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Blood, 1 October 2001, Vol. 98, No. 7, pp. 2210-2219
NEOPLASIA
Expression of scinderin in megakaryoblastic leukemia cells
induces differentiation, maturation, and apoptosis with release of
plateletlike particles and inhibits proliferation and
tumorigenesis
Rodolfo Zunino,
Qinggang Li,
Sergio Daniel Rosé,
María Margarita
Itatí Romero-Benítez,
Tatiana Lejen,
Nora
Cristina Brandan, and
José-María Trifaró
From the Department of Cellular and Molecular Medicine,
Faculty of Medicine, University of Ottawa, Ontario, Canada.
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.
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