Abstract 2310 Unexpected mechanisms of ETV6 dysfunction in hematologic disease

Germline and somatic missense mutations in the transcriptional repressor ETV6 are strongly associated with blood diseases, including thrombocytopenia and leukemia. These dominant negative mutations, which are scattered throughout the ETV6 DNA binding domain and a functionally unannotated linker region, cause the protein to mislocalize to the cytoplasm. We set out to answer the following question: why do seemingly unrelated ETV6 missense mutations cause similar protein mislocalization phenotypes? A combination of chemical, biochemical, and cellular approaches revealed multiple unique mechanisms through which ETV6 disease mutations disrupt proper protein localization. Our discoveries have: (i) inspired small molecule- and genetics-based strategies to rescue mutant ETV6 localization and function, (ii) enabled development of new animal models for ETV6 dysfunction in disease, and (iii) uncovered new regulatory mechanisms of ETV6 localization and function. We thank the Cancer Prevention and Research Institute of Texas, the Welch Foundation, and the National Institute of General Medical Sciences for funding this work.