Calin GA, Ferracin M, Cimmino A, et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005;353:1793-801.

MicroRNAs are specifically encoded small RNAs(~19-25 nucleotides) which regulate gene expression, including oncogenes and tumor suppressor genes, via interaction with messenger RNA. Calin et al. assessed microRNA profiles in 94 patients with CLL and correlated the findings with known CLL prognostic markers including ZAP70 expression and immunoglobulin heavy chain variable gene (IgVH) mutation status. MicroRNA profiles were determined by a microchip containing the precursor and active forms of 76 microRNAs. An expression signature of 13 microRNAs discriminated between patients with a favorable (ZAP70-, IgVH mutated; n=47) versus unfavorable (ZAP70+, IgVH unmutated; n=36) clinical course. High versus low level expression of nine of the 13 microRNAs was also found to correlate with time from diagnosis to initial therapy. Eleven of 75 patients were found to have germ-line or somatic mutations in a subset of the microRNAs, which may prove to be relevant to altered regulatory function and CLL pathogenesis.

MicroRNAs function by blocking messenger RNA (mRNA) translation via complementary base-pairing or by promoting mRNA destruction by nucleases, thus regulating the expression of specific proteins. This novel regulatory mechanism was completely unrecognized until its discovery ten years ago. As noted by Chen in an accompanying editorial (N Engl J Med 2005; 353:1768-71), an estimated 1,000 microRNA genes appear in the human genome. These often occur in clusters, including a cluster at the chromosome 13q14 locus which is frequently deleted in CLL and other lymphoproliferative neoplasms. Altered microRNA may dysregulate oncogene and tumor suppressor gene function, and thus play an important role in cancer pathogenesis. Since microRNAs also are involved in the regulation of cellular development and differentiation, including hematopoiesis, their altered expression may contribute to the neoplastic process on many levels. To date, cancer pathogenesis research has largely focused on oncogene dysregulation via point mutation, gene amplification, or chromosomal translocation, and on loss-of-function mutations in tumor suppressor genes via gene deletion or point mutations. The report by Calin and colleagues is an important advance in linking this novel microRNA regulatory mechanism to clinical and phenotypic findings in CLL, warranting further functional and correlative analyses of RNA interference in lymphoid malignancies and in other cancers.