Origins of “late” relapse in childhood acute lymphoblastic leukemia with TEL-AML1fusion genes

Approximately 20% of childhood B-precursor acute lymphoblastic leukemia (ALL) has a TEL-AML1fusion gene, often in association with deletions of the nonrearranged TELallele.TEL-AML1gene 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 IGHor 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 TELallele and IGH/TCRgene 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-AML1fusion had essentially the sameTELdeletion, though with evidence for microsatellite instability 5′ of TELgene 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-AML1and that a second, independent transformation event within this clone after treatment gives rise to a new leukemia masquerading as relapse.