Target cell frequency is a genetically determined risk factor in radiation leukaemogenesis

Abstract

Whole body exposure to ionizing radiation increases the risk of radiation-induced acute myeloid leukaemia (r-AML). r-AML is the result of the accumulation of mutations in a single haemopoietic stem cell, so risk is therefore a function of the number of mutations required to transform the stem cell and the mutation rate. There is a genetic component to the risk of AML within the general population, and low penetrance variant alleles encoding DNA repair enzymes have been genetically implicated in therapy-related AML susceptibility. However, what is largely ignored is that target cell number, which defines the number of genomes at risk from DNA damaging agents, is also part of the equation that defines risk. We will review the evidence from genetic studies of inbred mouse models that target cell frequency is a risk factor in radiation leukaemogenesis. Inbred mouse strains that differ in their susceptibility to radiation-induced r-AML and thymic lymphoma (r-TL), spontaneous TL and pristane-induced plasmacytoma (PCT) have been exploited to identify susceptibility loci. The target cell in AML is the haemopoietic stem cell, whereas TLs and PCT arise from more mature lymphoid progenitor cells. Inbred mice also differ significantly in all aspects of haemopoiesis, and these differences have been used to identify quantitative trait loci (QTL) that determine the frequency of specific haemopoietic stem, progenitor or mature blood cells. The co-localization of QTL that determine risk and target cell frequency in all three haemopoietic malignancies is strong evidence that target cell frequency is a risk factor in radiation leukaemogenesis.

Quantitative trait loci associated with susceptibility to therapy-related acute murine promyelocytic leukemia in hCG-PML/RARA transgenic mice

“…Studies in mice 17,30 and humans 31,32 support the concept that susceptibility to myeloid leukemia has a genetic component. In addition, environmental factors (eg, genotoxic therapy) and geneby-environment interactions contribute to t-AML susceptibility.…”

“…Intermediate phenotypes relevant for t-AML include the response to DNA damage, the efficiency of drug metabolism, and/or the frequency of cells vulnerable to transformation. Correspondingly, QTLs influencing stem cell number 30 and genes involved in DNA repair and drug metabolism [12][13][14] have been associated with t-AML susceptibility. Human studies have identified a limited number of genetic variants that are more prevalent in affected persons, but because of the complex nature of t-AML susceptibility, it is likely that important genetic determinants have not yet been identified.…”

ICRP Publication 131: Stem Cell Biology with Respect to Carcinogenesis Aspects of Radiological Protection

“…(2001) is instructive; using a PCR-based molecular approach, these workers showed that the frequency of the radiation-induced ‘loss of heterozygosity’ (LOH) of chromosome 2 within stem cells of CBA/H × C57BL/6 F 1 mice was no greater than the induced LOH in other control chromosomal regions evaluated. (A69) So what are the rate limiting steps? It has been suggested that the absolute number of marrow stem cells defines the number of potential radiation-transformable genomes, and in turn, overall leukaemogenic risk (Jawad et al., 2007). If this is the case, then it is the number of available targets within the defined radiation volume that determines the leukaemic rate, and in turn, the efficiency of the irradiation.…”

“…(A69) So what are the rate limiting steps? It has been suggested that the absolute number of marrow stem cells defines the number of potential radiation-transformable genomes, and in turn, overall leukaemogenic risk (Jawad et al., 2007). If this is the case, then it is the number of available targets within the defined radiation volume that determines the leukaemic rate, and in turn, the efficiency of the irradiation.…”

QTL analyses of lineage-negative mouse bone marrow cells labeled with Sca-1 and c-Kit

“…Genetic loci that confer a susceptibility to spontaneous or induced haemopoietic malignancies have also been mapped in mice, and differences in the relative frequency of the target cell (target size) may be one genetically determined risk factor (recently reviewed by Jawad et al 2007b). For example, QTL that determine the susceptibility to spontaneous pre-B and T lymphomas were both mapped to proximal chromosome 17 (Yamada et al 1994a(Yamada et al , 1994b, and thus implicates the H-2 complex in both the regulation of bone marrow stem and progenitor cell frequencies and a susceptibility to spontaneous lymphoid lymphomas.…”