Origins of "late" relapse in childhood acute lymphoblastic leukemia with TEL-AML1 fusion genes

Approximately 20% of childhood B-precursor acute lymphoblastic leukemia (AL L) has a TEL-AML I 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 gener ally presents with low- or medium-risk features and overall has a very good prognosis. Some patients, however, do have relapses late or after the cess ation of treatment, at least on some therapeutic protocols. They usually ac hieve sustained second remissions. Posttreatment relapses, or even very lat e relapses (5-20 years after diagnosis), in childhood ALL are clonally rela ted to the leukemic cells at diagnosis (by IGH or T-cell receptor [TCR] gen e sequencing) and are considered, therefore, to represent a slow re-emergen ce or escape of the initial clone seen at diagnosis. Microsatellite markers and fluorescence in situ hybridization identified deletions of the unrearr anged 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 tr eatment with TEL-AML 1 fusion had essentially the same TEL deletion, though with evidence for microsatellite Instability 5 ' of TEL gene deletion at d iagnosis, leading to extended 5 ' deletion at relapse. It Is speculated tha t, In some patients, combination chemotherapy for childhood ALL may fall to eliminate a fetal preleukemic clone with TEL-AML I and that a second, Inde pendent transformation event within this clone after treatment gives rise t o a new leukemia masquerading as relapse.