Immunogenotype changes prevail in relapses of young children with TEL-AML1-positive acute lymphoblastic leukemia and derive mainly from clonal selection.
OBJECTIVE
Variations of the immunogenotype and TEL deletions in children with TEL-AML1+ acute lymphoblastic leukemia support the hypothesis that relapses derive from a persistent TEL-AML1+ preleukemic/leukemic clone rather than a resistant leukemia. We aimed at elucidating the relationship between the immunogenotype patterns at diagnosis and relapse as well as their clinical and biological relevance.


METHODS
Immunoglobulin and T-cell receptor gene rearrangements were analyzed in 41 children with a TEL-AML1+ acute lymphoblastic leukemia and an early (up to 30 months after diagnosis; n = 12) or late (at 30 months or later; n = 29) disease recurrence by a standardized PCR approach.


RESULTS
In 68% of the patients (group I), we identified differences in the immunogenotype patterns, whereas no changes were observed in the remaining 32% (group II). The divergence resulted more often from clonal selection than clonal evolution and consisted predominantly of losses (0-6, median 5) and/or gains (0-4, median 1) of rearrangements. The frequency and number of clonal immunoglobulin/T-cell receptor rearrangements in group I was higher at diagnosis (2-13, median 5) than at relapse (2-7, median 4), whereas it was the lowest in group II (1-5, median 3). Although group I children were younger at diagnosis, there was no correlation between particular immunogenotype patterns and remission duration.


CONCLUSIONS
These findings imply that the clonal heterogeneity in younger children most likely reflects an ongoing high recombinatorial activity in the preleukemic/leukemic cells, whereas the more uniform repertoire observed in older children mirrors end-stage rearrangement patterns of selected cell clones that evolved during the prolonged latency period.
Panzer-Grümayer
E Renate
ER
Children's Cancer Research Institute, Vienna, Austria.
Cazzaniga
Giovanni
G
van der Velden
Vincent H J
VH
del Giudice
Laura
L
Peham
Martina
M
Mann
Georg
G
Eckert
Conny
C
Schrauder
Andre
A
Germano
Giuseppe
G
Harbott
Jochen
J
Basso
Giuseppe
G
Biondi
Andrea
A
van Dongen
Jacques J M
JJ
Gadner
Helmut
H
Haas
Oskar A
OA
D000293:Adolescent; D000367:Age Factors; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001402:B-Lymphocytes / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis* / Q000235:genetics*; D017353:Gene Deletion; D015321:Gene Rearrangement; D005821:Genetic Techniques; D005838:Genotype; D006801:Humans; D007107:Immune System / Q000473:pathology; D007136:Immunoglobulins / Q000737:chemistry / Q000378:metabolism; D007223:Infant; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics*; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012008:Recurrence; D012074:Remission Induction; D013997:Time Factors; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
D000911:Antibodies, Monoclonal; D050676:Core Binding Factor Alpha 2 Subunit; D007136:Immunoglobulins; D015514:Oncogene Proteins, Fusion; D011948:Receptors, Antigen, T-Cell; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein