A Novel Fusion between ETV6 and NCOA2 Defines a New Entity of Acute Leukemia with Co-Expression of T-Cell and Myeloid Markers.

We have identified a novel recurrent translocation and the genes involved therein, which is associated with both lymphoid and myeloid acute leukemia. Fluorescence in situ hybridization (FISH) and molecular analyses revealed an in-frame fusion of ETV6 (alias TEL) and NCOA2 (alias TIF2) in six cases of childhood acute leukemia. ETV6 encodes an ets transcription repressor and is frequently involved in chromosome rearrangements with a multitude of partners in lymphoid and myeloid leukemia, and to a lesser extent also in solid tumors. NCOA2 is a member of the p160 family of nuclear receptor transcriptional coactivators (NRCoAs), which have a common domain structure with a conserved N-terminal bHLH-PAS domain, a centrally located (nuclear) receptor interaction domain (RID/NID), and a C-terminal transcriptional activation domain (AD2). NRCoAs typically display HAT activity and/or directly interact with CBP. In this context, NCOA2 also contains a C-terminal CBP-interaction domain (CID), and thus is a transcription factor that mediates transcriptional activation in a ligand-dependent fashion by a mechanism involving chromatin remodeling. As a result of the translocation the pointed (PNT) protein interaction domain of ETV6 is fused to the C-terminus of NCOA2 including the CBP and AD2 motifs. The same C-terminal domains of NCOA2 are also involved in the previously identified MOZ-NCOA2 fusion, which is generated by a inv(8)(p11q13). The absence of the reciprocal NCOA2-ETV6 transcript in one of the cases, and the facts that MOZ-NCOA2 is transforming and that the reciprocal NCOA2-MOZ is not expressed, strongly suggest that the ETV6-NCOA2 chimeric protein and not the reciprocal NCOA2-ETV6 is responsible for leukemogenesis. Unlike in cases with a ETV6-RUNX1 fusion, which is frequently associated with a concurrent secondary deletion of the non-rearranged ETV6 allele, in all cases the second ETV6 and also one NCOA2 allele were retained and both genes were readily expressed. With respect to the immunophenotype, according to the European Group for the Immunological Characterization of Leukemias (EGIL), three of the cases were classified as T-ALL (one as T-I My+), two as biphenotypic leukemia (BAL), and one as AML with M1 phenotype. Nevertheless, all leukemias displayed aberrant co-expression of various T-cell and myeloid/NK markers, and were double-negative for CD4/CD8, suggesting transformation of early progenitors. In contrast to the MOZ-NCOA2 fusion, which is exclusively associated with AML, mostly of M4 and M5 subtype, the ETV6-NCOA2 fusion seems to define a new entity of acute leukemia with aberrant co-presence of T lymphoid and myeloid antigens.