CRLF3 plays a key role in the final stage of platelet genesis and is a potential therapeutic target for thrombocythemia

Cavan Bennett, Moyra Lawrence, Jose A. Guerrero, Simon Stritt, Amie K. Waller, Yahui Yan, Richard W. Mifsud, Jose Ballester-Beltrán, Ayesha Baig, Annett Mueller, Louisa Mayer, James Warland, Christopher J. Penkett, Parsa Akbari, Thomas Moreau, Amanda L. Evans, Souradip Mookerjee, Gary J. Hoffman, Kourosh Saeb-Parsy, David J. AdamsAmber L. Couzens, Markus Bender, Wendy N. Erber, Bernhard Nieswandt, Randy J. Read, Cedric Ghevaert

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2227-2239
Number of pages13
JournalBlood
Volume139
Issue number14
DOIs
Publication statusPublished - 7 Apr 2022

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