Formation of der(19)t(1;19)(q23;p13) in acute lymphoblastic leukemia

Abstract

The t(1;19)(q23;p13), which results in a fusion of TCF3 (previously E2A) at 19p13 with PBX1 at 1q23, is one of the most common translocations in acute lymphoblastic leukemia (ALL). It is seen either as a balanced t(1;19) or as an unbalanced der(19)t(1;19); occasional cases with coexisting t(1;19)- and der(19)-positive clones also have been described. Although it generally has been assumed that the unbalanced form arises from the balanced t(1;19) through loss of the derivative chromosome 1 followed by duplication of the normal homologue, this has never been proved. At least two other mechanisms are possible for the formation of the der(19): an initial trisomy 1 followed by translocation and subsequent loss of the der(1) or a rearrangement during the G2 phase of the cell cycle, with the derivative chromosomes 1 and 19 ending up in separate daughter cells. The different alternatives may be distinguished by investigation of markers proximal to the breakpoint in 1q23 because they would be expected to lead to different allelic patterns. Thus, loss of heterozygosity as a result of the presence of uniparental disomy (UPD)-both copies of a chromosome being derived from only one parent-for chromosome 1 would be present in all der(19)-harboring cases arising via the duplication pathway and in one-third of cases arising via the trisomy pathway, but in none of the der(19) formed via the G2 pathway. In this study, we used quantitative fluorescence PCR with polymorphic microsatellite markers to investigate chromosomes 1 and 19 in two t(1;19)- and four der(19)-positive ALLs. None of the der(19) cases displayed UPD for chromosome 1, excluding that this aberration arises through the duplication pathway. Because previous findings of cases with coexisting t(1;19) and der(19) clones are difficult to explain if the translocation originated in G2, the present results suggest that an unbalanced der(19) may arise from an initial trisomy 1 followed by t(1;19) translocation and loss of the derivative chromosome 1.

Nonrandom cell‐cycle timing of a somatic chromosomal translocation: The t(X;17) of alveolar soft‐part sarcoma occurs in G2

“…A similar analysis of the der(19)t(1;19)(q23;p13) of acute lymphoblastic leukemia (which encodes the E2A-PBX1 fusion gene) was recently published (Paulsson et al, 2005). Because, in that study, none of the 4 der(19) cases showed LOH for chromosome 1, the authors excluded a translocation occurring in G0/G1, followed by duplication of the remaining normal chromosome 1.…”

“…The remaining possibilities included formation of the der(19) in G2 or formation in G1 preceded by trisomy 1. Paulsson et al (2005) favored the latter scenario because coexisting t(1;19)/der(19) clones and trisomy 1 have been observed in some cases. However, such a mechanism has less support in ASPS because cases with coexisting t(X;17)/der(17) clones or þX have not been reported.…”

“…Remarkably little information is available regarding the cell-cycle timing of somatic chromosomal translocations (Paulsson et al, 2005). The der(17)t(X;17)(p11.2:q25) of alveolar soft-part sarcoma (ASPS) provides a setting in which to address this question.…”

The mystery of chromosomal translocations in cancer

“…The observation that the two normal homologues are not identical, with one dense and the other loosely structured, hence more likely to participate in DNA exchanges, may prove to be an important factor in this phenomenon (Koss, 1998). LOH in translocation between chromosomes 1 and 19 in acute lymphoblastic leukemias was discussed by Paulsson et al (2005). These authors proposed complex mechanisms for this translocation but did not consider the simple possibility that only one of the two homologues was subject to translocation.…”

Interphase FISH to detect PBX1/E2A fusion resulting from the der(19)t(1;19)(q23;p13.3) or t(1;19)(q23;p13.3) in paediatric patients with acute lymphoblastic leukaemia

“…Historically, the formation of the der(19) had been attributed to loss of the derivative chromosome 1, by non‐disjunction with corresponding replication of the normal chromosome 1 homologue, yielding two identical normal chromosomes 1 (Mellentin et al , 1990; Secker‐Walker et al , 1992; Pui et al , 1994; Hunger, 1996). A recent study, however, suggests that the unbalanced der(19) arises from an initial trisomy of chromosome 1 followed by the t(1;19) translocation and subsequent loss of the derivative chromosome 1 (Kajsa Paulsson et al , 2005). Ultimately, as the derivative chromosome 1 is lost, the patient will have trisomy of the long arm of chromosome 1 distal to the 1q23 band and monosomy of the short arm of chromosome 19 distal to the 19p13.3 band.…”