ETV6-NCOA2 expression in human or mouse hematopoietic non-thymic progenitors initiates T/myeloid leukemia
ETV6-NCOA2 induces lymphoid program in hematopoietic progenitors through de-repression of ETV6 targets
Mixed-phenotype acute leukemia is a rare subtype of leukemia in which both myeloid and lymphoid markers are co-expressed on the same malignant cells. The pathogenesis is largely unknown, and the treatment is challenging. We previously reported the specific association of the recurrent t(8;12)(q13;p13) chromosomal translocation, creating ETV6-NCOA2 fusion, with T/myeloid leukemias. Here we report that ETV6-NCOA2 initiates T/myeloid leukemia in preclinical models; ectopic expression of ETV6-NCOA2 in mouse bone-marrow hematopoietic progenitors induced T/myeloid lymphoma accompanied by spontaneous Notch1 activating mutations. Similarly, co-transduction of human cord-blood CD34+ progenitors with ETV6-NCOA2 and a non-transforming NOTCH1 mutant induced T/myeloid leukemia in immunodeficient mice; the immunophenotype and gene expression pattern was similar to that of patient-derived ETV6-NCOA2 leukemias. Mechanistically, we show that ETV6-NCOA2 forms a transcriptional complex with ETV6 and the histone acetyltransferase p300, leading to de-repression of ETV6 target genes. The expression of ETV6-NCOA2 in human and mouse non-thymic hematopoietic progenitor cells induces transcriptional dysregulation, which activates a lymphoid program while failing to repress the expression of myeloid genes such as CSF1 and MEF2C. The ETV6-NCOA2 induced arrest at early-immature T-cell developmental stage. The additional acquisition of activating NOTCH1 mutations transforms the early-immature ETV6-NCOA2 cells into T/myeloid leukemias. Here, we describe the first preclinical model to depict the initiation of T/myeloid leukemia by a specific somatic genetic aberration.