N-Ras(G12D) induces features of stepwise transformation in preleukemic human umbilical cord blood cultures expressing the AML1-ETO fusion gene.

Abstract:

:AML1-ETO (AE) is a fusion product of t(8;21) observed in 40% French-American-British M2 type of acute myeloid leukemia (AML). Clinical data suggest that Ras mutation is a frequent cooperating event in t(8;21) AML. Whether constitutively active Ras promotes leukemogenesis on the t(8;21) background has not been demonstrated experimentally. Here, we retrovirally expressed N-Ras(G12D) in AE-expressing human hematopoietic cells to investigate cooperativity. The AE/N-Ras(G12D) cultures were cytokine-independent, enriched for CD34 positivity, and possessed increased colony-forming and replating abilities. N-Ras(G12D) expression led to Bcl-2 up-regulation and reduced apoptosis. Ectopic Bcl-2 expression also resulted in enhanced colony-forming and replating abilities but was insufficient to sustain cytokine independence. AE/N-Ras(G12D) cells were more sensitive to Bcl-2 inhibition with ABT-737 than parent AE cells. Enhanced engraftment of AE/N-Ras(G12D) cells was observed on intrafemoral injection into immunodeficient mice, presumably because of improved survival in the bone marrow microenvironment. N-Ras(G12D) promotes progression toward transformation in AE-expressing cells, partially through up-regulating Bcl-2.

journal_name

Blood

journal_title

Blood

authors

Chou FS,Wunderlich M,Griesinger A,Mulloy JC

doi

10.1182/blood-2010-01-264119

subject

Has Abstract

pub_date

2011-02-17 00:00:00

pages

2237-40

issue

7

eissn

0006-4971

issn

1528-0020

pii

blood-2010-01-264119

journal_volume

117

pub_type

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