Site-specific translocation and evidence of postnatal origin of the t(1;19)E2A-PBX1fusion in childhood acute lymphoblastic leukemia

Abstract

The t(1;19) translocation yields a fusion between E2A and PBX1 genes and occurs in 5% of acute lymphoblastic leukemia in children and adults. We used chromosomal translocations and Ig heavy chain (IGH)͞T cell antigen receptor (TCR) rearrangements to develop an understanding of the etiology and natural history of this subtype of leukemia. We sequenced the genomic fusion between E2A and PBX1 in 22 preB acute lymphoblastic leukemias and two cell lines. The prenatal origin of the leukemia was assessed in 15 pediatric patients by screening for the clonotypic E2A-PBX1 translocation in neonatal blood spots, or Guthrie cards, obtained from the children at the time of birth. Two patients were determined to be weakly positive for the fusion at the time of birth, in contrast to previously studied childhood leukemia fusions, t(12;21), t(8;21), and t(4;11), which were predominantly prenatal. The presence of extensive N-nucleotides at the point of fusion in the E2A-PBX1 translocation as well as specific characteristics of the IGH͞TCR rearrangements provided additional evidence for a postnatal, preB cell origin. Intriguingly, 16 of 24 breakpoints on the 3.2-kb E2A intron 14 were located within 5 bp, providing evidence for a site-specific recombination mechanism. Breakpoints on the 232-kb PBX1 intron 1 were more dispersed but highly clustered proximal to exon 2. In sum, the translocation breakpoints displayed evidence of unique temporal, ontological, and mechanistic formation than the previously analyzed pediatric leukemia translocation breakpoints and emphasize the need to differentiate cytogenetic and molecular subgroups for studies of leukemia causality. P ediatric leukemias are a group of diverse diseases at the chromosome level, with various subtypes recognizable by recurrent translocations and aneuploidies. Although these genetic abnormalities help to categorize leukemias for treatment strategy and prognosis, they also may delineate specific causal pathways to malignancy. The consideration of individual molecular subtypes is providing clarity to epidemiological and biological studies. The best characterized example of this approach is the infant leukemias with MLL translocations (MLL ϩ ), for which epidemiologic associations and molecular analysis of breakpoints point to an in utero origin of the translocations, with reactive metabolites of genotoxic chemicals playing a potential key role (1-5). The MLL ϩ leukemias, along with the hyperdiploid subtype (leukemia clones with Ͼ50 chromosomes), also display significant associations with variants in genes encoding functional metabolic enzymes, thus implying a risk of leukemia imparted by the enzymes' substrates or products (6-8). Childhood leukemias with TEL-AML1 translocations, representing Ϸ25% of common acute lymphoblastic leukemia (cALL), share the in utero timing of translocation formation with MLL ϩ leukemias (9); however, there is currently no etiological mechanism for the formation of this translocation, apart from the nonhomologous end-joining processes that rejoin br...

Screening for leukemia- and clone-specific markers at birth in children with T-cell precursor ALL suggests a predominantly postnatal origin

“…This number of cells was detected in earlier studies on BCP ALL. [5][6][7]9,10 Despite this optimal sensitivity the molecular target was present at birth just in 1 of the 16 cases (Figure 1, sample no. 185).…”

“…[5][6][7][8][9] An exception to this is the t(1;19)-positive ALL. 10 Two reports also suggested an in utero origin of at least some cases of TCP ALL. 6,11 To explore the issue of the timing of TCP ALL development more systematically, we used patient-specific leukemia-and clone-specific markers to analyze neonatal blood spots as the earliest postnatal sample of children who developed TCP ALL later in life.…”

Etiology of common childhood acute lymphoblastic leukemia: the adrenal hypothesis

“…Less is known of the preleukemic (subclinical) phase for other subsets of childhood ALL, but Guthrie card and twin/triplet studies indicate that t(1;19)(q23;p13)[E2A-PBX1] translocation-positive cases and T-lineage ALL in general are initiated postnatally. [19][20][21] GCs are among the most important and effective inducers of apoptosis in normal and malignant lymphoblasts both in vitro and in vivo. 22,23 As monotherapy, both prednisolone and prednisone, which after absorption rapidly is converted to prednisolone, can induce morphological remission.…”

Analysis of genomic breakpoints in p190 and p210 BCR–ABL indicate distinct mechanisms of formation

“…The CAC in the heptamer had to be present and up to nine mismatches were allowed in the remaining heptamer and nonamer sequences. 32,33 Functional analysis of breakpoints to determine illegitimate RAG activity…”