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

T Szczepanski, MJ Willemse, ER van Wering, J.F. van Weerden, WA Kamps, JJM van Dongen*

*Corresponding author for this work

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    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 DH-JH 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 DH-JH 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.

    Original languageEnglish
    Pages (from-to)1415-1423
    Number of pages9
    JournalLeukemia
    Volume15
    Issue number9
    Publication statusPublished - Sep-2001

    Keywords

    • IGH gene
    • D-H-J(H) gene rearrangements
    • precursor-B-ALL
    • children
    • minimal residual disease
    • ACUTE LYMPHOBLASTIC-LEUKEMIA
    • IMMUNOGLOBULIN HEAVY-CHAIN
    • MINIMAL RESIDUAL DISEASE
    • TIME QUANTITATIVE PCR
    • CELL RECEPTOR GENES
    • HUMAN BONE-MARROW
    • SOUTHERN BLOT ANALYSIS
    • CLONAL REARRANGEMENTS
    • CHILDHOOD
    • DIVERSITY

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