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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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. Adams, Amber L. Couzens, Markus Bender, Wendy N. Erber, Bernhard Nieswandt, Randy J. Read, Cedric Ghevaert, Bennett, Cavan [0000-0002-9796-9381], Lawrence, Moyra [0000-0001-9386-5633], Waller, Amie K [0000-0002-9726-5560], Yan, Yahui [0000-0001-6934-9874], Ballester-Beltrán, Jose [0000-0002-3287-2925], Mayer, Louisa [0000-0003-4905-0669], Warland, James [0000-0003-1060-1865], Penkett, Christopher J [0000-0003-4006-7261], Akbari, Parsa [0000-0001-9210-4760], Moreau, Thomas [0000-0003-1090-6685], Mookerjee, Souradip [0000-0003-4904-1324], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Adams, David J [0000-0001-9490-0306], Couzens, Amber L [0000-0003-0057-6686], Bender, Markus [0000-0002-2381-116X], Erber, Wendy N [0000-0002-1028-9376], Nieswandt, Bernhard [0000-0003-1454-7413], Read, Randy J [0000-0001-8273-0047], Ghevaert, Cedric [0000-0002-9251-0934], and Apollo - University of Cambridge Repository
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Blood Platelets ,Platelet Count ,Immunology ,Humans ,Cell Biology ,Hematology ,Receptors, Cytokine ,Megakaryocytes ,Microtubules ,Biochemistry ,Thrombocythemia, Essential ,Thrombopoiesis - 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.
- Published
- 2022
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