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 V-H gene usage in adult B-lineage acute lymphoblastic leukemia (ALL). Theoretical values of V-H Segment usage were calculated with the assumption that all V-H 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 V(H)6 family rearrangements and, consequently, do not conform to this hypothesis. However, profiles of V-H 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 V-H clones in adult ALL revealed that the rate of V-H usage is proportional to the proximity of the V-H gene to the J(H) locus and that the relationship can be mathematically de-fined. Except for V(H)6, no other V-H gene is excessively used in adult ALL. V-H pseudogenes are rarely used (n = 2), which implies the existence of early mechanisms in the pathway to B-cell maturation to reduce wasteful V-H-(D-H)-J(H) recombination. 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. (Blood. 2001; 97:2716-2726) (C) 2001 by The American Society of Hematology.