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1. Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis

Author

Anindya Chatterjee, Joydeep Ghosh, Baskar Ramdas, Raghuveer Singh Mali, Holly Martin, Michihiro Kobayashi, Sasidhar Vemula, Victor H. Canela, Emily R. Waskow, Valeria Visconte, Ramon V. Tiu, Catherine C. Smith, Neil Shah, Kevin D. Bunting, H. Scott Boswell, Yan Liu, Rebecca J. Chan, and Reuben Kapur

Subjects
Biology (General), QH301-705.5
Abstract

Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.

Published
2014
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2. Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis

Author

Holly Martin, Victor Hugo Canela, Neil P. Shah, Raghuveer Singh Mali, Valeria Visconte, Anindya Chatterjee, Sasidhar Vemula, Joydeep Ghosh, Ramon V. Tiu, Rebecca J. Chan, Emily R. Waskow, Baskar Ramdas, Catherine C. Smith, Yan Liu, H. Scott Boswell, Kevin D. Bunting, Reuben Kapur, and Michihiro Kobayashi

Subjects
Myeloid, rac1 GTP-Binding Protein, Carcinogenesis, Medical Physiology, Inbred C57BL, Mice, 0302 clinical medicine, hemic and lymphatic diseases, STAT5 Transcription Factor, 2.1 Biological and endogenous factors, Guanine Nucleotide Exchange Factors, T-Lymphoma Invasion and Metastasis-inducing Protein 1, Aetiology, Phosphorylation, lcsh:QH301-705.5, STAT5, Cancer, Pediatric, 0303 health sciences, Leukemia, Myeloid leukemia, Hematology, 3. Good health, Leukemia, Myeloid, Acute, Protein Transport, Proto-Oncogene Proteins c-kit, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Signal transduction, Mastocytosis, Signal Transduction, Cell signaling, Childhood Leukemia, Pediatric Cancer, Acute, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Rare Diseases, Mastocytosis, Systemic, Genetics, medicine, Animals, Humans, Benzothiazoles, Protein Kinase Inhibitors, 030304 developmental biology, Cell Proliferation, Cell Nucleus, Phenylurea Compounds, Systemic, medicine.disease, Survival Analysis, Mice, Inbred C57BL, fms-Like Tyrosine Kinase 3, p21-Activated Kinases, lcsh:Biology (General), Focal Adhesion Protein-Tyrosine Kinases, Fms-Like Tyrosine Kinase 3, Mutation, Cancer research, biology.protein, Mutant Proteins, Biochemistry and Cell Biology
Abstract

SummaryOncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.

Published
2014

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