BCL2 and miR-15/16: from gene discovery to treatment

• Published in: Cell death and differentiation 2018-01, Vol.25 (1), p.21-26
• Main Authors: Pekarsky, Yuri, Balatti, Veronica, Croce, Carlo M
• Format: Article
• Language: English
• Subjects: 631/80; 692/699/67/68; Animals; Antineoplastic Agents - therapeutic use; Apoptosis; Biochemistry; Biomedical and Life Sciences; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cancer; Cell Biology; Cell Cycle Analysis; Chromosome 14; Chromosome 18; Chromosome Deletion; Chromosome Disorders - genetics; Chromosome translocations; Chromosomes; Chromosomes, Human, Pair 13 - genetics; Chronic lymphocytic leukemia; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Life Sciences; Lymphatic leukemia; Lymphoma; Mice; MicroRNAs - genetics; miRNA; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Review; Stem Cells; Sulfonamides - therapeutic use
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2017.159

In 1984, we investigated the t(14;18) chromosomal translocations that frequently occur in patients with follicular lymphoma. We first identified a locus on chromosome 18 involved in these translocations with the chromosome 14 containing the immunoglobulin heavy chain locus. Within this region on chromosome 18, we then discovered a gene that we called BCL2 , which was activated by the translocations. Since that time, many studies determined that BCL2 is one of the most important oncogenes involved in cancer by inhibiting apoptosis. In 2002, we studied 13q deletions in chronic lymphocytic leukemia (CLL) and found that the microRNA cluster miR-15a/miR-16-1 ( miR-15/16 ) is deleted by 13q deletions. In 2005, we discovered that miR-15/16 function as tumor suppressors by directly targeting BCL2 . Thus the loss of two negative regulators of BCL2 expression results in overexpression of BCL2 . Very recently, a specific BCL2 inhibitor ABT-199 (Venetoclax) was developed and approved by FDA for CLL treatment. Thus it took 32 years from fundamental discovery of a critical oncogene to the development of a drug capable to cure CLL. In this review, we discuss the discovery, functions and clinical relevance of miR-15/16 and BCL2 .