The Diverse Roles of ETV6 Alterations in B-Lymphoblastic Leukemia and Other Hematopoietic Cancers

Genetic alterations of the repressive ETS family transcription factor gene ETV6 are recurrent in several categories of hematopoietic malignancy, including subsets of B-cell and T-cell acute lymphoblastic leukemias (B-ALL and T-ALL), myeloid neoplasms, and mature B-cell lymphomas. ETV6 is essential for adult hematopoietic stem cells (HSCs), contributes to specific functions of some mature immune cells, and plays a key role in thrombopoiesis as demonstrated by familial ETV6 mutations associated with thrombocytopenia and predisposition to hematopoietic cancers, particularly B-ALL. ETV6 appears to have a tumor suppressor role in several hematopoietic lineages, as demonstrated by recurrent somatic loss-of-function (LoF) and putative dominant-negative alterations in leukemias and lymphomas. ETV6 rearrangements contribute to recurrent fusion oncogenes such as the B-ALL-associated transcription factor (TF) fusions ETV6::RUNX1 and PAX5::ETV6, rare drivers such as ETV6::NCOA6, and a spectrum of tyrosine kinase gene fusions encoding hyperactive signaling proteins that self-associate via the ETV6 N-terminal pointed domain. Another subset of recurrent rearrangements involving the ETV6 gene locus appear to function primarily to drive overexpression of the partner gene. This review surveys what is known about the biochemical and genome regulatory properties of ETV6 as well as our current understanding of how alterations in these functions contribute to hematopoietic and nonhematopoietic cancers.