CRLF3 plays a key role in the final stage of platelet genesis and is a potential therapeutic target for thrombocythemia.
Accepted version
Peer-reviewed
Repository URI
Repository DOI
Change log
Authors
Abstract
The process of platelet production has so far been understood to be a 2-stage process: megakaryocyte maturation from hematopoietic stem cells followed by proplatelet formation, with each phase regulating the peripheral blood platelet count. Proplatelet formation releases into the bloodstream beads-on-a-string preplatelets, which undergo fission into mature platelets. For the first time, we show that preplatelet maturation is a third, tightly regulated, critical process akin to cytokinesis that regulates platelet count. We show that deficiency in cytokine receptor-like factor 3 (CRLF3) in mice leads to an isolated and sustained 25% to 48% reduction in the platelet count without any effect on other blood cell lineages. We show that Crlf3-/- preplatelets have increased microtubule stability, possibly because of increased microtubule glutamylation via the interaction of CRLF3 with key members of the Hippo pathway. Using a mouse model of JAK2 V617F essential thrombocythemia, we show that a lack of CRLF3 leads to long-term lineage-specific normalization of the platelet count. We thereby postulate that targeting CRLF3 has therapeutic potential for treatment of thrombocythemia.
Description
Keywords
Journal Title
Conference Name
Journal ISSN
1528-0020
Volume Title
Publisher
Publisher DOI
Sponsorship
British Heart Foundation (None)
Medical Research Council (MR/R015724/1)
Medical Research Council (MR/V005413/1)
Medical Research Council (MC_PC_17230)
Wellcome Trust (203151/A/16/Z)
Wellcome Trust (209407/Z/17/Z)