, is activated in response to a variety of cytokines, and functions in survival and proliferation of cells. An activating JAK2V617F mutation has been found in most patients with myeloproliferative neoplasms, and patients treated with Jak2 inhibitors show significant hematopoietic toxicities. However, the role of Jak2 in adult hematopoietic stem cells (HSCs) has not been clearly elucidated. Using a conditional Jak2 knockout allele, we have found that Jak2 deletion results in rapid loss of HSCs/progenitors leading to bone marrow failure and early lethality in adult mice. Jak2 deficiency causes marked impairment in HSC function, and the mutant HSCs are severely defective in reconstituting hematopoiesis in recipient animals. Jak2 deficiency also causes significant apoptosis and loss of quiescence in HSC-enriched LSK (Lin -Sca-1+c-Kit+) cells. Jak2-deficient LSK cells exhibit elevated reactive oxygen species levels and enhanced p38 MAPK activation. Mutant LSK cells also show defective Stat5, Erk, and Akt activation in response to thrombopoietin and stem cell factor. Gene expression analysis reveals significant downregulation of genes related to HSC quiescence and self-renewal in Jak2-deficient LSK cells. These data suggest that Jak2 plays a critical role in the maintenance and function of adult HSCs. Stem Cells 2014;32:1878-1889

Original languageEnglish (US)
Pages (from-to)1878-1889
Number of pages12
JournalSTEM CELLS
Volume32
Issue number7
DOIs
StatePublished - Jul 2014

Fingerprint

Adult Stem Cells
Hematopoietic Stem Cells
Maintenance
Janus Kinases
Thrombopoietin
Stem Cell Factor
Hematopoiesis
p38 Mitogen-Activated Protein Kinases
Protein-Tyrosine Kinases
Reactive Oxygen Species
Cell Survival
Stem Cells
Down-Regulation
Bone Marrow
Alleles
Cell Proliferation
Apoptosis
Cytokines
Gene Expression
Mutation

Keywords

  • Apoptosis
  • Conditional knockout
  • Hematopoietic stem cells
  • JAK2 kinase
  • Proliferation
  • Self-renewal
  • Signal transduction

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Akada, H., Akada, S., Hutchison, R. E., Sakamoto, K., Wagner, K. U., & Mohi, G. (2014). Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells. STEM CELLS, 32(7), 1878-1889. https://doi.org/10.1002/stem.1711

Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells. / Akada, Hajime; Akada, Saeko; Hutchison, Robert E.; Sakamoto, Kazuhito; Wagner, Kay Uwe; Mohi, Golam.

In: STEM CELLS, Vol. 32, No. 7, 07.2014, p. 1878-1889.

Research output: Contribution to journalArticle

Akada, H, Akada, S, Hutchison, RE, Sakamoto, K, Wagner, KU & Mohi, G 2014, 'Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells', STEM CELLS, vol. 32, no. 7, pp. 1878-1889. https://doi.org/10.1002/stem.1711
Akada H, Akada S, Hutchison RE, Sakamoto K, Wagner KU, Mohi G. Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells. STEM CELLS. 2014 Jul;32(7):1878-1889. https://doi.org/10.1002/stem.1711
Akada, Hajime ; Akada, Saeko ; Hutchison, Robert E. ; Sakamoto, Kazuhito ; Wagner, Kay Uwe ; Mohi, Golam. / Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells. In: STEM CELLS. 2014 ; Vol. 32, No. 7. pp. 1878-1889.
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