Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias.
Genome-wide single nucleotide polymorphism analysis has revealed large-scale cryptic regions of acquired homozygosity in the form of segmental uniparental disomy in approximately 20% of acute myeloid leukemias. We have investigated whether such regions, which are the consequence of mitotic recombination, contain homozygous mutations in genes known to be mutational targets in leukemia. In 7 of 13 cases with uniparental disomy, we identified concurrent homozygous mutations at four distinct loci (WT1, FLT3, CEBPA, and RUNX1). This implies that mutation precedes mitotic recombination which acts as a "second hit" responsible for removal of the remaining wild-type allele, as has recently been shown for the JAK2 gene in myeloproliferative disorders.
Fitzgibbon
Jude
J
Cancer Research UK Medical Oncology Laboratory, Barts and the Royal London School of Medicine, Queen Mary College, London, United Kingdom.
Smith
Lan-Lan
LL
Raghavan
Manoj
M
Smith
Matthew L
ML
Debernardi
Silvana
S
Skoulakis
Spyros
S
Lillington
Debra
D
Lister
T Andrew
TA
Young
Bryan D
BD
D000208:Acute Disease; D001483:Base Sequence; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D016162:Genes, Wilms Tumor; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D024182:Uniparental Disomy; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D022763:CCAAT-Enhancer-Binding Protein-alpha; D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3