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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

Szczepanski, T., Willemse, MJ., van Wering, ER., van Weerden, J. F., Kamps, WA. & van Dongen, JJM., Sep-2001, In : Leukemia. 15, 9, p. 1415-1423 9 p.

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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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