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Heterogeneity of the T-cell receptor delta gene indicating subclone
formation in acute precursor B-cell leukemias
DW Ghali, S Panzer, S Fischer, A Argyriou-Tirita, OA Haas, H Kovar, H Gadner and ER Panzer-Grumayer
Children's Cancer Research Institute, St Anna Kinderspital, Clinical
Department of Blood Group Serology, University of Vienna, Austria.
Precursor B-cell acute lymphoblastic leukemias (B-ALLs) have been shown to
be oligoclonal at the Ig heavy-chain (IgH) gene level in up to 40% of cases
by Southern blot hybridization. In contrast, oligoclonality as deduced from
diversity of T-cell receptor (TcR)-delta gene rearrangements of the
immature types (ie, V delta 2-D delta 3, D delta 2-D delta 3) has not been
reported, so far. We detected oligoclonality characterized by the
coexistence of different junctional regions of identical V delta 2-D delta
3 rearrangements in four childhood precursor B-ALLs. No variation was found
in the IgH gene status. Therefore, we define these populations as
subclones. Two leukemias displayed the variants in an unequal proportion.
In the other two leukemias, for which similar quantities of the coexisting
rearrangements were detected, single cell-nuclei polymerase chain reaction
(PCR) showed two separate leukemic populations. Subclone formation could
not be demonstrated by Southern blot hybridization, but was detectable
after PCR amplification of the V delta 2-D delta 3 rearrangement and
separation by polyacrylamide gel electrophoresis. The variants arose
independently from each other, as deduced from their individual sequences.
Using subclone-specific oligonucleotides for hybridization to amplified DNA
obtained at diagnosis and during follow- up from bone marrow samples, we
demonstrate, (1) specificity of all subclone-deduced probes, (2) that one
residual leukemic cell can be detected in 10(4) to 10(5) normal mononuclear
cells in a semiquantitative assay, and (3) that none of the subclones
persisted after induction therapy. We propose that in a leukemic cell
population, TcR-delta gene diversity arises after rearrangements of the IgH
genes resulting in apparent clonality at the IgH gene level. However, cells
are oligoclonal, if the TcR-delta gene rearrangements are considered. As
various subclones may respond differently to chemotherapy, they may hamper
the detection of minimal residual disease. Therefore, we use all
subclone-specific oligonucleotides for hybridization to amplified DNA from
follow-up samples.
Volume 85,
Issue 10,
pp. 2795-2801,
05/15/1995
Copyright © 1995 by The American Society of Hematology
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