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B precursor acute lymphoblastic leukemia third complementarity‐determining regions predominantly represent an unbiased recombination repertoire: Leukemic transformation frequently occurs in fetal life
Author(s) -
Steenbergen Eric J.,
Verhagen Onno J. H. M.,
van Leeuwen Eleonore F.,
Behrendt Henk,
Merle Pauline A.,
Wester Mieke R.,
Von Dem Borne Albert E. G. Kr.,
van der Schoot C. Ellen
Publication year - 1994
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.1830240418
Subject(s) - biology , locus (genetics) , gene , complementarity determining region , genetics , repertoire , homology (biology) , recombination , gene rearrangement , peptide sequence , physics , acoustics
Abstract To determine whether the ALL (acute lymphoblastic leukemia) CDR3 (third complementarity‐determining region) repertoire represents the recombination repertoire, or shows evidence of selectional processes inherent to normal B cell differentiation or malignant transformation, we analyzed 68 ALL CDR3 regions and included 127 previously published sequences in the analyses. We found no evidence of selection prior to malignant transformation as recombination was random with 1/3 “in frame” and 2/3 “out of frame” joinings and usage of all three D reading frames was observed. D and J H gene segments were predominantly umutated which allowed a detailed analysis of gene usage and rearrangement characteristics. J H 4 and J H 6 usage (both 32.2%) was significantly different ( p = 0.005) from that observed in peripheral B lymphocytes. D gene family usage roughly represented D gene family size with the exception of the D XP and D A/K family which were over‐ and underrepresented ( p = 0.05), respectively. D‐D fusions were found in 26.2% of CDR3 regions. If less stringent criteria were applied DIR homology was found in 40/65 sequences, suggesting the frequent involvement of DIR gene segments in human CDR3 formation. The rearranged D genes were evenly distributed over the D locus, suggesting that D recombination is a predominantly random process, independent of physical location at the locus. Also, there was no correlation between J H gene usge and physical location of the rearranged D gene segment, which excludes a major contribution of the DJ H replacement recombination mechanism. In 36.1% of CDR3 regions N‐nucleotides at the DJ H junction were absent. This frequency is higher than observed for peripheral B lymphocytes. It is suggested that for a number of ALL the initial transformational event took place in early fetal life. We conclude that ALL CDR3 sequences show no evidence of selection prior to malignant transformation, nor of extensive changes subsequent to malignant transformation.