MLL TRANSLOCATIONS IN T-AML

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This research project will focus on the therapy-related acute myeloid leukemia (t-AML) patients who have translocations of chromosome 11, bank 11q23. These patients usually have acute monoblastic or myelomonocytic leukemia which is also associated with rearrangements of 11q23 in patients with de novo leukemia. Interestingly, a substantial fraction of the t-ALM patients with 11q23 involvement have received epipodophyllotoxins, either etoposide (VP16) or teniposide (VM26), as part of their treatment regimen for a primary malignancy. These drugs react with DNA topoisomerase II (topo II) and cause chromosome breaks when added to cultured cells. We have cloned the MLL gene that is involved both in the de novo and in the therapy-related 11q23 translocations. We will study the structure of the MLL gene, particularly in the MLL breakpoint cluster region (BCR), as well as the structure of one of the MLL partner genes most commonly involved in t-AML patients, AF9. We will study whether AP16 causes preferential breakage in MLL relative to other genes known to be involved in translocations, but not associated with prior exposure to this class of drugs. We will sequence the genomic translocation breakpoint regions from t-AML patients to determine whether any sequence motifs are present at the junctions, giving information about potential recombination mechanisms. Together, the structure and sequence studies may provide some insights as to the apparent sensitivity of these genomic regions to rearrangement after exposure to topo II targeting drugs. Finally, we will clone and analyze a new partner of MLL translocations that has been identified in two t- AML patients with a t(11;16)(q23;p13), and will determine whether this gene is involved in other translocations.