Rho kinase regulates the survival and transformation of cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL

Raghuveer Singh Mali; Baskar Ramdas; Peilin Ma; Jianjian Shi; Veerendra Munugalavadla; Emily Sims; Lei Wei; Sasidhar Vemula; Sarah C. Nabinger; Charles B. Goodwin; Rebecca J. Chan; Fabiola Traina; Valeria Visconte; Ramon V. Tiu; Timothy A. Lewis; Andrew M. Stern; Qiang Wen; John D. Crispino; H. Scott Boswell; Reuben Kapur

doi:10.1016/j.ccr.2011.07.016

Rho kinase regulates the survival and transformation of cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL

Raghuveer Singh Mali, Baskar Ramdas, Peilin Ma, Jianjian Shi, Veerendra Munugalavadla, Emily Sims, Lei Wei, Sasidhar Vemula, Sarah C. Nabinger, Charles B. Goodwin, Rebecca J. Chan, Fabiola Traina, Valeria Visconte, Ramon V. Tiu, Timothy A. Lewis, Andrew M. Stern, Qiang Wen, John D. Crispino, H. Scott Boswell, Reuben Kapur

Research output: Contribution to journal › Article

55 Scopus citations

Abstract

We show constitutive activation of Rho kinase (ROCK) in cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL, which is dependent on PI3K and Rho GTPase. Genetic or pharmacologic inhibition of ROCK in oncogene-bearing cells impaired their growth as well as the growth of acute myeloid leukemia patient-derived blasts and prolonged the life span of mice bearing myeloproliferative disease. Downstream from ROCK, rapid dephosphorylation or loss of expression of myosin light chain resulted in enhanced apoptosis, reduced growth, and loss of actin polymerization in oncogene-bearing cells leading to significantly prolonged life span of leukemic mice. In summary we describe a pathway involving PI3K/Rho/ROCK/MLC that may contribute to myeloproliferative disease and/or acute myeloid leukemia in humans.

Original language	English (US)
Pages (from-to)	357-369
Number of pages	13
Journal	Cancer Cell
Volume	20
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2011.07.016
State	Published - Sep 1 2011

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ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

Cite this

Mali, R. S., Ramdas, B., Ma, P., Shi, J., Munugalavadla, V., Sims, E., Wei, L., Vemula, S., Nabinger, S. C., Goodwin, C. B., Chan, R. J., Traina, F., Visconte, V., Tiu, R. V., Lewis, T. A., Stern, A. M., Wen, Q., Crispino, J. D., Boswell, H. S., & Kapur, R. (2011). Rho kinase regulates the survival and transformation of cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL. Cancer Cell, 20(3), 357-369. https://doi.org/10.1016/j.ccr.2011.07.016

Rho kinase regulates the survival and transformation of cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL. / Mali, Raghuveer Singh; Ramdas, Baskar; Ma, Peilin; Shi, Jianjian; Munugalavadla, Veerendra; Sims, Emily; Wei, Lei; Vemula, Sasidhar; Nabinger, Sarah C.; Goodwin, Charles B.; Chan, Rebecca J.; Traina, Fabiola; Visconte, Valeria; Tiu, Ramon V.; Lewis, Timothy A.; Stern, Andrew M.; Wen, Qiang; Crispino, John D.; Boswell, H. Scott ; Kapur, Reuben.

In: Cancer Cell, Vol. 20, No. 3, 01.09.2011, p. 357-369.

Research output: Contribution to journal › Article

Mali, RS, Ramdas, B, Ma, P, Shi, J, Munugalavadla, V, Sims, E, Wei, L, Vemula, S, Nabinger, SC, Goodwin, CB, Chan, RJ, Traina, F, Visconte, V, Tiu, RV, Lewis, TA, Stern, AM, Wen, Q, Crispino, JD, Boswell, HS & Kapur, R 2011, 'Rho kinase regulates the survival and transformation of cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL', Cancer Cell, vol. 20, no. 3, pp. 357-369. https://doi.org/10.1016/j.ccr.2011.07.016

Mali, Raghuveer Singh ; Ramdas, Baskar ; Ma, Peilin ; Shi, Jianjian ; Munugalavadla, Veerendra ; Sims, Emily ; Wei, Lei ; Vemula, Sasidhar ; Nabinger, Sarah C. ; Goodwin, Charles B. ; Chan, Rebecca J. ; Traina, Fabiola ; Visconte, Valeria ; Tiu, Ramon V. ; Lewis, Timothy A. ; Stern, Andrew M. ; Wen, Qiang ; Crispino, John D. ; Boswell, H. Scott ; Kapur, Reuben. / Rho kinase regulates the survival and transformation of cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL. In: Cancer Cell. 2011 ; Vol. 20, No. 3. pp. 357-369.

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abstract = "We show constitutive activation of Rho kinase (ROCK) in cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL, which is dependent on PI3K and Rho GTPase. Genetic or pharmacologic inhibition of ROCK in oncogene-bearing cells impaired their growth as well as the growth of acute myeloid leukemia patient-derived blasts and prolonged the life span of mice bearing myeloproliferative disease. Downstream from ROCK, rapid dephosphorylation or loss of expression of myosin light chain resulted in enhanced apoptosis, reduced growth, and loss of actin polymerization in oncogene-bearing cells leading to significantly prolonged life span of leukemic mice. In summary we describe a pathway involving PI3K/Rho/ROCK/MLC that may contribute to myeloproliferative disease and/or acute myeloid leukemia in humans.",

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AU - Shi, Jianjian

AU - Munugalavadla, Veerendra

AU - Sims, Emily

AU - Wei, Lei

AU - Vemula, Sasidhar

AU - Nabinger, Sarah C.

AU - Goodwin, Charles B.

AU - Chan, Rebecca J.

AU - Traina, Fabiola

AU - Visconte, Valeria

AU - Tiu, Ramon V.

AU - Lewis, Timothy A.

AU - Stern, Andrew M.

AU - Wen, Qiang

AU - Crispino, John D.

AU - Boswell, H. Scott

AU - Kapur, Reuben

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AB - We show constitutive activation of Rho kinase (ROCK) in cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL, which is dependent on PI3K and Rho GTPase. Genetic or pharmacologic inhibition of ROCK in oncogene-bearing cells impaired their growth as well as the growth of acute myeloid leukemia patient-derived blasts and prolonged the life span of mice bearing myeloproliferative disease. Downstream from ROCK, rapid dephosphorylation or loss of expression of myosin light chain resulted in enhanced apoptosis, reduced growth, and loss of actin polymerization in oncogene-bearing cells leading to significantly prolonged life span of leukemic mice. In summary we describe a pathway involving PI3K/Rho/ROCK/MLC that may contribute to myeloproliferative disease and/or acute myeloid leukemia in humans.

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10.1016/j.ccr.2011.07.016