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Genetic studies reveal an unexpected negative regulatory role for Jak2 in thrombopoiesis

Sara C Meyer1, Matthew D Keller1, Brittany A Woods2

  • 1Human Oncology and Pathogenesis Program.

Blood
|August 14, 2014
PubMed

Insights

JAK2 inhibition in platelets and megakaryocytes does not cause thrombocytopenia. JAK2 deletion in these cells leads to thrombocytosis and stem cell expansion, suggesting JAK inhibitors affect stem cells, not mature cells.

Area of Science:

  • Hematology
  • Molecular Biology
  • Immunology

Background:

  • JAK inhibitor therapy is associated with anemia and thrombocytopenia.
  • This is often attributed to direct JAK2 inhibition in blood cells.
  • The precise mechanisms remain incompletely understood.

Purpose of the Study:

  • To investigate the role of JAK2 in platelets (PLTs) and megakaryocytes (MKs).
  • To determine the impact of Jak2 deletion in PLTs and MKs on blood counts and stem/progenitor cells.
  • To clarify the cause of thrombocytopenia observed during JAK inhibitor treatment.

Main Methods:

  • Utilized Pf4-Cre-mediated Jak2 deletion in mouse models.
  • Analyzed blood counts, stem and progenitor cell populations.
  • Assessed Jak-Stat signaling pathways and thrombopoietin (TPO) levels.

Main Results:

  • Jak2 deletion in PLTs and MKs did not impair PLT production but led to thrombocytosis.
  • Observed expansion of MK progenitors and Lin(-)Sca1(+)Kit+ stem cells.
  • Serum TPO levels were maintained due to reduced TPO turnover by Jak2-deficient PLTs.

Conclusions:

  • JAK2 is not essential for terminal megakaryopoiesis or platelet production.
  • Loss of JAK2 in PLTs and MKs causes non-autonomous stem/progenitor cell expansion via altered TPO turnover.
  • Thrombocytopenia in JAK inhibitor therapy likely results from JAK2 inhibition in stem/progenitor cells, not mature megakaryocytes or platelets.

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