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

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, Reuben Kapur

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1333-1348
Number of pages16
JournalCell Reports
Volume9
Issue number4
DOIs
StatePublished - Nov 20 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis'. Together they form a unique fingerprint.

  • Cite this

    Chatterjee, A., Ghosh, J., Ramdas, B., Mali, R. S., Martin, H., Kobayashi, M., Vemula, S., Canela, V. H., Waskow, E. R., Visconte, V., Tiu, R. V., Smith, C. C., Shah, N., Bunting, K. D., Boswell, H. S., Liu, Y., Chan, R. J., & Kapur, R. (2014). Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis. Cell Reports, 9(4), 1333-1348. https://doi.org/10.1016/j.celrep.2014.10.039