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Unraveling the Consecutive Recombination Events in the Human IGK Locus¹

Anton W. Langerak^2,*, Bertrand Nadel, Anneke de Torbal^*, Ingrid L. M. Wolvers-Tettero^*, Ellen J. van Gastel-Mol^*, Brenda Verhaaf^*, Ulrich Jäger and Jacques J. M. van Dongen^*

^* Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; and Department of Internal Medicine I, Division of Hematology, University of Vienna, Vienna, Austria

In addition to the classical V-J, V- deleting element (Kde), and intron-Kde gene rearrangements, atypical recombinations involving J recombination signal sequence (RSS) or intronRSS elements can occur in the Ig (IGK) locus, as observed in human B cell malignancies. In-depth analysis revealed that atypical JRSS-intronRSS, V-intronRSS, and JRSS-Kde recombinations not only occur in B cell malignancies, but rather reflect physiological gene rearrangements present in normal human B cells as well. Excision circle analysis and recombination substrate assays can discriminate between single-step vs multistep rearrangements. Using this combined approach, we unraveled that the atypical V-intronRSS and JRSS-Kde pseudohybrid joints most probably result from ongoing recombination following an initial aberrant JRSS-intronRSS signal joint formation. Based on our observations in normal and malignant human B cells, a model is presented to describe the sequential (classical and atypical) recombination events in the human IGK locus and their estimated relative frequencies (0.2–1.0 vs <0.03). The initial JRSS-intronRSS signal joint formation (except for J1RSS-intronRSS) might be a side event of an active V(D)J recombination mechanism, but the subsequent formation of V-intronRSS and JRSS-Kde pseudohybrid joints can represent an alternative pathway for IGK allele inactivation and allelic exclusion, in addition to classical C deletions. Although usage of this alternative pathway is limited, it seems essential for inactivation of those IGK alleles that have undergone initial aberrant recombinations, which might otherwise hamper selection of functional Ig L chain proteins.

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