Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative disease.
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by expression of the p210-BCR-ABL fusion protein. We demonstrate in a murine model of p210-BCR-ABL-induced MPD that gene targeting of Rac1 and Rac2 significantly delays or abrogates disease development. Attenuation of the disease phenotype is associated with severely diminished p210-BCR-ABL-induced downstream signaling in primary hematopoietic cells. We utilize NSC23766, a small molecule antagonist of Rac activation, to validate biochemically and functionally Rac as a molecular target in both a relevant animal model and in primary human CML cells in vitro and in a xenograft model in vivo, including in Imatinib-resistant p210-BCR-ABL disease. These data demonstrate that Rac is an additional therapeutic target in p210-BCR-ABL-mediated MPD.
Thomas
Emily K
EK
Division of Experimental Hematology, Cincinnati Children's Research Foundation, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Cancelas
Jose A
JA
Chae
Hee-Don
HD
Cox
Adrienne D
AD
Keller
Patricia J
PJ
Perrotti
Danilo
D
Neviani
Paolo
P
Druker
Brian J
BJ
Setchell
Kenneth D R
KD
Zheng
Yi
Y
Harris
Chad E
CE
Williams
David A
DA
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D009368:Neoplasm Transplantation; D010641:Phenotype; D011743:Pyrimidines / Q000494:pharmacology; D020744:rac GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein
D000634:Aminoquinolines; D018952:Antigens, CD34; D016044:Fusion Proteins, bcr-abl; D011743:Pyrimidines; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C487513:NSC 23766; C107953:RAC1 protein, human