Loss of miR-15/16 in cancer

Carlo M. Croce, MD

Loss of miR-15a and -16-1 on chromosome 13q14 is the most common genetic change in CLL. We discovered that these microRNAs target BCL2, that is overexpressed in CLL since these two microRNAs are negative regulators of BCL2 expression. Recently we also found that they also regulate ROR1, an embryonal surface antigen, also overexpressed in the great majority of CLLs.

We knocked out both loci of miR-15/16, that in human map on chromosome 13q14 and 3q25 respectively, in the mouse. Most of the double KO mice (77%) developed AML, suggesting that the double KO of miR-15/16 could lead to the development of AML also in humans. We then tested 139 AML cases and 14 different AML cell lines by assessing miRNA expression, targeting protein expression, genetic loos and silencing. At the same time, we analyzed 93 cases of MDS. 79% of primary AML showed reduced expression of both miR-15 a and miR-15b. Furthermore, 40% of AML cell lines showed a reduced expression of miR-15a and miR-15b and overexpression of their direct/indirect targets. Similarly, MDS transforming into AML and AMLs derived from MDS showed combined loss of expression of these microRNAs.

Moreover, Blastic Crisis CML showed a reduction of the expression of miR-15a/-15b/16 compared to CML in chronic phase and overexpression of their targets.

Stratification of AML patients based on mir-15/16 expression could lead to targeted and combination therapies for this incurable disease.