Subtractive Interaction Proteomics Reveal a Network of Signaling Pathways Activated by an Oncogenic Transcription Factor in Acute Myeloid Leukemia

Abstract

SummaryAcute myeloid leukemias (AML) are characterized by recurrent genomic alterations, often in transcriptional regulators, which form the basis on which current prognostication and therapeutic intervention is overlaid. In AML transformation can often be attributed to single chromosomal aberrations encoding oncogenes, such as t(15;17)-PML/RARα or t(6;9)-DEK/CAN but it is unclear how these aberrant transcription factors drive leukemic signaling and influence cellular responses to targeted therapies. Here we show that by using a novel “subtractive interaction proteomics” approach, the high risk AML-inducing oncogene t(6;9)-DEK/CAN directly activates signaling pathways that are driven by the ABL1, AKT/mTOR, and SRC family kinases. The interplay of these signaling pathways creates a network with nodes that are credible candidates for combinatorial therapeutic interventions. These results reveal specific interdependencies between nuclear oncogenes and cancer signaling pathways thus providing a foundation for the design of therapeutic strategies to better address the complexity of cancer signaling.Graphical Abstract