Related Experiment Video
Updated: Aug 17, 2026
Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
Published on: January 7, 2019
Generation of rac3 null mutant mice: role of Rac3 in Bcr/Abl-caused lymphoblastic leukemia
Young Jin Cho1, Bin Zhang, Vesa Kaartinen
1Section of Molecular Carcinogenesis, Division of Hematology/Oncology Ms#54, Childrens Hospital Los Angeles, University of Southern California 4650 Sunset Boulevard, Los Angeles, California 90027, USA.
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.
Insights
Rac3 GTPase is not essential for embryonic development but plays a stimulatory role in leukemia. Eliminating Rac3 in mice prolonged survival, suggesting Rac3 inhibition may benefit patients with Ph-positive acute lymphoblastic leukemia.
Area of Science:
- Molecular biology
- Oncology
- Genetics
Background:
- Rac GTPases are indirectly implicated in various cancers.
- The specific role of Rac3 in normal and malignant cell function requires further investigation.
- Bcr/Abl tyrosine kinase is associated with human leukemias, and Vav1 activation suggests aberrant Rac signaling.
Purpose of the Study:
- To investigate the role of Rac3 in normal development and malignant cell function.
- To determine if Rac3 contributes to Bcr/Abl-induced leukemia in vivo.
- To explore Rac3 as a potential therapeutic target for Ph-positive acute lymphoblastic leukemia.
Main Methods:
- Generation of rac3 null mutant mice through gene targeting.
- Analysis of Bcr/Abl P190 transgenic mice expressing or lacking rac3.
- Detection of activated Rac GTPases in malignant hematopoietic cells.
Main Results:
- Rac3 null mice were viable and fertile, indicating Rac3 is dispensable for embryonic development.
- Activated Rac3, but not Rac1 or Rac2, was detected in Bcr/Abl-induced malignant lymphoblasts.
- Lack of rac3 was associated with increased survival in female P190 Bcr/Abl transgenic mice.
Conclusions:
- This study provides the first direct evidence for a stimulatory role of Rac GTPases in leukemia development in vivo.
- Rac3 is implicated in the progression of Bcr/Abl-induced leukemia.
- Targeting Rac3 activity, potentially with geranyl-geranyltransferase inhibitors, may offer clinical benefits for patients with Ph-positive acute lymphoblastic leukemia.
Related Concept Videos
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
02:38The Ras Gene
Ras is a superfamily...
01:24Small GTPases - Ras and Rho
Three regulatory proteins control their activity: