Protracted and variable latency of acute lymphoblastic leukemia after TEL-AML1 gene fusion in utero

We report a pair of identical twins with concordant acute lymphoblastic leukemia (ALL). Unusually, their diagnoses were spaced 9 years apart at ages 5 and 14, Leukemic cells in both twins had a TEL-AML1 rearrangement, which was characterized at the DNA level by an adaptation of a long distance polymerase chain reaction (PCR) method. The genomic fusion sequence was identical in the two leukemias, indicative of a single cell origin in one fetus, in utero. At the time twin 1 was diagnosed (aged 5 years), the bone marrow of twin 2 was hematologically normal. However, retrospective scrutiny of the DNA from an archived slide with clonotypic TEL-AML1 primers showed that the presumptive preleukemic clone was present and disseminated 9 years before a clinical diagnosis. These data provide novel insight into the natural history of childhood leukemia and suggest that consequent to a prenatal initiation of a leukemic clone, most probably by TEL-AML fusion itself, the latency of ALL can be both extremely variable and protracted. This, in turn, is likely to reflect the timing of critical secondary events. (C) 1999 by The American Society of Hematology

Molecular discrimination between relapsed and secondary acute lymphoblastic leukemia: Proposal for an easy strategy

Background. Discrimination between late relapse of acute lymphoblastic leukemia (ALL) and secondary ALL might be clinically important, because the former might still respond favorably to chemotherapy and/or bone marrow transplantation, whereas secondary ALL is associated with poor prognosis. Procedure. We present a pre-B-ALL patient in whom disease recurred 2 years after completion of treatment. Differences in cytomorphology and immunophenotyping raised a suspicion of secondary ALL. We performed detailed molecular studies of immunoglobulin and T-cell receptor genes for discrimination between relapsed and secondary ALL. Results. Southern blot analysis showed an oligoclonal immunoglobulin heavy chain (IGH) gene configuration at diagnosis and a monoclonal configuration at relapse. The size of one of the rearranged bands at relapse was identical to one of the taint rearranged bands at diagnosis. However, heteroduplex PCR analysis demonstrated that none of the clonal IGH gene rearrangements at diagnosis and at relapse was fully identical. Sequencing of several clonal PCR products revealed an identical DH6-13IH6b junction shared by two different rearrangements at diagnosis and one rearrangement at relapse, thereby proving the clonal relationship between diagnosis and late relapse in this patient. Conclusions. We propose a stepwise molecular approach for discrimination between relapsed and secondary ALL based on the rapid and cheap heteroduplex PCR technique, including mixing of clonal (homoduplex) PCR products identified at diagnosis and at relapse. Direct sequencing and comparative sequence analysis of IGH gene rearrangements at diagnosis and at relapse should be regarded as an ultimate standard, but can be limited to the rare cases, in which no identical clonal PCR products at diagnosis and at relapse were detected with the mixed heteroduplex PCR analyses. Med. Pediatr. Oncol. 36:352-358, 2001. (C) 2001 Wiley-Liss, Inc