HOX11L2/TLX3is transcriptionally activated through T-cell regulatory elements downstream of BCL11Bas a result of the t(5;14)(q35;q32)

The t(5;14)(q35;q32) chromosomal translocation is specifically observed in up to 20% of childhood T-cell acute lymphoblastic leukemia (T-ALL). It affects the BCL11B/CTIP2locus on chromosome 14 and the RANBP17-TLX3/HOX11L2region on chromosome 5. It leads to ectopic activation of TLX3/HOX11L2.To investigate the reasons of the association between t(5;14) and T-ALL, we isolated the translocation breakpoints in 8 t(5;14) patients. Sequence analyses did not involve recombinase activity in the genesis of the translocation. We used DNAse1 hypersensitive experiments to locate transcriptional regulatory elements downstream of BCL11B.By transient transfection experiments, 2 of the 6 regions demonstrated cis-activation properties in T cells and were also effective on the TLX3promoter. Our data indicate that the basis of the specific association between t(5;14) and T-ALL lies on the juxtaposition of TLX3to long-range cis-activating regions active during T-cell differentiation.