Advances in the understanding of susceptibility to treatment‐related acute myeloid leukaemia

Abstract

SummaryTreatment-related acute myeloid leukaemia (t-AML) is a devastating complication following exposure to the cytotoxic and genotoxic agents used to treat a primary malignancy. Whilst the incidence of t-AML is rising, it still only occurs in a minority of patients who have received chemotherapy and/or radiotherapy treatment and hence it is important to identify factors that may confer susceptibility to the development of the condition. This paper reviews the literature and discusses the advances and limitations in our understanding of susceptibility factors to t-AML. In particular, it concentrates upon genetic polymorphisms in detoxification genes and in genes belonging to the major DNA repair pathways. This review also considers more novel susceptibility factors, such as those proposed to determine stem cell number. Increased understanding of t-AML susceptibility may enable steps to be taken to prevent its development and increase the effectiveness of treatment of the disease.

Therapy-related acute myeloid leukaemia with t(8;16)(p11;p13);MOZ-CBP and polymorphisms in detoxifying and DNA repair genes

“…2 This reduces or eliminates the effectiveness of the enzyme leading to inadequate clearance of potentially genotoxic metabolites. Polymorphisms in genes encoding DNA repair enzymes were detected in all three patients ( Table 2).…”

“…However, an unwelcome consequence of this success has been an increase in the incidence of secondary malignancies. [1][2][3] Therapy-related myeloid neoplasms, including therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplasia, can occur in patients after therapy for both solid tumours and haematological malignancies. 3,4 The cumulative risk of t-AML at 10 years after treatment for breast cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma and ovarian cancer, for example, has been estimated as 1.5, 3.8, 7.9 and 8.5%, respectively.…”

“…3,5,6 The risk of t-AML may also, in part, be due to inherited genetic factors. 2 These factors include polymorphisms within genes encoding detoxifying enzymes, such as members of the P450 protein family (CYP1A1), the quinone oxidoreductase enzyme (NQO1) and members of the glutathione S-transferase (GST) family, and polymorphisms within genes encoding DNA repair enzymes. 2 Detoxifying enzymes comprise two main groups.…”

“…2 These factors include polymorphisms within genes encoding detoxifying enzymes, such as members of the P450 protein family (CYP1A1), the quinone oxidoreductase enzyme (NQO1) and members of the glutathione S-transferase (GST) family, and polymorphisms within genes encoding DNA repair enzymes. 2 Detoxifying enzymes comprise two main groups. The first or phase I enzymes, such as Cytochrome P450s, yield highly reactive metabolites, which are subsequently detoxified and metabolized by the second or phase II enzymes, such as NQO1 and GSTs.…”

“…The first or phase I enzymes, such as Cytochrome P450s, yield highly reactive metabolites, which are subsequently detoxified and metabolized by the second or phase II enzymes, such as NQO1 and GSTs. 2,7 DNA repair enzymes such as RAD51, XPD and XRCC3 are required to maintain genetic integrity and stability. Polymorphisms in the genes encoding either of these types of enzymes have been reported to increase susceptibility to a number of malignancies.…”