Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice

MicroRNAs and cancer: Profile, profile, profile

“…Strongly supporting this paradigm are the results by Raveche et al describing abnormal miR-16 locus with synteny to human 13q14 linked to CLL in New Zealand Black (NZB) mice. 53 Together these 2 studies, one in human CLL and the second in a mouse model of the human disease confirm that miR-16 is the first example of a miRNA involved in cancer predisposition. 22,54 The frequency of this predisposing event in various kindreds with familial cancers should be investigated by large association studies.…”

Role of miR-15/16 in CLL

“…46 An experiment of genome-wide linkage scan conducted in the laboratory of Dr. Raveche identified the loci associated with CLL development in this strain. 47 Thirty-five percent of the animals generated from the backcross between NZB and the control strain DBA/2 presented with lymphoproliferative disease (LPD) of B cells. Three loci located on chromosomes 14, 18, and 19 were found to be associated with this disease.…”

“…Half of all cases of human CLL show a deletion on chromosome 13q14.3 whose region is syntenic with the region on NZB chromosome 14 where the locus associated with LPD was found. 47 The miR-15/16 cluster, contained in an intron of the gene DLEU2, is present in both human and mouse regions of synteny. Interestingly, by DNA sequencing of multiple NZB tissues, a point mutation in the 3 0 -flanking segment of the precursor miRNA, miR-16-1, was found to resemble the C-T point mutation previously identified in the miR-16-1 3 0 -flanking region of human patients.…”

“…Interestingly, by DNA sequencing of multiple NZB tissues, a point mutation in the 3 0 -flanking segment of the precursor miRNA, miR-16-1, was found to resemble the C-T point mutation previously identified in the miR-16-1 3 0 -flanking region of human patients. 20,47 No other strain of mice, including the NZW strain, the closest relative of NZB, was found to carry the same mutation. As expected, analysis of the levels of mature miRNA revealed a reduced expression of miR-16 in lymphoid tissues of NZB mice.…”

“…In addition, cell cycle alterations such as G1 arrest and decrease in S phase cells were induced by exogenous miR-16 delivery into a NZB malignant cell line. 47 To confirm the importance of miR-15/16 deletion in the pathogenesis of CLL, Dr. Dalla-Favera's laboratory generated the first genetically manipulated mice. 48 This model was based on conditional alleles mimicking the loss of either the minimal deleted region (MDR) that spans the entire gene Dleu2, as was characterized in human CLL, or only the miR-15/16 cluster with no altered expression of Dleu2.…”