Immunoglobulin heavy-chain gene rearrangement in adult acute lymphoblastic leukemia reveals preferential usage of JH-proximal variable gene segments

The aim of this study was to characterize individual-segment and overall patterns of VH gene usage in adult B-lineage acute lymphoblastic leukemia (ALL). Theoretical values of VH segment usage were calculated with the assumption that all VH segments capable of undergoing rearrangement have an equal probability of selection for recombination. Leukemic clones from 127 patients with adult B-lineage acute leukemias were studied by fingerprinting by means of primers for the framework 1 and joining segments. Clones from early preimmune B cells (245 alleles identified) show a predominance of VH6 family rearrangements and, consequently, do not conform to this hypothesis. However, profiles of VH gene family usage in mature B cells, as investigated in peripheral blood (6 samples), B-cell lymphomas (36 clones) and chronic lymphocytic leukemia (56 clones), are in agreement with this theoretical profile. Sequence analyses of 64 VH clones in adult ALL revealed that the rate of VH usage is proportional to the proximity of the VH gene to the JH locus and that the relationship can be mathematically defined. Except for VH6, no other VH gene is excessively used in adult ALL. VH pseudogenes are rarely used (n = 2), which implies the existence of early mechanisms in the pathway to B-cell maturation to reduce wasteful VH-(DH)-JHrecombination. Finally, similar to early immunoglobulin-H rearrangement patterns in the mouse, B cells of ALL derive from a pool of cells more immature than the cells in chronic lymphoid B-cell malignancies.