deletion of the Mdr can cause disease. This trend is not evident in miR-15a/16-1-deleted mice, probably due to the lower penetrance of the phenotype. Mdr−/− mice died earlier than their wild type littermates, suggesting that the homozygous mice eventually succumb to their tumors at an advanced age [56, 57]. On the contrary, the survival of miR-15a/16-1−/− mice was not significantly different from wild type littermates, suggesting that these mice show a milder disease course than their Mdr counterparts. In conclusion, both Mdr−/− and miR-15a/16-1−/− mice developed lymphoproliferations with an indolent disease course reminiscent of human CLL, with Mdr−/− mice displaying a more aggressive phenotype. The significantly more aggressive phenotype displayed by Mdr−/− mice suggests that additional genetic elements within the MDR locus may contribute to the tumor suppressive function. One candidate for such a role is the DLEU2 gene itself. Besides providing the primary transcript for the production of miR-15a/16-1, it produces a spliced cytoplasmic RNA that may have important regulatory functions not yet detected [56, 57].
