Ig Heavy Chain Gene Rearrangements in T-Cell Acute Lymphoblastic Leukemia Exhibit Predominant Dh6-19 and Dh7-27 Gene Usage, Can Result in Complete V-D-J Rearrangements, and Are Rare in T-Cell Receptor β Lineage

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Abstract
Rearranged IGH genes were detected by Southern blotting in 22% of 118 cases of T-cell acute lymphoblastic leukemia (ALL) and involved monoallelic and biallelic rearrangements in 69% (18/26) and 31% (8/26) of these cases, respectively. IGH gene rearrangements were found in 19% (13/69) of CD3− T-ALL and in 50% of TCRγδ+ T-ALL (12/24), whereas only a single TCRβ+ T-ALL (1/25) displayed a monoallelicIGH gene rearrangement. The association with the T-cell receptor (TCR) phenotype was further supported by the striking relationship between IGH and TCR delta (TCRD) gene rearrangements, ie, 32% of T-ALL (23/72) with monoallelic or biallelicTCRD gene rearrangements had IGH gene rearrangements, whereas only 1 of 26 T-ALL with biallelic TCRD gene deletions contained a monoallelic IGH gene rearrangement. Heteroduplex polymerase chain reaction (PCR) analysis with Vh and Dh family-specific primers in combination with a Jhconsensus primer showed a total of 39 clonal products, representing 7 (18%) Vh-(Dh-)Jh joinings and 32 (82%) Dh-Jh rearrangements. Whereas the usage of Vh gene segments was seemingly random, preferential usage of Dh6-19 (45%) and Dh7-27 (21%) gene segments was observed. Although the Jh4 and Jh6 gene segments were used most frequently (33% and 21%, respectively), a significant proportion of joinings (28%) used the most upstream Jh1 and Jh2 gene segments, which are rarely used in precursor-B-ALL and normal B cells (1% to 4%). In conclusion, the high frequency of incomplete Dh-Jh rearrangements, the frequent usage of the more downstream Dh6-19 and Dh7-27 gene segments, and the most upstream Jh1 and Jh2 gene segments suggests a predominance of immature IGH rearrangements in immature (non-TCRβ+) T-ALL as a result of continuing V(D)J recombinase activity. More mature β-lineage T-ALL with biallelic TCRD gene deletions apparently have switched off their recombination machinery and are less prone to cross-lineageIGH gene rearrangements. The combined results indicate thatIGH gene rearrangements in T-ALL are postoncogenic processes, which are absent in T-ALL with deleted TCRD genes and completed TCR alpha (TCRA) gene rearrangements.

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