miR-15 and miR-16 induce apoptosis by targeting BCL2. Chronic lymphocytic leukemia (CLL) is characterized by B cells overexpressing the antiapoptotic BCL2 protein. miR-15a and miR-16-1 are deleted or down-regulated in most CLLs. The study shows that miR-15a and miR-16-1 expression is inversely correlated with BCL2 expression in CLL and that both microRNAs negatively regulate BCL2 at the posttranscriptional level. BCL2 repression by these microRNAs induces apoptosis in a leukemic cell line model. Therefore, miR-15 and miR-16 are natural antisense Bcl2 interactors that could be used for therapy of Bcl2-overexpressing tumors. BCL2 is a central player in the genetic program of eukaryotic cells favoring survival by inhibiting cell death. Overexpression of BCL2 has been reported in many types of human cancers. In CLL, BCL2 overexpression is linked to the disease's pathogenesis. miRNAs are a class of genes involved in human tumorigenesis. miR-15a and miR-16-1 are located in a cluster at 13q14.3 and their down-regulation is found in approximately 65% of B cell CLL patients. The study identifies a mechanism of regulation of BCL2 expression in hematopoietic cancer cells consisting of posttranscriptional down-regulation by miR-15 and miR-16. This interaction has an important functional consequence: the activation of the intrinsic apoptosis pathway. The study confirms that miR-15 and miR-16 directly interact with the 3'UTR of BCL2, leading to its repression and subsequent apoptosis. The results show that miR-15 and miR-16 can be used as therapeutic targets for BCL2-overexpressing tumors. The study also discusses the dual role of miRNAs as oncogenes or tumor suppressors, depending on the cell type and target. The findings highlight the importance of miR-15 and miR-16 in the regulation of BCL2 and their potential as therapeutic agents in BCL2-overexpressing cancers.miR-15 and miR-16 induce apoptosis by targeting BCL2. Chronic lymphocytic leukemia (CLL) is characterized by B cells overexpressing the antiapoptotic BCL2 protein. miR-15a and miR-16-1 are deleted or down-regulated in most CLLs. The study shows that miR-15a and miR-16-1 expression is inversely correlated with BCL2 expression in CLL and that both microRNAs negatively regulate BCL2 at the posttranscriptional level. BCL2 repression by these microRNAs induces apoptosis in a leukemic cell line model. Therefore, miR-15 and miR-16 are natural antisense Bcl2 interactors that could be used for therapy of Bcl2-overexpressing tumors. BCL2 is a central player in the genetic program of eukaryotic cells favoring survival by inhibiting cell death. Overexpression of BCL2 has been reported in many types of human cancers. In CLL, BCL2 overexpression is linked to the disease's pathogenesis. miRNAs are a class of genes involved in human tumorigenesis. miR-15a and miR-16-1 are located in a cluster at 13q14.3 and their down-regulation is found in approximately 65% of B cell CLL patients. The study identifies a mechanism of regulation of BCL2 expression in hematopoietic cancer cells consisting of posttranscriptional down-regulation by miR-15 and miR-16. This interaction has an important functional consequence: the activation of the intrinsic apoptosis pathway. The study confirms that miR-15 and miR-16 directly interact with the 3'UTR of BCL2, leading to its repression and subsequent apoptosis. The results show that miR-15 and miR-16 can be used as therapeutic targets for BCL2-overexpressing tumors. The study also discusses the dual role of miRNAs as oncogenes or tumor suppressors, depending on the cell type and target. The findings highlight the importance of miR-15 and miR-16 in the regulation of BCL2 and their potential as therapeutic agents in BCL2-overexpressing cancers.