The role of Cul5 in megakaryopoiesis. HSCs are capable of rapidly differentiating into Mk via a subset of CD41⁺ VWF⁺ HSC-like cells termed stemlike megakaryocyte progenitors (SL-MkPs). SL-MkPs, in turn, differentiate into Mk. This pathway serves as a demand-adapted mechanism for rapid platelet production in response to inflammation and other cues. Cul5, which serves as a scaffold for CRL complexes, regulates this process via suppression of IL-3–mediated activation of STAT5. In its absence, IL-3 signaling triggers excess expansion of SL-MkPs and subsequent thrombocytosis. IL-3R, IL-3 receptor. Figure created with BioRender.com.