KLF4 suppresses transformation of pre-B cells by ABL oncogenes.
Genes that are strongly repressed after B-cell activation are candidates for being inactivated, mutated, or repressed in B-cell malignancies. Kr??ppel-like factor 4 (Klf4), a gene down-regulated 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 G(1) phase of the cell cycle. KLF4-mediated death, but not cell-cycle arrest, can be rescued by Bcl-X(L) overexpression. Transformed pro/pre-B cells expressing KLF4 display increased expression of p21(CIP) 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.[1]References
- KLF4 suppresses transformation of pre-B cells by ABL oncogenes. Kharas, M.G., Yusuf, I., Scarfone, V.M., Yang, V.W., Segre, J.A., Huettner, C.S., Fruman, D.A. Blood (2007) [Pubmed]
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