Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA- topoisomerase II

Abstract

Chromosome band 11q23 is frequently involved in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) de novo, as well as in myelodysplastic syndromes (MDS) and lymphoma. Five percent to 15% of patients treated with chemotherapy for a primary neoplasm develop therapy-related AML (t-AML) that may show rearrangements, usually translocations involving band 11q23 or, less often, 21q22. These leukemias develop after a relatively short latent period and often follow the use of drugs that inhibit the activity of DNA-topoisomerase II (topo II). We previously identified a gene, MLL (myeloid-lymphoid leukemia or mixed-lineage leukemia), at 11q23 that is involved in the de novo leukemias. We have studied 17 patients with t-MDS/t-AML, 12 of whom had cytogenetically detectable 11q23 rearrangements. Ten of the 12 t-AML patients had received topo II inhibitors and 9 of these, all with balanced translocations of 11q23, had MLL rearrangements on Southern blot analysis. None of the patients who had not received topo II inhibitors showed an MLL rearrangement. Of the 5 patients lacking 11q23 rearrangements, some of whom had monoblastic features, none had an MLL rearrangement, although 4 had received topo II inhibitors. Our study indicates that the MLL gene rearrangements are similar both in AML that develops de novo and in t-AML. The association of exposure to topo II- reactive chemotherapy with 11q23 rearrangements involving the MLL gene in t-AML suggests that topo II may play a role in the aberrant recombination events that occur in this region both in AML de novo and in t-AML.

RUNX1 meets MLL: epigenetic regulation of hematopoiesis by two leukemia genes

“…Cancer patients treated with topoisomerase II inhibitor, such as etoposide, show high occurrence of MLL chromosomal translocation. 60,61 More than 70 types of partner genes have been found to generate fusion proteins by chromosomal translocations with MLL. 59 The common MLL fusion partners are AF4, ENL, AF9, AF6, ELL and AF10.…”

Towards targeted therapy for infant acute lymphoblastic leukaemia

“…etoposide) and anthracyclines. At first, intensive treatment with topo‐II inhibitors appeared to predominantly result in the development of MLL rearranged AML (Super et al , 1993; Pui et al , 1995b); however, increasing cases of therapy‐related MLL are emerging (reviewed by Andersen et al , 2001). These findings led to the hypothesis that transplacental exposure to topo‐II inhibitors may be involved in the aetiology of infant MLL (Ross et al , 1994).…”

Cytogenetic and Molecular Evaluation in Myelodysplastic Syndrome and in Acute and Chronic Leukemia

“…The major AML translocations are presented in Table 4. Several of these are clinically important through their association with distinctive modes of disease presentation and prognosis [7][8][9][10][11] (Table 5). These translocations can also be detected by molecular genetic techniques.…”