title: Precursor-B-ALL with D(H)-J(H) gene rearrangements have an immature immunogenotype with a high frequency of oligoclonality and hyperdiploidy of chromosome 14.
abstract: The IGH gene configuration was investigated in 97 childhood precursor-B-ALL patients at initial diagnosis. Rearrangements were found by Southern blotting in all but three patients (97%) and in 30 cases (31%) we observed oligoclonal IGH gene rearrangements. Heteroduplex PCR analysis revealed at least one clonal PCR product in all Southern blot-positive cases. In 89 patients (92%) complete V(D)J rearrangements were found, while incomplete D(H)-J(H) rearrangements occurred in only 21 patients (22%). In 5% of cases the D(H)-J(H) rearrangements were the sole IGH gene rearrangements. Sequence analysis of the 31 identified incomplete rearrangements revealed preferential usage of segments from the D(H)2, D(H)3 and D(H)7 families (78%). While D(H)2 and D(H)3 gene rearrangements occur frequently in normal B cells and B cell precursors, the relatively frequent usage of D(H)7-27 (19%) in precursor-B-ALL patients is suggestive of leukemic transformation during prenatal lymphopoiesis. Among J(H) gene segments in the incomplete D(H)-J(H) rearrangements, the J(H)6 segment was significantly overrepresented (61%). This observation together with the predominant usage of the most upstream D(H) genes indicates that many of the identified clonal D(H)-J(H) gene rearrangements in precursor-B-ALL probably represent secondary recombinations, having deleted pre-existing D(H)-J(H) joinings. The patients with incomplete D(H)-J(H) gene rearrangements were frequently characterized by hyperdiploid karyotype with additional copies of chromosome 14 and/or by IGH oligoclonality. The presence of incomplete D(H)-J(H) joinings was also significantly associated with a less mature immunogenotype: overrepresentation of V(H)6-1 gene segment usage, absence of biallelic TCRD deletions, and low frequency of TCRG gene rearrangements. This immature immunogenotype of precursor-B-ALL with incomplete IGH gene rearrangements was not associated with more aggressive disease.
authors.affiliation: Department of Immunology, University Hospital Rotterdam/Erasmus University Rotterdam, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Szczepański
authors.forename: M J
authors.initials: MJ
authors.lastname: Willemse
authors.forename: E R
authors.initials: ER
authors.lastname: van Wering
authors.forename: J F
authors.initials: JF
authors.lastname: van Weerden
authors.forename: W A
authors.initials: WA
authors.lastname: Kamps
authors.forename: J J
authors.initials: JJ
authors.lastname: van Dongen
mesh_terms: D000293:Adolescent; D015139:Blotting, Southern; D002648:Child; D002675:Child, Preschool; D002883:Chromosomes, Human, Pair 14; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics*; D005803:Genes, Immunoglobulin / Q000235:genetics*; D005838:Genotype; D020180:Heteroduplex Analysis; D006801:Humans; D007125:Immunogenetics; D007133:Immunoglobulin Joining Region / Q000235:genetics*; D007223:Infant; D015448:Leukemia, B-Cell / Q000235:genetics*; D018365:Neoplasm, Residual / Q000235:genetics; D016133:Polymerase Chain Reaction
chemical_list: D007133:Immunoglobulin Joining Region