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

doi:10.1016/j.celrep.2014.10.039

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

53 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 language	English (US)
Pages (from-to)	1333-1348
Number of pages	16
Journal	Cell reports
Volume	9
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2014.10.039
State	Published - Nov 20 2014
Externally published	Yes

Funding

We thank Ms. Marilyn Wales for providing administrative support, Dr. D. Wade Clapp and Dr. Jonathan Chernoff (Fox Chase Cancer Center) for providing PAK1−/− mice, members of Dr. Christie M. Orschell’s laboratory and Dr. James Henderson (Millipore). This work was supported in part by grants from NIH (R01HL077177 to R.K., R01HL081111 to R.K., R01CA173852 to R.K., and R01CA134777 to R.J.C. and R.K.) and Riley Children’s Foundation. A.C. is an American Cancer Society postdoctoral fellow supported by PF13-065-01 and by T32HL007910 from NIH.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2014.10.039

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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

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title = "Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2014 The Authors.",

year = "2014",

month = nov,

day = "20",

doi = "10.1016/j.celrep.2014.10.039",

language = "English (US)",

volume = "9",

pages = "1333--1348",

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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, HS, Liu, Y, Chan, RJ & 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

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T1 - Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis

AU - Chatterjee, Anindya

AU - Ghosh, Joydeep

AU - Ramdas, Baskar

AU - Mali, Raghuveer Singh

AU - Martin, Holly

AU - Kobayashi, Michihiro

AU - Vemula, Sasidhar

AU - Canela, Victor H.

AU - Waskow, Emily R.

AU - Visconte, Valeria

AU - Tiu, Ramon V.

AU - Smith, Catherine C.

AU - Shah, Neil

AU - Bunting, Kevin D.

AU - Boswell, H. Scott

AU - Liu, Yan

AU - Chan, Rebecca J.

AU - Kapur, Reuben

PY - 2014/11/20

Y1 - 2014/11/20

N2 - 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.

AB - 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.

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

Abstract

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ASJC Scopus subject areas

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