Therapy-related leukemias

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

“…4A,left). In accord with the reported precision in the reciprocal breakpoint junctions of KMT2A translocations in treatment-related leukemias that implicates DNA DSBs at/near the breakpoints (Lovett et al 2001;Whitmarsh et al 2003;Povirk 2006;Felix 2012), more KMT2A recombinome genes contained TOP2A DSBs (Fig. 4A, middle) than all coding genes, particularly with etoposide, the drug most commonly associated with KMT2A-R treatment-related leukemia (Felix 2012).…”

“…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.…”

“…4B-E; Roulston et al 1998;Smith et al 1998;Mistry et al 2005;Ottone et al 2009;Felix 2012). Remarkably, compared with all coding genes, known cancer fusion genes per se (i.e., genes involved in translocations) (Mitelman et al 2016) also were more likely to contain TOP2A CCRs (Fig.…”

A safer regimen for high‐risk neuroblastoma

“…The forms of leukemia associated with these two drug classes are generally distinct despite administration in combination protocols (reviewed in Refs. 1, 2). The archetypal cytogenetic features of alkylating agent‐related leukemias are complete or partial deletions of chromosomes 5 and 7 and complex, unbalanced numerical and structural cytogenetic abnormalities, whereas balanced translocations are the molecular cytogenetic hallmarks in leukemias related to the topoisomerase II poisons, the most common of which involve the MLL gene at chromosome band 11q23 (reviewed in Refs.…”

“…The archetypal cytogenetic features of alkylating agent‐related leukemias are complete or partial deletions of chromosomes 5 and 7 and complex, unbalanced numerical and structural cytogenetic abnormalities, whereas balanced translocations are the molecular cytogenetic hallmarks in leukemias related to the topoisomerase II poisons, the most common of which involve the MLL gene at chromosome band 11q23 (reviewed in Refs. 1, 2). Alkylating agent‐related leukemias typically have a longer latency and present with antecedent myelodysplasia, whereas leukemias associated with topoisomerase II poisons have heterogeneous morphologic features that represent a spectrum of acute leukemias and MDS reflecting the underlying translocations (reviewed in Refs.…”