FAK Mediates a Compensatory Survival Signal Parallel to PI3K-AKT in PTEN-Null T-ALL Cells
2015
Dewen You | Junping Xin | Andrew Volk | Wei Wei | Rachel Schmidt | Gina Scurti | Sucha Nand | Eun-Kyoung Breuer | Paul C. Kuo | Peter Breslin | Ameet R. Kini | Michael I. Nishimura | Nancy J. Zeleznik-Le | Jiwang Zhang
Mutations and inactivation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) are observed in 15%–25% of cases of human T cell acute lymphoblastic leukemia (T-ALL). Pten deletion induces myeloproliferative disorders (MPDs), acute myeloid leukemia (AML), and/or T-ALL in mice. Previous studies attributed Pten-loss-related hematopoietic defects and leukemogenesis to excessive activation of phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling. Although inhibition of this signal dramatically suppresses the growth of PTEN-null T-ALL cells in vitro, treatment with inhibitors of this pathway does not cause a complete remission in vivo. Here, we report that focal adhesion kinase (Fak), a protein substrate of Pten, also contributes to T-ALL development in Pten-null mice. Inactivation of the FAK signaling pathway by either genetic or pharmacologic methods significantly sensitizes both murine and human PTEN-null T-ALL cells to PI3K/AKT/mTOR inhibition when cultured in vitro on feeder layer cells or a matrix and in vivo.
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