Investigation of the genetics of acute myeloid leukaemia (AML) has revealed the underlying basis of the disease and led to targets for therapy. High-resolution single nucleotide polymorphism (SNP) arrays detected regions of loss of heterozygosity and DNA copy number changes, augmenting the results of conventional cytogenetic analysis in AML. Fifteen out of 72 (20%) primary AML samples exhibited large regions of homozygosity that could not be accounted for by visible chromosomal abnormalities in the karyotype. Further analysis confirmed that these patterns were due to partial uniparental disomy (UPD). Remission marrow was available from five patients showing UPD in their leukemias, and in all cases the homozygosity was found to be restricted to the diagnostic leukemic clone. These cryptic nonrandom chromosomal abnormalities are characteristic of mitotic recombination. In 7 of 13 cases with UPD, concurrent homozygous mutations were identified at four distinct loci (WTI, FLT3, CEBPA, and RUNXI). This implies that mutation precedes mitotic recombination which acts as a "second hit" responsible for removal of the remaining wild-type allele. Clonal evolution from heterozygous to homozygous mutations by mitotic recombination would provide a mechanism for relapse of AML. Analysis of 27 paired diagnostic and relapsed AML samples demonstrated newly acquired segmental UPDs at relapse in 11 AML samples (40%). Six were segmental UPDs of chromosome 13q, which led to a change from heterozygosity to homozygosity for internal tandem duplication of FLT3. Three further AML samples had evidence of acquired segmental UPD of 13q in a subclone of the relapsed leukemia. One patient acquired segmental UPD of 19q which led to homozygosity for a CEBPA mutation 207 C-'T. Finally, a single AML patient acquired segmental UPD of chromosome 4q, for which the candidate gene is unknown. In conclusion, the acquisition of segmental UPD and the resulting homozygous mutation is a common event associated with relapse of AML.