Numerous Genomic Abnormalities in AML with Normal Karyotype.

Acute myeloid leukemia (AML) is a clonal hematopoietic malignant disease; about 45–50% of AML samples have no detectable chromosomal abnormality. We wanted to determine if alterations of the genome were present in these AML samples using a sensitive technique and to determine what were these common abnormalities. Thirty-seven normal karyotype AMLs were analyzed with high-density single-nucleotide polymorphism microarray (250K SNP-chip) using the new algorithm AsCNAR (allele-specific copy-number analysis using anonymous references). Nineteen samples (51%) showed either one or more genomic abnormalities including duplication, deletion and loss of heterozygosity with normal copy number [we call this somatic uniparental disomy (UPD)]. Importantly, 12 patients (32%) had UPD, causing duplication of either mutant FLT3 (2 cases), mutant JAK2 (1 case) or mutant AML1/RUNX1 (1 case); and each of these samples had loss of the normal allele. Ten patients (27%) had small copy number changes including deletions of either NF1, ETV6/TEL, or the CDKN2A (p16/INK4A and p14/ARF) and CDKN2B (p15/INK4B) gene complex; these genes can normally function as tumor suppressor genes. mRNA microarray analysis was done on all samples. One case clearly showed a relationship between chromosomal changes and mRNA expression levels: loss or gain of chromosomes leading to decrease or increase mRNA expression of genes; however, in general a loss or gain of a gene could not be detected by microarray analysis. This study suggests that at least one half of AML patients with normal karyotype have readily identifiable genomic abnormalities as found by SNP-chip and AsCNAR. Especially notable is the high frequency of UPD. This technique may become a routine, rapid, robust technique for prognostic stratification of patients and to screen for novel therapeutic targets.