Leukemogenic rearrangements at the mixed lineage leukemia gene (MLL)—multiple rather than a single mechanism

Abstract

Despite manifold efforts to achieve reduced-intensity and -toxicity regimens, secondary leukemia has remained the most severe side effect of chemotherapeutic cancer treatment. Rearrangements involving a short telomeric <1 kb region of the mixed lineage leukemia (MLL) gene are the most frequently observed molecular changes in secondary as well as infant acute leukemia. Due to the mode-of-action of epipodophyllotoxins and anthracyclines, which have widely been used in cancer therapy, and support from in vitro experiments, cleavage of this MLL breakpoint cluster hotspot by poisoned topoisomerase II was proposed to trigger the molecular events leading to malignant transformation. Later on, clinical patient data and cell-based studies addressing a wider spectrum of stimuli identified cellular stress signaling pathways, which create secondary DNA structures, provide chromatin accessibility, and activate nucleases other than topoisomerase II at the MLL. The MLL destabilizing signaling pathways under discussion, namely early apoptotic DNA fragmentation, transcription stalling, and replication stalling, may all act in concert upon infection-, transplantation-, or therapy-induced cell cycle entry of hematopoietic stem and progenitor cells (HSPCs), to permit misguided cleavage and error-prone DNA repair in the cell-of-leukemia-origin.

Genome-wide TOP2A DNA cleavage is biased toward translocated and highly transcribed loci

“…We also uncover another subset of TOP2A CCRs correlated with the H3K4me1/H3K27ac and H3K4me1 marks of strong and weak enhancers (Creyghton et al 2010) that suggest a previously unsuspected function of TOP2A in long-range regulation of gene activation. Our discovery that marks of active transcription along gene bodies, marks of open chromatin, and marks of enhancers colocalize with TOP2A CCRs within separate genomic environments implicates TOP2A Altogether our data indicate a new, more general DNA-damaging role of TOP2A cleavage in oncogenic translocations beyond those attributed to exposures to TOP2 poisons in leukemia (Felix 2012;Gole and Wiesmuller 2015) and a modular organization of TOP2A CCRs with factors in the epigenome and transcriptional machinery as a fundamental feature of human cells that impacts translocations and transcription. Because our methodology was developed in a transformed leukemia cell line, in its further applications, it will be important to compare genome-wide TOP2 cleavage patterns between isoforms in different primary cell types representing normal development and disease states to build on these discoveries.…”

A fate worse than death: apoptosis as an oncogenic process

“…The MLL locus is highly susceptible to breakage and rearrangement, this can generate oncogenic MLL fusion proteins which lack methyltransferase activity 85 . Rearrangements in MLL are recurrent oncogenic drivers in a variety of leukaemias including acute myeloid leukaemia (AML) and acute lymphoid leukaemia (ALL) 86 . Importantly from the perspective of this discussion, MLL is the most commonly re-arranged gene in therapy-related neoplasms including AML and MDS 86 .…”

“…Rearrangements in MLL are recurrent oncogenic drivers in a variety of leukaemias including acute myeloid leukaemia (AML) and acute lymphoid leukaemia (ALL) 86 . Importantly from the perspective of this discussion, MLL is the most commonly re-arranged gene in therapy-related neoplasms including AML and MDS 86 . While MLL rearrangements are associated with topoisomerase II inhibitor treatment, several lines of evidence argue that this is not solely through inhibition of topoisomerase II function; in these settings apoptosis may play a role in generating MLL rearrangements.…”

Généralités médicales et spécificités thérapeutiques des cancers du nouveau-né et du nourrisson

“…Leur prise en charge n'est pas consensuelle et fait débat, en particulier pour les leucémies néonatales. La survie des enfants de moins d'un an atteints de leucémie est de 60 % ; celle des formes néonatales est inférieure à 30 % [2,15]. À la naissance, les LAM prédominent, et dans la première année de vie, leur incidence est équivalente aux leucémies aiguës lymphoblastiques (LAL).…”