Investigations on microRNAs in human chronic lymphocytic leukemia and control of cancer-associated molecular pathways

A variety of studies on microRNAs in human chronic lymphocytic leukemia (CLL) opened the way to the assessment of the importance of this large class of genes in human cancer. The first example of involvement of miRNAs in a human neoplasm was provided by the discovery of mir-15a and mir-16-1 locus within the minimal region of deletion at chromosome 13q14 in human CLL. The proof that a large number of miRNAs are deregulated in malignant cells was initially given by genome-wide expression studies of miRNAs in CLL. The finding of a prognostic miRNA signature was discovered in human CLL. One of the first molecular links with cancer molecular pathways came by the discovery of the regulation of the BCL2 oncogene operated by miR-15a/miR-16-1, which is aberrant in CLL cells. Finally, the potential cancer predisposing role of miRNAs was suggested by the discovery of mir-15a/mir-16-1 germ-line mutations in families associated with an increased risk of CLL. Together with the CLL studies, many additional investigations increased the importance of the field as they proved that numerous miRNAs are deregulated in human cancers and may act either as oncogenes or tumor suppressor genes. Aberrant miRNA expression has been linked to cell cycle progression, loss of differentiation, increased survival, invasion and metastasis. The discovery that miRNAs interact with oncogenes and tumor suppressor genes established multiple links with molecular pathways implicated in malignant transformation. These findings hold the promise that miRNAs could become important diagnostic and therapeutic tools.