This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08-CA-09-003: Micro-RNAs in Cancer. The objective of this challenge grant is to define the contribution of microRNAs (miRNAs) to transformation in acute myelogenous leukemia (AML). There is emerging data suggesting that non-coding RNAs, in particular miRNAs, play an important role in the regulation of gene expression. Moreover, dysregulation of miRNAs, through deletion, point mutation, or promoter methylation has been implicated in the pathogenesis of human cancer. We hypothesize that altered miRNA expression and/or function play a significant role in the pathogenesis of AML. Most current studies utilize array-based or quantitative reverse-transcription-polymerase chain reaction (RT-PCR) approaches to measure miRNA expression. However, these approaches do not interrogate all known (or predicted) miRNAs and are unable to detect mutations in miRNAs. Our preliminary data show that next-generation sequencing technologies allow for the efficient detection of miRNA genetic variants, the identification of novel expressed miRNAs, and the characterization of miRNA isomer (isomiRs) expression patterns. Specifically, in our analysis of a patient with AML, more than 70 novel miRNAs were detected. In addition, 3 novel single nucleotide variants and 3 novel small insertions/deletions within the precursor region of miRNA genes were detected. In this challenge grant, we propose to use these technological advances to identify commonly mutated or dysregulated miRNAs in AML. Using the information gained from these studies, we intend to create molecular diagnostic tools for risk stratification, and we will identify candidate genes for targeted therapeutic approaches. The following specific aims are proposed.
Aim 1. We will characterize miRNA expression using massive parallel sequencing in the leukemic blasts of at least 40 patients with de novo AML.
Aim 2. We will identify genetic variants of miRNA genes and define the frequencies of somatic mutations in 400 cases of de novo AML
Acute myelogenous leukemia (AML) is a blood cancer with a poor prognosis. Our research is directed at understanding the genetic mutations that contribute to AML. This research will improve our understanding of the pathogenesis of AML and may lead to the development of new therapeutics.
| Link, Daniel C (2012) Molecular genetics of AML. Best Pract Res Clin Haematol 25:409-14 |
