Poster abstracts
Poster number 30 submitted by Ganesh Koshre
Profiling of Acute Myeloid Leukemia (AML) identifies Essential and Targetable RNA Binding Proteins (RBPs)
Ganesh R. Koshre (The Ohio State University, Comprehensive Cancer Center), Chenyu Lin (The Ohio State University, Comprehensive Cancer Center), Jalal K Siddiqui (The Ohio State University, Comprehensive Cancer Center), Anne Lee (School of Medicine, New York University, NY), Iannis Aifantis (School of Medicine, New York University, NY)
Abstract:
Acute myeloid leukemia (AML) is driven by oncogenic mutations that result in the transformation of myeloid cells. Mutations within FLT3 and IDH1/2 represent the most commonly genetic lesions. AML is treated with chemotherapy, which is highly effective, however resistance is common. To identify novel mechanisms supporting AML growth and chemoresistance, we profiled the transcriptome, proteome, and RNA-Binding protein (RBP)-RNA interactome in primary AML samples. For this analysis, we used Myeloid cells from cord blood. Using this combinatorial approach, we identified wide-spread changes in RBP levels and their RNA targets in AML. Importantly, we found that many of these regulatory events were confined to either FLT3 or IDH1/2 mutant tumors. Using computational and mathematical approaches, we identified >50 RBPs that were enriched on RNA in AML, relative to controls. Analyzing eCLIP-data of these RBPs were found a subset of 12 RBPs that regulated mRNAs required to support tumorigenic processes including proliferation, genome integrity and anti-apoptosis. We then independently tested the importance of these RBPs in cultured AML cells using shRNAs and CRISPR-Cas9 engineering. We found that four of these genes were essential to AML cells, and that the loss of an additional 7 RBPs sensitized AML cells to chemotherapy. We are currently dissecting the mechanisms of how these RBPs function to support AML growth.
Keywords: Acute Myeloid Leukemia (AML), RNA Binding Proteins (RBPs)