KLF4 suppresses transformation of pre-B cells by ABL oncogenes

• Published in: Blood 2007-01, Vol.109 (2), p.747-755
• Main Authors: Kharas, Michael G., Yusuf, Isharat, Scarfone, Vanessa M., Yang, Vincent W., Segre, Julia A., Huettner, Claudia S., Fruman, David A.
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; Biological and medical sciences; Cell Cycle; Cell Death; Cell Transformation, Neoplastic - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; G1 Phase; Gene Expression Regulation, Leukemic - genetics; Hematologic and hematopoietic diseases; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Medical sciences; Mice; Mice, Transgenic; Neoplasia; Oncogene Proteins v-abl - genetics; Oncogene Proteins v-abl - metabolism; Salivary alpha-Amylases; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-03-011106

Genes that are strongly repressed after B-cell activation are candidates for being inactivated, mutated, or repressed in B-cell malignancies. Krüppel-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 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.