Divergent Core Transcriptional Regulatory Circuitries to Highlight Context-Specific Vulnerabilities in AML
Acute myeloid leukemia (AML) is one of the deadliest pediatric cancers, responsible for 10% of total cancer mortality in children. AML is caused by mutations in normal bone marrow stem cells that make them grow out of control (i.e. become malignant). There are many AML-causing mutations and they result in many different subtypes of AML with very different responsiveness to treatment and outcomes. We need a better mechanistic understanding of both common and divergent (i.e. subtype-specific) pathways leading to AML.
We propose to systematically identify and characterize the most critical transcription factors (proteins that regulate the function of genes) in various types of AML, called 'core regulatory circuitries' (CRCs). By identifying the common and divergent CRCs in the context of the various AML subtypes, we will gain new insights into the most critical mechanisms of AML survival. Importantly, our preliminary data show that CRCs can accurately predict AML vulnerabilities – they reliably highlight critical genes without which AML cancer cells cannot survive. We propose to extend our data by characterizing AML CRCs in an integrated, unbiased way, in all major subtypes of AML. This will give us a unified understanding of the common and different ways in which AML arises, as well as create an unprecedented way of predicting common and subtype-specific AML vulnerabilities. Our data will create the basis for a new functional classification of AML and identify new targets for drug development.