Regulation of leukemic cell adhesion, proliferation, and survival by -catenin

In epithelial cells -catenin plays a critical role as a component of the cell-cell adhesion apparatus and as a coactivator of the TCF/LEF (T-cell transcription factor/lymphoid enhancer binding factor) family of transcription factors. Deregulation of -catenin has been implicated in the malignant transformation of cells of epithelial origin. However, a function for -catenin in hematologic malignancies has not been reported. -Catenin is not detectable in normal peripheral blood T cells but is expressed in T–acute lymphoblastic leukemia cells and other tumor lines of hematopoietic origin and in primary lymphoid and myeloid leukemia cells. -Catenin function was examined in Jurkat T–acute lymphoblastic leukemia cells. Overexpression of dominant-negative -catenin or dominant-negative TCF reduced -catenin nuclear signaling and inhibited Jurkat proliferation and clonogenicity. Similarly, these constructs inhibited proliferation of K562 and HUT-102 cells. Reduction of -catenin expression with -catenin antisense down-regulated adhesion of Jurkat cells in response to phytohemagglutinin. Incubation of Jurkat cells with anti-Fas induced caspasedependent limited proteolysis of -catenin Nand C-terminal regions and rapid redistribution of -catenin to the detergent-insoluble cytoskeleton, concomitant with a marked decline in nuclear -catenin signaling. Fas-mediated apoptosis was potentiated by inhibition of -catenin nuclear signaling. The data suggest that -catenin can play a significant role in promoting leukemic cell proliferation, adhesion, and survival. (Blood. 2002; 100:982-990)