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 alpha beta lineage.
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 TCRgammadelta+ T-ALL (12/24), whereas only a single TCRalpha beta+ T-ALL (1/25) displayed a monoallelic IGH 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 biallelic TCRD 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 JH consensus 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-TCRalpha beta+) T-ALL as a result of continuing V(D)J recombinase activity. More mature alpha beta-lineage T-ALL with biallelic TCRD gene deletions apparently have switched off their recombination machinery and are less prone to cross-lineage IGH gene rearrangements. The combined results indicate that IGH 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.
Szczepański
T
T
Department of Immunology, University Hospital Rotterdam/Erasmus University Rotterdam, Rotterdam, The Netherlands.
Pongers-Willemse
M J
MJ
Langerak
A W
AW
Harts
W A
WA
Wijkhuijs
A J
AJ
van Wering
E R
ER
van Dongen
J J
JJ
D000328:Adult; D015139:Blotting, Southern; D017252:CD3 Complex / Q000032:analysis; D002648:Child; D017353:Gene Deletion; D015321:Gene Rearrangement; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000276:immunology; D016133:Polymerase Chain Reaction; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics
D017252:CD3 Complex; D007143:Immunoglobulin Heavy Chains; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta