Chromosomal translocations involving the MLL gene: molecular mechanisms

Abstract

A wide array of recurrent, non-random chromosomal translocations are associated with hematologic malignancies; experimental models have clearly demonstrated that many of these translocations are causal events during malignant transformation. Translocations involving the MLL gene are among the most common of these non-random translocations. Leukemias with MLL translocations have been the topic of intense interest because of the unusual, biphenotypic immunophenotype of these leukemias, because of the unique clinical presentation of some MLL translocations (infant leukemia and therapy-related leukemia), and because of the large number of different chromosomal loci that partner with MLL in these translocations. This review is focused on the potential mechanisms that lead to MLL translocations, and will discuss aberrant VDJ recombination, Alu-mediated recombination, non-homologous end joining, as well as the effect of DNA topoisomerase II poisons and chromatin structure.

Figure 1. MLL partial tandem duplication (PTD)

The germline (GL) MLL locus is shown; exons 1–16 are indicated (the remaining 3’ exons are omitted for clarity). Regions of Alu repeats are indicated, as is the MLL breakpoint cluster region (bcr). Centromere to telomere orientation is indicated. The MLL partial tandem duplication (PTD) is depicted.A recombination event occurs between Alu sequences in intron 1 and intron 6, leading to a duplication of exons 2–6 between exons 6 and 7. Exon sizes and intronic distances are not to scale.

Figure 2. Chromosomal translocation consistent with a DNA topoisomerase II subunit exchange

The germline NUP98, TOP1, and both derivative chromosomes from a patient with t-AML were cloned and sequenced [51]. In this model, topo II monomers initially bound to NUP98 are indicated with solid ovals; monomers initially bound to TOP1 are indicated with cross-hatched ovals. A 4-bp staggered DNA DSB occurs as indicated, and an inter-chromosomal stand exchange occurs, with the NUP98 and TOP1 sequences aligning as indicated. Religation occurs as indicated, leaving 2 nucleotide mismatches (T-G on the der 11; C-A on the der 20). Repair of the mismatches leads to the final sequences shown as the der 11 and der 20. Note that the 4 nucleotides in bold italics (CACC) are present at the breakpoint on both the der 11 and der 20 chromosomes.