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Blood, 15 October 2001, Vol. 98, No. 8, pp. 2508-2517
NEOPLASIA
Transformation of interleukin-3-dependent cells without
participation of Stat5/bcl-xL: cooperation of akt with raf/erk leads to
p65 nuclear factor  B-mediated antiapoptosis involving
c-IAP2
Vasily M. Gelfanov,
Gem S. Burgess,
Sara Litz-Jackson,
Alastair J. King,
Mark S. Marshall,
Harikrishna Nakshatri, and
H.
Scott Boswell
From the Walther Cancer Institute and Division of
Hematology/Oncology, Departments of Medicine and Surgery, Indiana
University School of Medicine and VA Medical Center, Indianapolis, IN.
Tyrosine kinase oncogenes such as p210BCR-ABL
activate multiple signal pathways. As a result, it is difficult to
infer the functional relevance of a pathway acting alone or in
cooperation with another. One or 2 second-tier kinases represented in
the p21ras and phosphatidylinositol-3-kinase (PI-3-kinase) pathways (activated RafCAAX and gag-akt, respectively) were expressed in parental H7 interleukin-3 (IL-3)-dependent myeloid cells.
IL-3-dependent cells served, independently, as recipients of
p210BCR-ABL, which activated p21ras and PI-3-kinase pathways, including
raf/erk and akt, respectively, en route to transformation. By contrast,
neither RafCAAX nor gag-akt when expressed in parental cells in
isolation produced factor-independent cells. On the other hand, H7
cells expressing both RafCAAX and gag-akt (H7gag-akt/RafCAAX) were
transformed. Such transformation in H7gag-akt/RafCAAX was accomplished
in the absence of active versions of Shc or cbl, and there was no
evidence of Stat activity and only modest amounts of bcl-xL, a Stat5
transcriptional target protein, all of which characterized the cells
transformed by BCR-ABL. However, H7gag-akt/RafCAAX cells and
H7BCR-ABL cells cultured in the absence of IL-3 shared strikingly
increased p65 nuclear factor  B (NFB) activity. Treatment of cells
with a specific NFB inhibitor, parthenolide, led to loss of
NFB activity and down-regulation of antiapoptotic c-IAP2. In
cells with only gag-akt/RafCAAX, this was sufficient to allow polyADP
ribosyltransferase (PARP)-degradative apoptosis, but in cells
with p210BCR-ABL, apoptosis was blocked, possibly by a
Stat5/bcl-xL-dependent mechanism. Therefore, one hematopoietic
antiapoptotic program, among others, available to certain tyrosine
kinase oncogenes involves a cooperative response between raf/erk and
akt, unambiguous components of p21ras and PI-3-kinase pathways, to
induce p65 NFB and c-IAP2.
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