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. Boswell, Yan Liu, Rebecca Chan, Reuben Kapur

Research output: Contribution to journalArticle

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

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Focal Adhesion Protein-Tyrosine Kinases
Chemical activation
Transcription
Acute Myeloid Leukemia
Neoplasms
Genes
Mutation
Molecules
Survival
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Chatterjee, A., Ghosh, J., Ramdas, B., Mali, R. S., Martin, H., Kobayashi, M., ... 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

Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis. / 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.; Liu, Yan; Chan, Rebecca; Kapur, Reuben.

In: Cell Reports, Vol. 9, No. 4, 20.11.2014, p. 1333-1348.

Research output: Contribution to journalArticle

Chatterjee, A, Ghosh, J, Ramdas, B, Mali, RS, Martin, H, Kobayashi, M, Vemula, S, Canela, VH, Waskow, ER, Visconte, V, Tiu, RV, Smith, CC, Shah, N, Bunting, KD, Boswell, H, Liu, Y, Chan, R & Kapur, R 2014, 'Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis', Cell Reports, vol. 9, no. 4, pp. 1333-1348. https://doi.org/10.1016/j.celrep.2014.10.039
Chatterjee A, Ghosh J, Ramdas B, Mali RS, Martin H, Kobayashi M et al. Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis. Cell Reports. 2014 Nov 20;9(4):1333-1348. https://doi.org/10.1016/j.celrep.2014.10.039
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. ; Liu, Yan ; Chan, Rebecca ; Kapur, Reuben. / Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis. In: Cell Reports. 2014 ; Vol. 9, No. 4. pp. 1333-1348.
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