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

• Published in: Cell reports (Cambridge) 2014-11, Vol.9 (4), p.1333-1348
• Main Authors: Chatterjee, Anindya, Ghosh, Joydeep, Ramdas, Baskar, Mali, Raghuveer Singh, Martin, Holly, Kobayashi, Michihiro, Vemula, Sasidhar, Canela, Victor H., Waskow, Emily R., Visconte, Valeria, Tiu, Ramon V., Smith, Catherine C., Shah, Neil, Bunting, Kevin D., Boswell, H. Scott, Liu, Yan, Chan, Rebecca J., Kapur, Reuben
• Format: Article
• Language: English
• Subjects: Animals; Benzothiazoles - pharmacology; Carcinogenesis - drug effects; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Proliferation - drug effects; fms-Like Tyrosine Kinase 3 - metabolism; Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Guanine Nucleotide Exchange Factors - metabolism; Humans; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mastocytosis, Systemic - pathology; Mice, Inbred C57BL; Mutant Proteins - metabolism; Mutation - genetics; p21-Activated Kinases - antagonists & inhibitors; p21-Activated Kinases - metabolism; Phenylurea Compounds - pharmacology; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Transport - drug effects; Proto-Oncogene Proteins c-kit - metabolism; rac1 GTP-Binding Protein - metabolism; Signal Transduction - drug effects; STAT5 Transcription Factor - metabolism; Survival Analysis; T-Lymphoma Invasion and Metastasis-inducing Protein 1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.10.039

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. [Display omitted] •FAK/Tiam1/Rac1/PAK1 regulate active Stat5 downstream from oncogenic KIT and FLT3•FAK/Tiam1/PAK1 inhibition prolongs survival of mice harboring KIT and FLT3 mutations•AC220-resistant mutants of FLT3 are sensitive to inhibition by FAK/Tiam1/PAK1 axis A significant impediment in treatment of leukemia, induced by oncogenic FLT3 and KIT receptors, is inadequate understanding of critical signaling pathways that lead to the development of this disease. In this study, Chatterjee et al. show an essential role of FAK/Tiam1/Rac1/PAK1 pathway in regulating nuclear translocation of Stat5 leading to leukemogenesis, in the context of oncogenic mutations of FLT3 and KIT, and provide multiple potential therapeutic targets to treat leukemia.