Chunk #4 — Introduction — MiR-15/16 and DLEU7 at 13q14: a unique collaboration of coding and noncoding genes in indolent CLL — MiR-15/16 at 13q14, discovery and function
5 of LEU2 gene [12, 13]. The translocation breakpoint was mapped in the same region [12]. Since LEU2 had previously been excluded as a likely candidate tumor suppressor gene in CLL [8, 9, 11, 14] we continued to search for genes within the region and finally discovered that a cluster of two noncoding microRNA genes miR-15a and miR-16-1, is located precisely within the deleted region ant at the translocation breakpoint [12]. Interestingly, this miR-15a/miR-16-1 cluster is deleted or down-regulated in ~66% of CLL cases [12]. In contrast, expression of other genes in the region such as DLEU1, DLEU2, RFP5 did not seem affected by 13q14 deletions [8, 9, 13]. To determine possible mechanism of miR-15/16 tumor suppressor function, subsequent study examined expression levels of miR-15/16 and BCL2 (a predicted target of both, miR-15 and miR-16) in CLL [15]. These results showed that miR-15a and miR-16-1 expression is inversely correlated to Bcl2 expression in CLL and that both microRNAs negatively regulate BCL2 at a posttranscriptional level [15]. Consequently, BCL2 repression by these microRNAs induces apoptosis in a leukemic cell line [15], and miR-15/16 showed a tumor suppressor function in vivo by inhibiting the growth of tumor engraftments of leukemic cells in
