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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.

The TEL-AMLl fusion is the result of t(12;21) (p13;q22), the most frequent chromosomal translocation in childhood B-cell ALL. Recent studies have found a positive correlation with TEL-AMLl and EpoR expression. Three possible mechanisms of up-regulation were investigated in this study: Gene expression analysis, DNA methylation and microRNAs. Microarray analysis compared TEL-AMLl positive and negative gene expression profiles to identify differentially expressed genes. Genes with well known roles in haematopoiesis were also examined. GATA-2 showed a similar expression profile to EpoR, with a higher expression found in TEL-AMLl positive cells. Over-expression of GATA-2 increased EpoR expression further in TEL-AMLl positive cells providing evidence of a link between GATA-2 and EpoR expression in the presence of the fusion protein. DNA methylation analysis of EpoR and GATA-2 promoter regions showed a much higher level of methylation in TEL-AMLl negative cells. After treatment with a demethylating agent EpoR levels did not increase indicating EpoR expression was not epigenetically controlled. However, demethylation of GATA-2 increased expression in both TEL-AMLl positive and negative samples indicating a direct role for DNA methylation with GATA-2 expression. MicroRNAs are short non-coding RNA molecules with the ability to post-transcriptionally regulate genes by binding to the 3•UTR. Taqman microRNA arrays allowed simultaneous analysis of 667 commonly found microRNAs in both TEL-AMLl positive and negative cells. Arrays were analysed and compared with target prediction results to identify microRNAs that could target EpoR and GATA-2. Over-expression of miR-362 showed down-regulation of EpoR protein levels. Over-expression of miR-650 showed down-regulation of both GATA-2 and EpoR. Together these results support a theory of an "EpoR friendly" environment in TEL-AMLl positive cells to aid and promote EpoR expression. This includes an increase in GATA-2 and a decrease in DNA methylation and microRNA expression. These factors are reversed in TEL-AMLl negative cells to hinder EpoR expression.