Article

Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells

University of California, Irvine, Department of Molecular Biology and Biochemistry, 3242 McGaugh Hall, Irvine, CA 92697-3900, USA.
Blood (Impact Factor: 10.43). 07/2004; 103(11):4268-75. DOI: 10.1182/blood-2003-07-2193
Source: PubMed

ABSTRACT BCR-ABL and v-ABL are oncogenic forms of the Abl tyrosine kinase that can cause leukemias in mice and humans. ABL oncogenes trigger multiple signaling pathways whose contribution to transformation varies among cell types. Activation of phosphoinositide 3-kinase (PI3K) is essential for ABL-dependent proliferation and survival in some cell types, and global PI3K inhibitors can enhance the antileukemia effects of the Abl kinase inhibitor imatinib. Although a significant fraction of BCR-ABL-induced human leukemias are of B-cell origin, little is known about PI3K signaling mechanisms in B-lineage cells transformed by ABL oncogenes. Here we show that activation of class I(A) PI3K and downstream inactivation of FOXO transcription factors are essential for survival of murine pro/pre-B cells transformed by v-ABL or BCR-ABL. In addition, analysis of mice lacking individual PI3K genes indicates that products of the Pik3r1 gene contribute to transformation efficiency by BCR-ABL. These findings establish a role for PI3K signaling in B-lineage transformation by ABL oncogenes.

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    • "The BCR-ABL1 fusion protein resulting from t(9;22) activates the PI3K/mTOR pathway directly in both chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) ALL (17). Although tyrosine kinase inhibitors (TKIs) targeting mutant ABL1 have revolutionized treatment of Ph+ leukemias in adults and children, resistance mutations are a known sequelae of TKI therapy that often result in eventual treatment failure. "
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    • "By Western blotting, AKT showed only a minimal degree of phosphorylation at position Ser473 in the ALL-LTC compared to the Jurkat cell line. This is similar to published data showing weak AKT phosphorylation in p190BCR-ABL transformed murine pro/pre-B cells, despite these cell´s dependency on PI3K signaling [53]. More importantly however, we observed no consistent dephosphorylation of AKT following inhibition of either BCR-ABL or PI3K signaling, raising the possibility that other targets within the PI3K signaling pathway may be more important than AKT. "
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