Immunoglobulin heavy-chain gene rearrangement in adult acute lymphoblasticleukemia reveals preferential usage of J(H)-proximal variable gene segments

The aim of this study was to characterize individual-segment and overall pa tterns of V-H gene usage in adult B-lineage acute lymphoblastic leukemia (A LL). Theoretical values of V-H Segment usage were calculated with the assum ption that all V-H segments capable of undergoing rearrangement have an equ al probability of selection for recombination. Leukemic clones from 127 pat ients with adult B-lineage acute leukemias were studied by fingerprinting b y means of primers for the framework 1 and joining segments. Clones from ea rly 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 investig ated in peripheral blood (6 samples), B-cell lymphomas (36 clones) and chro nic lymphocytic leukemia (56 clones), are in agreement with this theoretica l profile. Sequence analyses of 64 V-H clones in adult ALL revealed that th e 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. Excep t for V(H)6, no other V-H gene is excessively used in adult ALL. V-H pseudo genes are rarely used (n = 2), which implies the existence of early mechani sms in the pathway to B-cell maturation to reduce wasteful V-H-(D-H)-J(H) r ecombination. Finally similar to early immunoglobulin-H rearrangement patte rns 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; 97:27 16-2726) (C) 2001 by The American Society of Hematology.