1. CRLF3 plays a key role in the final stage of platelet genesis and is a potential therapeutic target for thrombocythemia.
- Author
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Bennett C, Lawrence M, Guerrero JA, Stritt S, Waller AK, Yan Y, Mifsud RW, Ballester-Beltrán J, Baig A, Mueller A, Mayer L, Warland J, Penkett CJ, Akbari P, Moreau T, Evans AL, Mookerjee S, Hoffman GJ, Saeb-Parsy K, Adams DJ, Couzens AL, Bender M, Erber WN, Nieswandt B, Read RJ, and Ghevaert C
- Subjects
- Humans, Megakaryocytes metabolism, Microtubules, Platelet Count, Receptors, Cytokine, Thrombopoiesis genetics, Blood Platelets metabolism, Thrombocythemia, Essential drug therapy
- 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., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
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