Extensive molecular mapping of TCRα/δ- and TCRβ-involved chromosomal translocations reveals distinct mechanisms of oncogene activation in T-ALL

• Published in: Blood 2012-10, Vol.120 (16), p.3298-3309
• Main Authors: Le Noir, Sandrine, Ben Abdelali, Raouf, Lelorch, Marc, Bergeron, Julie, Sungalee, Stephanie, Payet-Bornet, Dominique, Villarèse, Patrick, Petit, Arnaud, Callens, Céline, Lhermitte, Ludovic, Baranger, Laurence, Radford-Weiss, Isabelle, Grégoire, Marie-José, Dombret, Hervé, Ifrah, Norbert, Spicuglia, Salvatore, Romana, Serge, Soulier, Jean, Nadel, Bertrand, Macintyre, Elizabeth, Asnafi, Vahid
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Base Sequence; Biological and medical sciences; Child; Child, Preschool; Chromosome aberrations; Chromosome Mapping; DNA, Neoplasm - genetics; Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor - genetics; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor - genetics; Gene Rearrangement, delta-Chain T-Cell Antigen Receptor - genetics; Hematologic and hematopoietic diseases; Humans; In Situ Hybridization, Fluorescence; Infant; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical genetics; Medical sciences; Middle Aged; Molecular Sequence Data; Oncogenes - physiology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Real-Time Polymerase Chain Reaction; Recombination, Genetic - genetics; Sequence Homology, Nucleic Acid; Translocation, Genetic; Young Adult
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-04-425488

Chromosomal translocations involving the TCR loci represent one of the most recurrent oncogenic hallmarks of T-cell acute lymphoblastic leukemia (T-ALL) and are generally believed to result from illegitimate V(D)J recombination events. However, molecular characterization and evaluation of the extent of recombinase involvement at the TCR-oncogene junction has not been fully evaluated. In the present study, screening for TCRβ and TCRα/δ translocations by FISH and ligation-mediated PCR in 280 T-ALLs allowed the identification of 4 previously unreported TCR-translocated oncogene partners: GNAG, LEF1, NKX2-4, and IL2RB. Molecular mapping of genomic junctions from TCR translocations showed that the majority of oncogenic partner breakpoints are not recombinase mediated and that the regulatory elements predominantly used to drive oncogene expression differ markedly in TCRβ (which are exclusively enhancer driven) and TCRα/δ (which use an enhancer-independent cryptic internal promoter) translocations. Our data also imply that oncogene activation takes place at a very immature stage of thymic development, when Dδ2-Dδ3/Dδ3-Jδ1 and Dβ-Jβ rearrangements occur, whereas the bulk leukemic maturation arrest occurs at a much later (cortical) stage. These observations have implications for T-ALL therapy, because the preleukemic early thymic clonogenic population needs to be eradicated and its disappearance monitored.