Expression of scinderin in megakaryoblastic leukemia cells induces differentiation, maturation, apoptosis with release of platelet-like particles, and inhibits proliferation and tumorigenesis.

Abstract

Proliferation of atypical megakaryoblasts is a characteristic of megakaryoblastic leukemia. Cell lines established from patients with this disorder show presence of gelsolin but absence of scinderin expression, two filamentous actin severing proteins present in normal megakaryocytes and platelets. Vector-mediated expression of scinderin (pcDNA3-Sc) in the megakaryoblastic cell line MEG-01 induced a decrease in F-actin and gelsolin as evaluated by immunocytochemistry, image analysis and immunoblotting. This was accompanied by an increased Rac2 expression followed by activation of PAK/MEKK.SEK/JNK/c-jun, c-fos and the Raf/MEK/ERK transduction pathways. Transduction pathway activation was responsible for cell differentiation, polyploidization, maturation and apoptosis with release of platelet-like particles. Platelet-like particles expressed surface CD41 a antigen, had dense core vesicles, a high affinity serotonin transport and a circular array of microtubules. Treatment of platelet-like particles with thrombin induced aggregation and release of serotonin. Cell proliferation and the cells' ability to form tumours in nude mice were also inhibited by expression of scinderin. The lack of scinderin expression in megakaryoblastic leukemia cells seems to be responsible for their inability to enter into differentiation and maturation pathways characteristic of their normal counterparts.