Rapid proliferation of atypical megakaryoblasts is a characteristic of megakaryoblastic
leukemia. Cells from patients with this disorder and cell lines established from this type of
leukemia showed the presence of
gelsolin but the absence of
scinderin expression, 2 filamentous actin-severing
proteins present in normal megakaryocytes and platelets. Vector-mediated expression of
scinderin in the megakaryoblastic cell line MEG-01 induced a decrease in both
F-actin and
gelsolin. This was accompanied by increased Rac2 expression and by activation of the PAK/
MEKK.SEK/JNK/c-jun, c-fos transduction pathway. The Raf/MEK/ERK pathway was also activated in these cells. Transduction pathway activation was followed by cell differentiation, polyploidization, maturation, and apoptosis with release of platelet-like particles. Particles expressed surface CD41a
antigen (
glycoprotein IIb/IIIa or
fibrinogen receptor), had dense bodies, high-affinity
serotonin transport, and circular array of microtubules. Treatment of particles with
thrombin induced
serotonin release and aggregation that was blocked by CD41a
antibodies. PAC-1
antibodies 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 form
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 platelet-like particles. 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.