Genetic susceptibility to radiation-induced acute myeloid leukaemia (r-AML)
CBA/H inbred mice are susceptible to radiation-induced acute myeloid leukaemia (r-AML) while C57BL/6 mice are resistant to r-AML. CBA/H mice also have higher haemopoietic stem cell number (HSC) than C57BL/6 mice raising the possibility that HSC frequency is a risk factor in r-AML. F2 mice were therefore analysed to map QTL that determine the frequency of phenotypically defined bone marrow cells. The Lin-Sca-1+c-Kit+ cell QTL in F2 mice mapped to chromosomes 1 (65cM), 17 (6cM), and 18 (21cM), genetic evidence that they are HSC, while the more mature Lin-Sca-1+FLK-2+ cell QTL mapped to chromosome 9 (33cM), a novel progenitor cell frequency QTL. The same F2 mice were also scored for difference in peripheral blood and bone marrow red blood cell counts (RBC), and spleen weight, so QTL were mapped for these phenotypes. Different autosomal loci affect bone marrow (chromosome 5, 9, 11, and 19) and peripheral blood RBC counts (chromosome 4), and spleen weight (chromosomes 3, 15, and 17). This suggests that the relative contributions of spleen and bone marrow erythropoiesis to peripheral RBC counts are genetically determined in mouse. A human AML genetic association study was carried out to assess the contribution of variant alleles to risk of AML in patients with de novo or therapy-related AML (t-AML) compared to age matched controls. In humans, a variant HLX1 allele was associated with a 4-fold increased risk of t-AML. Together with a variant RAD51 DNA repair allele, the variant HLX1 allele increased the risk of t-AML by 14-fold. The variant HLX1 gene may determine stem cell frequency (target size) during chemo-/radiotherapy therapy and a reduced ability to repair therapy-induced DNA damage will increase the risk of malignant transformation.