The third step of thrombopoiesis is defective upon lack of CRLF3 in mice. (A) According to Bennet et al, platelet generation is dependent on 3 distinct stages: Megakaryocyte (MK) differentiation from hematopoietic progenitors (1), proplatelet formation (2), and the maturation of preplatelets to platelets within the circulation (3). Loss of CRLF3 results in thrombocytopenia despite unaltered MK differentiation and proplatelet formation owing to impaired preplatelet maturation within circulation. (B) Deletion of CRLF3 in a mouse model of essential thrombocythemia (ET) (Jak2^V617F) decreases platelet counts and improves disease outcome. DMS, demarcation membrane system. Image was created using Biorender.com.