DNA fragility at the KMT2A / MLL locus: insights from old and new technologies

Abstract

The Mixed-Lineage Leukaemia ( MLL/KMT2A ) gene is frequently rearranged in childhood and adult acute leukaemia (AL) and in secondary leukaemias occurring after therapy with DNA topoisomerase targeting anti-cancer agents such as etoposide (t-AL). MLL/KMT2A chromosome translocation break sites in AL patients fall within an 8 kb breakpoint cluster region (BCR). Furthermore, MLL/KMT2A break sites in t-AL frequently occur in a much smaller region, or hotspot, towards the 3′ end of the BCR, close to the intron 11/exon 12 boundary. These findings have prompted considerable effort to uncover mechanisms behind the apparent fragility of the BCR and particularly the t-AL hotspot. Recent genome-wide analyses have demonstrated etoposide-induced DNA cleavage within the BCR, and it is tempting to conclude that this cleavage explains the distribution of translocation break sites in t-AL. However, the t-AL hotspot and the centre of the observed preferential DNA cleavage are offset by over 250 nucleotides, suggesting additional factors contribute to the distribution of t-AL break sites. We review these recent genomic datasets along with older experimental results, analysis of TOP2 DNA cleavage site preferences and DNA secondary structure features that may lead to break site selection in t-AL MLL/KMT2A translocations.

Myeloperoxidase inhibition protects bone marrow mononuclear cells from DNA damage induced by the TOP2 poison anti‐cancer drug etoposide

“…Furthermore, in our previous cell line‐based study, we found that MPO activity had an approximately three‐fold greater effect on TOP2B‐CC complex formation than on TOP2A. This is significant as TOP2B appears to be required for the majority of etoposide‐induced MLL and RUNX1 chromosomal breaks [10,34,35] in a human lymphoblastoid cell line model and for etoposide‐mediated carcinogenesis in a mouse model [36].…”

“…Notably, TOP2-associated t-AL cases often harbour characteristic balanced chromosome translocations [3] including those involving the KMT2A/MLL locus or t (15,17) (PML-RARA), t(8,21)(AML/RUNX1-ETO) and inv(16) (MYH11-CBFB) translocations [7]. These chromosome translocations are believed to occur following DNA DSBs induced by poisoned TOP2 activity [3,[8][9][10] and are crucial early events in the development of these therapy-related leukaemias; the resulting fusion genes, for example MLL-AF9, are able to induce leukaemia in animal models [11,12]. Therefore, a means of specifically protecting bone marrow haematopoietic progenitors and precursors from the DNA damaging effects of TOP2 poisons would have significant clinical benefit.…”

A novel KMT2A::DCP1B rearrangement in chronic neutrophilic leukemia

“…3 Cells with impaired KMT2A function have reduced DNA damage response and increased susceptibility to DNA damage-induced cell death. 4 KMT2A regulates HSC self-renewal and differentiation, and its loss results in reduced production of various blood cell types.…”