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Molecular and Cellular Biology, July 2005, p. 5777-5785, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5777-5785.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Generation of rac3 Null Mutant Mice: Role of Rac3 in Bcr/Abl-Caused Lymphoblastic Leukemia

Young Jin Cho,1,{dagger} Bin Zhang,1,{dagger} Vesa Kaartinen,2 Leena Haataja,1,{ddagger} Ivan de Curtis,3 John Groffen,1 and Nora Heisterkamp1*

Section of Molecular Carcinogenesis, Division of Hematology/Oncology,1 Developmental Biology Program, Departments of Pathology and Surgery, Childrens Hospital Los Angeles, and Saban Research Institute and Keck School of Medicine, University of Southern California, Los Angeles, California,2 Cell Adhesion Unit, Department of Molecular Biology and Functional Genomics, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy3

Received 30 November 2004/ Returned for modification 18 January 2005/ Accepted 8 April 2005

Numerous studies indirectly implicate Rac GTPases in cancer. To investigate if Rac3 contributes to normal or malignant cell function, we generated rac3 null mutants through gene targeting. These mice were viable, fertile, and lacked an obvious external phenotype. This shows Rac3 function is dispensable for embryonic development. Bcr/Abl is a deregulated tyrosine kinase that causes chronic myelogenous leukemia and Ph-positive acute lymphoblastic leukemia in humans. Vav1, a hematopoiesis-specific exchange factor for Rac, was constitutively tyrosine phosphorylated in primary lymphomas from Bcr/Abl P190 transgenic mice, suggesting inappropriate Rac activation. rac3 is expressed in these malignant hematopoietic cells. Using lysates from BCR/ABL transgenic mice that express or lack rac3, we detected the presence of activated Rac3 but not Rac1 or Rac2 in the malignant precursor B-lineage lymphoblasts. In addition, in female P190 BCR/ABL transgenic mice, lack of rac3 was associated with a longer average survival. These data are the first to directly show a stimulatory role for Rac in leukemia in vivo. Moreover, our data suggest that interference with Rac3 activity, for example, by using geranyl-geranyltransferase inhibitors, may provide a positive clinical benefit for patients with Ph-positive acute lymphoblastic leukemia.

* Corresponding author. Mailing address: Division of Hematology/Oncology Ms#54, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027. Phone: 323-669-4595. Fax: 323-671-3613. E-mail: heisterk{at}hsc.usc.edu.

{dagger} These authors had equal contributions.

{ddagger} Present address: Larry Hillblom Islet Research Center, UCLA Division of Endocrinology, 900 Veteran Avenue, Los Angeles, CA 90095-7073.

Molecular and Cellular Biology, July 2005, p. 5777-5785, Vol. 25, No. 13
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.13.5777-5785.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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