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

Meyer, Sara C; Keller, Matthew D; Woods, Brittany A; LaFave, Lindsay M; Bastian, Lennart; Kleppe, Maria; Bhagwat, Neha; Marubayashi, Sachie; Levine, Ross L (2014). Genetic studies reveal an unexpected negative regulatory role for Jak2 in thrombopoiesis. Blood, 124(14), pp. 2280-2284. American Society of Hematology 10.1182/blood-2014-03-560441

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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 PLTs and MKs did not compromise PLT formation but caused thrombocytosis, and resulted in expansion of MK progenitors and Lin(-)Sca1(+)Kit+ cells. Serum thrombopoietin (TPO) was maintained at normal levels in Pf4-Cre-positive Jak2(f/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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory

UniBE Contributor:

Meyer, Sara Christina

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1528-0020

Publisher:

American Society of Hematology

Language:

English

Submitter:

Julia Elisa Garcia

Date Deposited:

28 Dec 2023 08:11

Last Modified:

28 Dec 2023 08:21

Publisher DOI:

10.1182/blood-2014-03-560441

PubMed ID:

25115888

BORIS DOI:

10.48350/190307

URI:

https://boris.unibe.ch/id/eprint/190307

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