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.

Etoposide‐initiated MLL rearrangements detected at high frequency in human primitive hematopoietic stem cells with in vitro and in vivo long‐term repopulating potential

“…MLL rearrangements, including inversions and foreign sequence fusions, are readily detectable within the surviving HSC after a sublethal etoposide exposure, indicating that stem cells are highly susceptible to acquiring potentially oncogenic repair structures. Our results are consistent with the development of MLL-rearranged therapyrelated leukemias in a small fraction of patients receiving chemotherapy regimens that include topo II poisons (25,26). Although it is difficult to estimate the frequency of etoposide-induced rearrangements in this population, we observed them at approximately 10-fold higher frequency than spontaneously arising aberrations analogous to de novo AML leukemias (duplications, inversions, foreign sequence fusions).…”

“…Clinical evidence shows a clear relation between prior exposure to topoisomerase II (topo II) poisons and subsequent development of therapy-related acute leukemia (t-AML or t-ALL) characterized by chromosomal rearrangements involving the MLL gene (23). AML is the most frequent secondary malignancy after treatment with topo II poisons and is characterized by MLL translocations in 80% of cases (23)(24)(25)(26)(27). Many MLL rearrangements isolated from patients with t-AML localize within a well-characterized 8.3 kb break-point cluster region (bcr) that contains putative topo II cleavage recognition sequences and repetitive elements (28)(29)(30).…”

Bioflavonoids promote stable translocations between MLL‐AF9 breakpoint cluster regions independent of normal chromosomal context: Model system to screen environmental risks

“…Etoposide is a well-established inhibitor of topo II, promotes DSBs across the genome as well as specifically within the MLL bcr, and promotes MLL chromosomal translocations (Blanco et al, 2003;Libura et al, 2005;Felix et al, 2006). MLL breakpoint sequences associated with infant acute leukemia are similar to those in t-AML following etoposidecontaining regimens (Super et al, 1993;Broeker et al, 1996). Thus, it has been hypothesized that exposure to biochemically similar compounds including bioflavonoids may contribute to infant leukemia from in utero exposure from maternal diet (Ross, 2000;Vanhees et al, 2011;Bariar et al, 2013).…”

Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease

“…The mixed lineage leukemia (MLL) protein represents one such transcriptional regulator. Chromosomal rearrangements of the MLL gene typify acute leukemias of infancy as well as therapy-related leukemias (Hunger et al, 1993;Super et al, 1993;Felix et al, 1995;Behm et al, 1996). However, the critical stage of hematopoietic development targeted by each MLL fusion protein is unclear.…”