title: Rho kinase regulates the survival and transformation of cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL.
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.
authors: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, USA.
authors: Raghuveer Singh
authors: RS
authors: Mali
authors: Baskar
authors: B
authors: Ramdas
authors: Peilin
authors: P
authors: Ma
authors: Jianjian
authors: J
authors: Shi
authors: Veerendra
authors: V
authors: Munugalavadla
authors: Emily
authors: E
authors: Sims
authors: Lei
authors: L
authors: Wei
authors: Sasidhar
authors: S
authors: Vemula
authors: Sarah C
authors: SC
authors: Nabinger
authors: Charles B
authors: CB
authors: Goodwin
authors: Rebecca J
authors: RJ
authors: Chan
authors: Fabiola
authors: F
authors: Traina
authors: Valeria
authors: V
authors: Visconte
authors: Ramon V
authors: RV
authors: Tiu
authors: Timothy A
authors: TA
authors: Lewis
authors: Andrew M
authors: AM
authors: Stern
authors: Qiang
authors: Q
authors: Wen
authors: John D
authors: JD
authors: Crispino
authors: H Scott
authors: HS
authors: Boswell
authors: Reuben
authors: R
authors: Kapur
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009196:Myeloproliferative Disorders / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018994:Myosin Light Chains / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D019089:Stem Cell Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051941:fms-Like Tyrosine Kinase 3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D018994:Myosin Light Chains; D034741:RNA, Small Interfering; D019089:Stem Cell Factor; D019869:Phosphatidylinositol 3-Kinases; C497970:FLT3 protein, human; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D016044:Fusion Proteins, bcr-abl; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins