ETV6-NCOA2: a novel fusion gene in acute leukemia associated with coexpression of T-lymphoid and myeloid markers and frequent NOTCH1 mutations.
OBJECTIVE
The ETV6 gene has been reported to be fused to a multitude of partner genes in various hematologic malignancies with 12p13 aberrations. Cytogenetic analysis of six cases of childhood acute lymphoblastic leukemia revealed a novel recurrent t(8;12)(q13;p13), suggesting involvement of ETV6.


METHODS
Fluorescence in situ hybridization was used to confirm the involvement of ETV6 in the t(8;12)(q13;p13) and reverse transcription-PCR was used to identify the ETV6 partner gene. Detailed immunologic characterization was done, and owing to their lineage promiscuity, the leukemic blast cells were analyzed for NOTCH1 mutations.


RESULTS
We have identified a novel recurrent t(8;12)(q13;p13), which results in a fusion between the transcriptional repressor ETV6 (TEL) and the transcriptional coactivator NCOA2 (TIF2) in six cases of childhood leukemia expressing both T-lymphoid and myeloid antigens. The ETV6-NCOA2 transcript encodes a chimeric protein that consists of the pointed protein interaction motif of ETV6 that is fused to the COOH terminus of NCOA2, including the cyclic AMP-responsive element binding protein-binding protein (CBP) interaction and the AD2 activation domains. The absence of the reciprocal NCOA2-ETV6 transcript in one of the cases suggests that the ETV6-NCOA2 chimeric protein and not the reciprocal NCOA2-ETV6 is responsible for leukemogenesis. In addition, ETV6-NCOA2 leukemia shows a high frequency of heterozygous activating NOTCH1 mutations, which disrupt the heterodimerization or the PEST domains.


CONCLUSIONS
The ETV6-NCOA2 fusion may define a novel subgroup of acute leukemia with T-lymphoid and myeloid features, which is associated with a high prevalence of NOTCH1 mutations.
Strehl
Sabine
S
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Kinderspitalgasse 6, A-1090 Vienna, Austria. sabine.strehl@ccri.at
Nebral
Karin
K
König
Margit
M
Harbott
Jochen
J
Strobl
Herbert
H
Ratei
Richard
R
Struski
Stephanie
S
Bielorai
Bella
B
Lessard
Michel
M
Zimmermann
Martin
M
Haas
Oskar A
OA
Izraeli
Shai
S
D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics*; D050596:Oncogene Fusion / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D051881:Receptor, Notch1 / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097764:ETS Translocation Variant 6 Protein
D051958:Nuclear Receptor Coactivator 2; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D051881:Receptor, Notch1; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C498001:NCOA2 protein, human; C497761:NOTCH1 protein, human