Expression of scinderin in megakaryoblastic leukemia cells induces differentiation, maturation, and apoptosis with release of plateletlike particles and inhibits proliferation and tumorigenesis

Rapid proliferation of atypical megakaryoblasts Is a characteristic of mega karyoblastic leukemia. Cells from patients with this disorder and cell line s established from this type of leukemia showed the presence of gelsolin bu t the absence of scinderin expression, 2 filamentous actin-severing protein s present In normal megakaryocytes and platelets. Vector-mediated expressio n of scinderin In the megakaryoblastic cell line MEG-01 induced a decrease In both F-actin and gelsolin. This was accompanied by increased Rac2 expres sion and by activation of the PAK/MEKK.SEK/JNK/c-jun, c-fos transduction pa thway. The Raf/MEK/ERK pathway was also activated In these cells. Transduct ion pathway activation was followed by cell differentiation, polyploidizati on, maturation, and apoptosis with release of platelet-like particles. Part icles expressed surface CD41a antigen (glycoprotein IIb/IIIa or fibrinogen receptor), had dense bodies, high-affinity serotonin transport, and circula r array of microtubules. Treatment of particles with thrombin Induced serot onin release and aggregation that was blocked by CD41 a antibodies. PAC-1 a ntibodies also blocked aggregation. Exposure of cells to PD98059, a blocker of MEK, inhibited antigen CD41a expression, Increases In cell volume, and number of protoplasmic extensions. Cell proliferation and cell ability to f orm tumors in nude mice were also Inhibited by the expression of scinderin. MEG-01 cells expressing scinderin had the same fate In vivo as in culture. Thus, when injected into nude mice, they entered apoptosis and released pl atelet-like particles. The lack of scinderin expression in megakaryoblastic leukemia cells seems to be responsible for their inability to enter into d ifferentiation and maturation pathways characteristic of their normal count erparts. (C) 2001 by The American Society of Hematology.