Genetic studies reveal an unexpected negative regulatory role for jak2 in thrombopoiesis Journal Article

Authors: Meyer, S. C.; Keller, M. D.; Woods, B. A.; LaFave, L. M.; Bastian, L.; Kleppe, M.; Bhagwat, N.; Marubayashi, S.; Levine, R. L.
Article Title: Genetic studies reveal an unexpected negative regulatory role for jak2 in thrombopoiesis
Abstract: JAK inhibitor treatment is limited by the variable development of anemia and thrombocytopenia thought to be due to on-target JAK2 inhibition. We evaluated the impact of Jak2 deletion in platelets (PLTs) and megakaryocytes (MKs) on blood counts, stem/ progenitor cells, and Jak-Stat signaling. Pf4-Cre-mediated Jak2 deletion in PLTsandMKs did not compromise PLT formation but caused thrombocytosis, and resulted in expansion ofMKprogenitors and Lin2Sca11Kit1 cells. Serum thrombopoietin (TPO) wasmaintained at normal levels in Pf4-Cre-positive Jak2f/f mice, consistent with reduced internalization/ turnover by Jak2-deficient PLTs. These data demonstrate that Jak2 in terminal megakaryopoiesis is not required for PLT production, and that Jak2 loss in PLTs and MKs results in non-autonomous expansion of stem/progenitors and of MKs and PLTs via dysregulated TPO turnover. This suggests that the thrombocytopenia frequently seen with JAK inhibitor treatment is not due to JAK2 inhibition in PLTs and MKs, but rather due to JAK2 inhibition in stem/progenitor cells. (Blood. 2014;124(14):2280-2284).
Keywords: signal transduction; controlled study; gene deletion; janus kinase 2; nonhuman; genetic analysis; protein function; protein blood level; animal cell; mouse; stem cell factor; enzyme inhibition; thrombocyte; thrombocytopenia; stem cell; cell culture; blood cell count; cre recombinase; megakaryocyte; internalization; thrombocytosis; stat protein; thrombopoietin; stem cell expansion; turnover time; thrombocytopoiesis; stem cell antigen 1; megakaryopoiesis; article
Journal Title: Blood
Volume: 124
Issue: 14
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2014-10-02
Start Page: 2280
End Page: 2284
Language: English
DOI: 10.1182/blood-2014-03-560441
PROVIDER: scopus
PMCID: PMC4183987
PUBMED: 25115888
Notes: Export Date: 3 November 2014 -- Source: Scopus
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MSK Authors
  1. Ross Levine
    490 Levine
  2. Neha Bhagwat
    21 Bhagwat
  3. Maria Kleppe
    30 Kleppe
  4. Brittany Anne Woods
    9 Woods
  5. Matthew D Keller
    24 Keller
  6. Sara Christina Meyer
    9 Meyer