Presence of clone-specific markers at birth in children with acute lymphoblastic leukaemia

Abstract

Recent studies have suggested that development of childhood acute lymphoblastic leukaemia may often be initiated in utero. To provide further evidence of an prenatal origin of childhood leukaemia, we conducted a molecular biological investigation of nine children with B-precursor acute lymphoblastic leukaemia carrying the chromosomal translocation t(12;21), the most common subtype of all childhood acute lymphoblastic leukaemia. Specifically, for each child we identified the non-constitutive chromosomal sequences made up by the t(12;21) fusion gene. From these, leukaemia clone-specific DNA primers were constructed and applied in nested polymerase chain reaction analyses of DNA extracted from the patients' Guthrie cards obtained at birth. Leukaemia clone-specific fusion gene regions were demonstrated in Guthrie card DNA of three patients, age 2 years 11 months, 3 years 4 months, and 5 years 8 months at leukaemia diagnosis. Our findings are consistent with previous observations, and thus provide further evidence that the development of t(12;21) B-precursor acute lymphoblastic leukaemia may be initiated in utero. Review of the current literature moreover indicates that age at leukaemia may be inversely correlated with the burden of cells with leukaemia clonal markers, i.e. leukaemia predisposed cells at birth, and that certain types of childhood acute lymphoblastic leukaemia develop as a multiple step process involving both pre-and postnatal genetic events.

Prenatal origin of childhood acute lymphoblastic leukemia, association with birth weight and hyperdiploidy

“…14,15 Leukemia-specific fusion genes were detected on blood spots of newborn Guthrie cards in a limited number of patients with t(4;11) and t(12;21) translocation. [16][17][18][19] However, only a minority of children with ALL have a detectable leukemiaspecific chromosomal translocation. 20 Therefore, clone-specific antigen receptor gene rearrangements used for the detection of minimal residual disease have been applied in a small number of patients with ALL to investigate the evolution of leukemia.…”

Quantitation of RNA decay in dried blood spots during 20 years of storage

“…However, the range of analytical possibilities is limited by the small amount of blood available. Several research groups have recovered DNA from these filter papers following long-term storage, with subsequent molecular analyses including whole genome amplification and detection of specific mutations or genetic rearrangements (6)(7)(8). In 1992, Zhang and McCabe (9) and Matsubara et al (10) isolated RNA from dried blood spots after up to 4 years of storage.…”

Etiology of common childhood acute lymphoblastic leukemia: the adrenal hypothesis

“…11 Thus, chimeric genes or clonal immune gene rearrangements have been demonstrated in Guthrie cards from children who later developed ALL. [11][12][13][14][15][16] It is worth noting that ETV6/RUNX1 translocations have also been demonstrated by reverse transcription-PCR in approximately 1% of healthy newborns at a level of 10 À3 -10 À4 cells 17 and in 1% of healthy blood donors, although at a two-log lower frequency. 18 Accordingly, the risk of common ALL in the 2-5 year age group is likely to reflect both the persistence and level of preleukemic cells in the child and the risk of these being affected by further leukemogenic mutations.…”