Invariant Deletion of One Mir-34b/C Locus in CLL with del11q.

Abstract

CLL with del11q constitutes a clinical syndrome characterized by a relatively aggressive disease course, short response duration to therapies and compromised overall survival. CLL with del11q carries mutations in ATM in about one third of cases, which may further negatively affect prognosis. Little is known about additional molecular changes within or due to del11q in CLL and it remains unclear what the selective advantage of acquisition of del11q is for CLL cells.To gain insights into the physiology of CLL with del11q, we have mapped this lesion using the Affymetrix 50K SNP array platform in 178 CLL cases using DNA from sorted CD19+ cells versus paired buccal DNA. Focusing on the region that spans ATM, a minimal deleted region (MDR) of approximately 8 Mb was identified, spanning approximately 106.6–114.6 Mb physical position.Scanning the MDR for genes with the potential to affect the physiology of cancerous cells uncovered invariant monoallelic deletion of the miR-34b/c gene, the only known human microRNA gene within the del11q MDR. miR-34a-c have been implicated as direct p53 target genes by a number of groups and these microRNAs have been shown to be direct regulators of pro-proliferative and anti-apoptotic genes, including E2F3, Cyclin E2, Cdk6 and Bcl2. Given that ATM acts upstream of p53 in the ds-DNA damage response pathway, it appears that del11q lesions in CLL affect p53 apoptotic effector functions through two independent processes (ATM loss or mutation and miR-34b/c loss).Work is in progress measuring miR-34 b/c expression levels in a large CLL cohort and correlating miR-34b/c levels with expression levels of critical miR-34 targets in CLL. In summary, our data implicate miR-34b/c loss as a potential contributor to the physiology of del11q in CLL and should stimulate investigations into miR-34 function as a response predictor of therapy for CLL.