RET-mediated autophagy suppression as targetable co-dependence in acute myeloid leukemia

Many cases of acute myeloid leukemia (AML) are associated with mutational activation of RTKs such as FLT3. However, RTK inhibitors have limited clinical efficacy as single agents, indicating that AML is driven by concomitant activation of different signaling molecules. We used a functional genomic approach to identify RET, encoding an RTK not previously implicated in AML, as essential gene in different AML subtypes, and observed that RET-dependent AML cells show activation of RET signaling via ARTN/GFRA3 and NRTN/GFRA2 ligand/co-receptor complexes. Gene expression profiling was performed for 260 AML patients using an RNA microarray (Affymetrix HG U133plus2). RET mRNA expression was analyzed with the probe RET 211421_s_at. GSEA was performed on genes that were preranked according to their transcriptional fold change in AML patients high versus low RET mRNA expression, for a manually curated autophagy gene signature.