Mutations in the let-7 binding site - a mechanism of RAS activation in juvenile myelomonocytic leukemia?

Abstract

Juvenile myelomonocytic leukemia (JMML) is a rare hematologic malignancy in childhood and accounts for less than 3% of all childhood hematologic malignancies. 1 The role of hyperactive RAS in JMML is underlined by the fact that approximately 80% of JMML develop due to gain-of-function mutations in NRAS, KRAS, PTPN11 and SOS1 or homozygous loss-of-function mutations in NF1 or c-CBL. 2-4 These genes are all components of the RAS/ERK signaling network, implicating deregulation of this signaling pathway in JMML pathogenesis. Therefore, it may be speculated that JMML lacking known mutations of genes playing a role in RAS signaling may carry other mutations, which result in activation of this pathway. Recently, germline mi-RNA gene variations were pro posed to affect the expression levels of tumor suppressor or oncogenes and, thereby, familial/hereditary cancer risk. 5 The let-7 mi-RNA family targets many important genes including cell cycle regulators such as CDC25A and CDK6, a number of early embryonic genes including HMGA2, Mlin-41 and IMP-1 and promoters of growth including RAS and C-MYC. In Caenorhabditis elegans let7 mutant seam cells fail to exit the cell cycle and to terminally differentiate, thus demonstrating continuous prolif eration, a hallmark of cancer. 6 Human RAS expression was also shown to be regulated by let-7. 7 Evidence of a role of let-7 in cancer came from the observation that lung tumor tissues display significantly reduced let-7 levels and significantly increased RAS protein levels relative to nor mal lung tissue. 8