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Blood, 1 August 2001, Vol. 98, No. 3, pp. 558-564
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Origins of "late" relapse in childhood acute lymphoblastic
leukemia with TEL-AML1 fusion genes
Anthony M. Ford,
Karin Fasching,
E. Renate Panzer-Grümayer,
Margit Koenig,
Oskar A. Haas, and
Mel F. Greaves
From the Leukaemia Research Fund Centre, Institute of
Cancer Research, London, United Kingdom; and the CCRI Children's
Cancer Research Institute and the Ludwig Boltzmann-Institute for
Cytogenetic Diagnosis, St Anna Kinderspital, Vienna, Austria.
Approximately 20% of childhood B-precursor acute lymphoblastic
leukemia (ALL) has a TEL-AML1 fusion gene, often in
association with deletions of the nonrearranged TEL allele.
TEL-AML1 gene fusion appears to be an initiating event and
usually occurs before birth, in utero. This subgroup of ALL generally
presents with low- or medium-risk features and overall has a very good
prognosis. Some patients, however, do have relapses late or after the
cessation of treatment, at least on some therapeutic protocols. They
usually achieve sustained second remissions. Posttreatment relapses, or even very late relapses (5-20 years after diagnosis), in
childhood ALL are clonally related to the leukemic cells at diagnosis
(by IGH or T-cell receptor [TCR] gene sequencing)
and are considered, therefore, to represent a slow re-emergence or
escape of the initial clone seen at diagnosis. Microsatellite markers
and fluorescence in situ hybridization identified deletions of the
unrearranged TEL allele and IGH/TCR gene
rearrangements were analyzed; the results show that posttreatment
relapse cells in 2 patients with TEL-AML1-positive ALL
were not derived from the dominant clone present at diagnosis but were
from a sibling clone. In contrast, a patient who had a relapse while on
treatment with TEL-AML1 fusion had essentially the same
TEL deletion, though with evidence for microsatellite
instability 5' of TEL gene deletion at
diagnosis, leading to extended 5' deletion at
relapse. It is speculated that, in some patients, combination
chemotherapy for childhood ALL may fail to eliminate a fetal
preleukemic clone with TEL-AML1 and that a second,
independent transformation event within this clone after treatment
gives rise to a new leukemia masquerading as relapse.
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