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

Author

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

Published
2022
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2. CRLF3 plays a key role in the final stage of platelet genesis and is a potential therapeutic target for thrombocythemia

Author

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

Subjects
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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