Selection of immunoglobulin diversity gene reading frames in B cell lymphoproliferative disorders

Assembly of immunoglobulin (Ig) heavy (H) variable (V), diversity (D) and joining (J) gene segments constitutes an important determinant of commitment to the B cell lineage. The randomly selected D gene segment of a given VDJ complex can potentially be found in all three possible reading frames (RFs). In the present study, we examined the distribution of D gene RF in 'immature' and 'mature' B cell lymphoproliferative disorders (BCLD). We analyzed the clonotypic VDJ junctional sequences of our previously reported cases of follicular lymphoma (FL), as well as bcl-2/IgH junctions with recognized D elements. A marked under-representation of RF1 was observed, with almost equal usage of RF2 and RF3. A literature search for VDJ published sequences in various BCLD identified a similar pattern of D gene RF usage in multiple myeloma (MM), with marked predilection for RFs 2 and 3. In B cell chronic lymphocytic leukemia (B-CLL), the pattern of D-RF was 25% for RF1, 46% for RF2 and 29% for RF3, while in B cell precursor acute lymphoblastic leukemia (precursor-B-ALL) all three RFs were used with similar frequencies. The marked under-representation of RF1 in FL and MM clonogenic rearranged D genes suggests selection on the basis of antigenic properties, possibly due to constraints in forming a flexible loop within CDR3. In contrast, the more even distribution of D-RF usage in B-CLL and precursor-B-ALL suggests that, for these disorders, transformation of a immature type B cell repertoire has occurred.