Deregulation of homologous recombination DNA repair in alkylating agent treated stem cell clones: a possible role in the aetiology of chemotherapy-induced leukaemia

Chemotherapeutic regimes involving alkylating agents, such as methylators and crosslinking nitrogen mustards, represent a major risk factor for acute myeloid leukaemia. A high frequency of microsatellite instability and evidence of MSH2 loss in alkylating chemotherapy-related acute myeloid leukaemia (t-AML) suggests that DNA mismatch repair (MMR) dysfunction may be an initiating event in disease evolution. Subsequent accumulation of secondary genetic changes as a result of DNA MMR loss may ultimately lead to the gross chromosomal abnormalities seen in t-AML. Homologous recombination repair (HRR) maintains chromosomal stability by the repair of DNA double-strand breaks, and is therefore a possible target for deregulation in MMR dysfunctional t-AML. In order to test this hypothesis Msh2- proficient and -deficient murine embryonic stem (ES) cells were used to examine the effects of MMR status and methylating agent treatment on cellular expression of DNA double-strand break repair genes. HRR gene expression was significantly deregulated in Msh2 null ES cell clones compared to wild-type clones. Furthermore, some Msh2 null clones expressed high levels of Rad51 specifically, a critical component of HRR. Such Rad51 superexpressing clones were also observed when expression was determined in monocytic myeloid cells differentiated from ES cells. A deregulated HRR phenotype could be partially recapitulated in MMR-competent wild-type cells by treatment with the methylating agent, N-methyl-N-nitrosourea. Furthermore, treatment with melphalan, a leukaemogenic DNA crosslinking chemotherapy nitrogen mustard predicted to elicit HRR, selected against cells with deregulated HRR. These data suggest a t-AML mechanism whereby DNA MMR loss promotes the emergence of HRR gene superexpressing clones, with concomitant chromosomal instability. However, melphalan selection against clones with deregulated HRR suggests that persistence and expansion of unstable clones may require additional genetic alterations that promote cell survival

A common genetic variant in XPD associates with risk of 5q- and 7q-deleted acute myeloid leukaemia

Numerous structural genetic abnormalities observed in acute myeloid leukemia (AML) illustrate the heterogeneity of this disease, which likely has contributed to difficulty in identifying susceptibility alleles for AML. We previously reported that carriers of the glutamine-encoding allele at codon 751 of the xeroderma pigmentosum group D (XPD) DNA repair gene were significantly more likely to have a karyotype associated with a less favorable prognosis, and hypothesized that this observation was driven by an association between the codon 751 variant and risk of developing AML with specific structural abnormalities. Using a case series of 927 patients with AML, we show here that the XPD codon 751 glutamine-encoding variant significantly associates with risk of developing AML with a chromosome 5q deletion (odds ratio [OR] 2.09; 95% confidence interval [CI] 1.14-3.81; n = 69; P = .02) or a chromosome 7q deletion (OR 2.27; 95% CI 1.09-4.71; n = 47; P = .03), but not with any other commonly recurring cytogenetic lesion