¹Department of Immunology, University Hospital Rotterdam/Erasmus University Rotterdam, Rotterdam, The Netherlands

²Dutch Childhood Leukemia Study Group, The Hague, The Netherlands

³Department of Pediatrics, Subdivision Hematology-Oncology, Sophia Children's Hospital/Erasmus University Rotterdam, Rotterdam, The Netherlands

Virtually all immunoglobulin kappa (IGK) gene deletions are mediated via rearrangements of the so-called kappa deleting element (Kde). Kde rearrangements occur either to V gene segments (V-Kde rearrangements) or to the heptamer recombination signal sequence in the J-C intron. Kde rearrangements were analyzed by the polymerase chain reaction (PCR) and heteroduplex analysis in 130 B-lineage leukemias: 63 precursor-B-acute lymphoblastic leukemias (ALL) and 67 chronic B cell leukemias. To obtain detailed information about Kde rearrangements, we sequenced 109 of the 189 detected junctional regions. V gene family usage in the V-Kde rearrangements in our series of B-lineage leukemias was comparable to V gene family usage in functional V-J rearrangements in normal and malignant mature B cells, except for a higher frequency of V II family usage in precursor-B-ALL. Junctional region sequencing of the Kde rearrangements in precursor-B-ALL revealed a mean insertion of 4.7 nucleotides and a mean deletion of 9.5 nucleotides, resulting in an extensive junctional diversity, whereas in chronic B cell leukemias the insertion (1.9) and deletion (6.0) were significantly lower. The relatively extensive junctional diversity of the Kde rearrangements in precursor-B-ALL allowed us to design leukemia/patient-specific oligonucleotide probes, which were proven to be useful for detection of minimal residual disease (MRD) with sensitivities of 10^-4 to 10^-5. Kde rearrangements occur in approximately 50% of precursor-B-ALL cases and are likely to remain stable during the disease course, because Kde rearrangements are assumed to be 'end-stage' rearrangements, which cannot easily be replaced by continuing rearrangement processes. These findings indicate that junctional regions of Kde rearrangements in precursor-B-ALL represent new valuable patient-specific PCR targets for detection of MRD.

IGK genes; kappa deleting element (Kde); rearrangements; precursor-B-ALL; B-lineage leukemias; MRD