After Carlo Croce stressed the importance of the miR-15 and 16 genes in del 13q14 CLL we had a bit of problem because the smallest minimally deleted region (MDR) that we had found in Bournemouth excluded those genes. Many deletions did include them, but a significant number did not. Now an explanation is available . The paper is part of the collaboration between Bournemouth and the Karolinska. One of our stars, Martin Corcoran has gone to work in Stockholm to carry on this endeavor.
It turns out that the Leu2 gene, which is in the MDR of 13q14 acts as a promoter gene for miR-15a and miR-16-1, so that if it is deleted they are down regulated. In several cases they were able to show that miR-15a and miR-16-1 were intact, but non-functional because the Leu2 gene was deleted. Although the miR genes have been shown to have an effect on bcl-2, it appears that the more important effect is on the G1 Cyclins E1 and D1. Leu2 negatively regulates these oncoproteins through the effects of miR-15a and miR-16-1. This deletion of either Leu2 or the miR genes will allow cell proliferation to increase because the G Cyclins have lost their braking system.
Further information that comes from this paper demonstrates that Leu2 is negatively regulated by the Myc oncoprotein, which is activated in many hematological malignancies and might be involved in some cases of Richter's transformation.