Submitted March 20, 2006
Accepted August 18, 2006
KLF4 suppresses transformation of pre-B cells ABL oncogenes
Michael G. Kharas, Isharat Yusuf, Vanessa M. Scarfone, Vincent W. Yang, Julie A. Segre, Claudia S. Huettner, and David A. Fruman*
Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine,, CA
Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, CA
Department of Medicine, Emory University, Atlanta, GA
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
The Blood Center of SE Wisconsin, Milwaukee, WI
Dep. of Molecular Biology and Biochemistry, Center for Immunology, University of California-Irvine
* Corresponding author; email: dfruman{at}uci.edu.
Genes that are strongly repressed after B-cell activation are candidates for being inactivated, mutated, or repressed in B-cell malignancies. Kruppel-like factor 4 (Klf4), a gene downregulated in activated murine B cells, is expressed at low levels in several types of human B-cell lineage lymphomas and leukemias. The human Klf4 gene has been identified as a tumor suppressor gene in colon and gastric cancer; in concordance with this, overexpression of KLF4 can suppress proliferation in several epithelial cell types. Here we investigate the effects of KLF4 on pro/pre-B cell transformation by v-Abl and BCR-ABL, oncogenes that cause leukemia in mice and humans. We show that overexpression of KLF4 induces arrest and apoptosis in the G1 phase of the cell cycle. KLF4-mediated death, but not cell cycle arrest, can be rescued by Bcl-XL overexpression. Transformed pro/pre-B cells expressing KLF4 display increased expression of p21CIP and decreased expression of c-Myc and cyclin D2. Tetracycline-inducible expression of KLF4 in B cell progenitors of transgenic mice blocks transformation by BCR-ABL and depletes leukemic pre-B cells in vivo. Collectively our work identifies KLF4 as a putative tumor suppressor in B-cell malignancies.
