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Open Access Research article

A novel spliced fusion of MLL with CT45A2 in a pediatric biphenotypic acute leukemia

Nuno Cerveira12, Claus Meyer3, Joana Santos12, Lurdes Torres12, Susana Lisboa12, Manuela Pinheiro12, Susana Bizarro12, Cecília Correia12, Lucília Norton4, Rolf Marschalek3 and Manuel R Teixeira125*

Author Affiliations

1 Department of Genetics of the Portuguese Oncology Institute, Porto, Portugal

2 Cancer Genetics Group, Research Centre of the Portuguese Oncology Institute, Porto, Portugal

3 Institute of Pharmaceutical Biology, Diagnostic Centre of Acute Leukemia (DCAL), Goethe-University of Frankfurt, Frankfurt/Main, Germany

4 Department of Pediatrics, Portuguese Oncology Institute, Porto, Portugal

5 Biomedical Sciences Institute (ICBAS), Porto, Portugal

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BMC Cancer 2010, 10:518  doi:10.1186/1471-2407-10-518

Published: 29 September 2010

Abstract

Background

Abnormalities of 11q23 involving the MLL gene are found in approximately 10% of human leukemias. To date, nearly 100 different chromosome bands have been described in rearrangements involving 11q23 and 64 fusion genes have been cloned and characterized at the molecular level. In this work we present the identification of a novel MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia.

Methods

Cytogenetics, fluorescence in situ hybridization (FISH), molecular studies (RT-PCR and LDI-PCR), and bioinformatic sequence analysis were used to characterize the CT45A2 gene as novel MLL fusion partner in pediatric acute leukemia.

Results

Fluorescence in situ hybridization of bone marrow G-banded metaphases demonstrated a cryptic insertion of 11q23 in Xq26.3 involving the MLL gene. Breakpoint fusion analysis revealed that a DNA fragment of 653 kb from 11q23, containing MLL exons 1-9 in addition to 16 other 11q23 genes, was inserted into the upstream region of the CT45A2 gene located at Xq26.3. In addition, a deletion at Xq26.3 encompassing the 3' region of the DDX26B gene (exons 9-16) and the entire CT45A1 gene was identified. RNA analysis revealed the presence of a novel MLL-CT45A2 fusion transcript in which the first 9 exons of the MLL gene were fused in-frame to exon 2 of the CT45A2 gene, resulting in a spliced MLL fusion transcript with an intact open reading frame. The resulting chimeric transcript predicts a fusion protein where the N-terminus of MLL is fused to the entire open reading frame of CT45A2. Finally, we demonstrate that all breakpoint regions are rich in long repetitive motifs, namely LINE/L1 and SINE/Alu sequences, but all breakpoints were exclusively identified outside these repetitive DNA sequences.

Conclusion

We have identified CT45A2 as a novel spliced MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia, as a result of a cryptic insertion of 11q23 in Xq26.3. Since CT45A2 is the first Cancer/Testis antigen family gene found fused with MLL in acute leukemia, future studies addressing its biologic relevance for leukemogenesis are warranted.