IMMUNOGLOBULIN AND T-CELL RECEPTOR GENE REARRANGEMENT PATTERNS IN ACUTE LYMPHOBLASTIC-LEUKEMIA ARE LESS MATURE IN ADULTS THAN IN CHILDREN -IMPLICATIONS FOR SELECTION OF PCR TARGETS FOR DETECTION OF MINIMAL RESIDUAL DISEASE

In order to gain insight into immunoglobulin (Ig) and T cell receptor (TCR) gene rearrangements in adult acute lymphoblastic leukemia (ALL), we studied 48 adult patients: 26 with precursor-B-ALL and 22 with T-A LL. Southern blotting (SB) with multiple DNA probes for the IGH, IGK, TCRB, TCRG, TCRD and TAL1 loci revealed rearrangement patterns largely comparable to pediatric ALL, but several differences were found for p recursor-B-ALL patients. Firstly, adult patients showed a lower level of oligoclonality in the IGH gene locus (five out of 26 patients; 19%) despite a comparable incidence of IGH gene rearrangements (24 out of 26 patients; 92%). Secondly, all detected IGK gene deletions (n = 12) concerned rearrangements of the kappa deleting element (Kde) to V kapp a gene segments, which represent two-thirds of the Kde rearrangements in pediatric precursor-B-ALL and only half of the Kde rearrangements i n mature B cell leukemias. Thirdly, a striking predominance of immatur e D delta 2-D delta 3 cross-lineage recombinations was observed (seven out of 16 TCRD rearrangements; 44%), whereas more mature V delta 2-D delta 3 gene rearrangements occurred less frequently (six out of 16 TC RD rearrangements; 38% vs > 70% in pediatric precursor-B-ALL). Togethe r these data suggest that the Ig/TCR genotype of precursor-B-ALL is mo re immature and more stable in adults than in children. We also evalua ted whether heteroduplex analysis of polymerase chain reaction (PCR) p roducts of rearranged Ig and TCR genes can be used for identification of molecular targets for minimal residual disease (MRD) detection. Usi ng five of the major gene targets (IGH, IGK, TCRG, TCRD and TALI delet ion), we compared the SE data and heteroduplex PCR results. High conco rdance between the two methods ranging from 96 to 100% was found for I GK, TCRG and TAL1 genes. The concordance was lower for IGH (70%) and T CRD genes (90%), which may be explained by incomplete or 'atypical' re arrangements or by translocations detectable only by SE. Finally, the heteroduplex PCR data indicate, that MRD monitoring is possible in alm ost 90% of adult precursor-B-ALL and >95% of adult T-ALL patients.