The DNA double-strand break response is abnormal in myeloblasts from patients with therapy-related acute myeloid leukemia

Abstract

The complex chromosomal aberrations found in therapy related acute myeloid leukemia (t-AML) suggest that the DNA double strand break (DSB) response may be altered. In this study we examined the DNA DSB response of primary bone marrow cells from t-AML patients and performed next-generation sequencing of 37 canonical homologous recombination (HR) and non-homologous end-joining (NHEJ) DNA repair genes, and a subset of DNA damage response genes using tumor and paired normal DNA obtained from t-AML patients. Our results suggest that the majority of t-AML patients (11 of 15) have tumor cell-intrinsic, functional dysregulation of their DSB response. Distinct patterns of abnormal DNA damage response in myeloblasts correlated with acquired genetic alterations in TP53 and the presence of inferred chromothripsis. Furthermore, the presence of trisomy 8 in tumor cells was associated with persistently elevated levels of DSBs. Although tumor-acquired point mutations or small indels in canonical HR and NHEJ genes do not appear to be a dominant means by which t-AML leukemogenesis occurs, our functional studies suggest that an abnormal response to DNA damage is a common finding in t-AML.

Differential expression of homologous recombination DNA repair genes in the early and advanced stages of myelodysplastic syndrome

“…NHEJ is an error‐prone system with low fidelity and likely contributes to the acquisition of new mutations. This theory, using the model of clonal hematopoiesis of MDS, is supported by the observations that erroneous repairs of DSB play a role in established MDS mouse models and that inefficient DSB repair contributes to sAML …”

Therapy-related myeloid neoplasms: when genetics and environment collide

“…Interestingly, breast cancers arising in patients with germline BRCA1/2 mutations are associated with concurrent somatic TP53 mutations, suggesting cooperativity 29,30 . We postulate that TP53 dysfunction is integral to BRCA1/2 mutation-associated tumors, potentially selecting for the high frequency of TP53 mutations in t-MN, a disease that is also characterized by defects in the DNA damage response 31 .…”

Caspase-9 is required for normal hematopoietic development and protection from alkylator-induced DNA damage in mice

“…11 Current evidence suggests that changes in DDR and apoptosis may contribute to the pathogenesis of this disease. 12 Somatic mutations of TP53 are more common in tAML than in de novo AML, and tAML samples typically have lower expression of TP53. 13,14 Hypermethylation of the BRCA1 promoter is also more common in tAML than in de novo AML.…”