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

Cho, Young Jin, Zhang, Bin, Kaartinen, Vesa, Haataja, Leena, de Curtis, Ivan, Groffen, John, Heisterkamp, Nora·2005·Molecular and Cellular Biology
DOI 10.1128/mcb.25.13.5777-5785.2005
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Abstract

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.

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Cited by

Metadata

Authors
Cho, Y. J., Zhang, B., Kaartinen, V., Haataja, L., de Curtis, I., Groffen, J., & Heisterkamp, N.
Affiliations
  • Section of Molecular Carcinogenesis, Division of Hematology/Oncology
  • 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
  • Cell Adhesion Unit, Department of Molecular Biology and Functional Genomics, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2005-07-01
Volume
25
Issue
13
Pages
5777-5785
ISSN
1098-5549
DOI
10.1128/mcb.25.13.5777-5785.2005
Cited by
50
References
0
Language
en
Licence
journals.asm.org/non-commercial-tdm-license (tdm)

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