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

Abstract

The process of platelet production has so far been understood to be a two-stage process: megakaryocyte (MK) maturation from haematopoietic stem cells followed by proplatelet formation, with each phase regulating the peripheral blood platelet count. Proplatelet formation releases “beads-on-a-string” preplatelets into the blood stream that 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 25-48% reduction in the platelet count without any effect on other blood cell lineages. We microtubule stability, possibly due to increased microtubule glutamylation via CRLF3’s interaction with key members of the Hippo pathway. Using a mouse model of JAK2V617F Essential Thrombocythaemia (ET), we show that a lack of CRLF3 leads to a long-term lineage-specific normalisation of the platelet count. We thereby postulate that targeting CRLF3 has therapeutic potential for treatment of thrombocythaemia.