Extensive molecular mapping of TCRα/δ and TCRβ involved chromosomal translocations reveals distinct mechanisms of oncogenes activation in T-ALL
Menée sur 280 échantillons prélevés sur des patients atteints d'une leucémie lymphoblastique aiguë T, cette étude française met en évidence des mécanismes d'activation des oncogènes liés à des translocations chromosomiques impliquant des loci du récepteur TCR
Chromosomal translocations involving the T Cell Receptor (TCR) loci represent one of the most recurrent oncogenic hallmarks of T-cell acute lymphoblastic leukaemia (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. Screening for TCRβ and TCRα/δ translocations by FISH and LM-PCR in 280 T-ALLs allowed identification of four 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 (exclusively enhancer driven) and TCRα/δ translocations, when use of an enhancer-independent cryptic internal promoter is frequent. 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, since the "pre-leukemic" early thymic clonogenic population needs to be eradicated and its disappearance monitored.
Blood 2012