Abstract
Mutations and inactivation of phosphatase and tensin homolog deleted from chromosome 10 (. PTEN) are observed in 15%-25% of cases of human Tcell 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 invitro, treatment with inhibitors of this pathway does not cause a complete remission invivo. 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 invitro on feeder layer cells or a matrix and invivo.
Original language | English (US) |
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Pages (from-to) | 2055-2068 |
Number of pages | 14 |
Journal | Cell Reports |
Volume | 10 |
Issue number | 12 |
DOIs | |
State | Published - Mar 31 2015 |
Externally published | Yes |
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology