Rho Kinase Regulates the Survival and Transformation of Cells Bearing Oncogenic Forms of KIT, FLT3, and BCR-ABL

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2011 Sep 13

PMID 21907926

Citations 57

Authors

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

Affiliations

Soon will be listed here.

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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References

Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S . Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998; 279(5350):577-80. DOI: 10.1126/science.279.5350.577. View

Shirao S, Kashiwagi S, Sato M, Miwa S, Nakao F, Kurokawa T . Sphingosylphosphorylcholine is a novel messenger for Rho-kinase-mediated Ca2+ sensitization in the bovine cerebral artery: unimportant role for protein kinase C. Circ Res. 2002; 91(2):112-9. DOI: 10.1161/01.res.0000026057.13161.42. View

Sebbagh M, Renvoize C, Hamelin J, Riche N, Bertoglio J, Breard J . Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat Cell Biol. 2001; 3(4):346-52. DOI: 10.1038/35070019. View

Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M . Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science. 1996; 273(5272):245-8. DOI: 10.1126/science.273.5272.245. View

Leung T, Chen X, Manser E, Lim L . The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton. Mol Cell Biol. 1996; 16(10):5313-27. PMC: 231530. DOI: 10.1128/MCB.16.10.5313. View

Terauchi Y, Tsuji Y, Satoh S, Minoura H, Murakami K, Okuno A . Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nat Genet. 1999; 21(2):230-5. DOI: 10.1038/6023. View

Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H . Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia. 1998; 12(9):1333-7. DOI: 10.1038/sj.leu.2401130. View

Demetri G, von Mehren M, Blanke C, Van Den Abbeele A, Eisenberg B, Roberts P . Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002; 347(7):472-80. DOI: 10.1056/NEJMoa020461. View

Riento K, Ridley A . Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol. 2003; 4(6):446-56. DOI: 10.1038/nrm1128. View

10.

Greenman C, Stephens P, Smith R, Dalgliesh G, Hunter C, Bignell G . Patterns of somatic mutation in human cancer genomes. Nature. 2007; 446(7132):153-8. PMC: 2712719. DOI: 10.1038/nature05610. View

11.

Lugo T, Pendergast A, Muller A, Witte O . Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990; 247(4946):1079-82. DOI: 10.1126/science.2408149. View

12.

Koschmieder S, Gottgens B, Zhang P, Iwasaki-Arai J, Akashi K, Kutok J . Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis. Blood. 2004; 105(1):324-34. DOI: 10.1182/blood-2003-12-4369. View

13.

Lange B, Valtieri M, Santoli D, Caracciolo D, Mavilio F, Gemperlein I . Growth factor requirements of childhood acute leukemia: establishment of GM-CSF-dependent cell lines. Blood. 1987; 70(1):192-9. View

14.

Pratz K, Sato T, Murphy K, Stine A, Rajkhowa T, Levis M . FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood. 2009; 115(7):1425-32. PMC: 2826764. DOI: 10.1182/blood-2009-09-242859. View

15.

Daley G, Van Etten R, Baltimore D . Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990; 247(4944):824-30. DOI: 10.1126/science.2406902. View

16.

Frost M, Ferrao P, Hughes T, Ashman L . Juxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. Mol Cancer Ther. 2002; 1(12):1115-24. View

17.

Elson E . Cellular mechanics as an indicator of cytoskeletal structure and function. Annu Rev Biophys Biophys Chem. 1988; 17:397-430. DOI: 10.1146/annurev.bb.17.060188.002145. View

18.

Zhang Y, Bo J, Taffet G, Chang J, Shi J, Reddy A . Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosis. FASEB J. 2006; 20(7):916-25. DOI: 10.1096/fj.05-5129com. View

19.

Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K . Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996; 10(12):1911-8. View

20.

Vemula S, Ramdas B, Hanneman P, Martin J, Beggs H, Kapur R . Essential role for focal adhesion kinase in regulating stress hematopoiesis. Blood. 2010; 116(20):4103-15. PMC: 2993618. DOI: 10.1182/blood-2010-01-262790. View