title: FAK mediates a compensatory survival signal parallel to PI3K-AKT in PTEN-null T-ALL cells.
abstract: 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.
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA. Electronic address: deyou@luc.edu.
authors: Dewen
authors: D
authors: You
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Junping
authors: J
authors: Xin
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA; Molecular Biology Program, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Andrew
authors: A
authors: Volk
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Wei
authors: W
authors: Wei
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Rachel
authors: R
authors: Schmidt
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA; Department of Surgery, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Gina
authors: G
authors: Scurti
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA; Loyola University Medical Center, Maywood, IL 60153, USA; Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Sucha
authors: S
authors: Nand
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA; Department of Radiation Oncology, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Eun-Kyoung
authors: EK
authors: Breuer
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA; Department of Surgery, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Paul C
authors: PC
authors: Kuo
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA; Department of Biology, Loyola University Chicago, Chicago, IL 60660, USA; Department of Molecular and Cellular Physiology, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Peter
authors: P
authors: Breslin
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA; Department of Pathology, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Ameet R
authors: AR
authors: Kini
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA; Department of Surgery, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Michael I
authors: MI
authors: Nishimura
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA; Molecular Biology Program, Loyola University Chicago, Maywood, IL 60153, USA; Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Nancy J
authors: NJ
authors: Zeleznik-Le
authors: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA; Department of Pathology, Loyola University Chicago, Maywood, IL 60153, USA; Molecular Biology Program, Loyola University Chicago, Maywood, IL 60153, USA. Electronic address: jzhang@luc.edu.
authors: Jiwang
authors: J
authors: Zhang
mesh_terms: D000818:Animals; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse