Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis

Abstract

Recent advances in genome-wide single-nucleotide polymorphism (SNP) analyses have revealed previously unrecognized microdeletions and uniparental disomy (UPD) in a broad spectrum of human cancers. As acute myeloid leukemia (AML) represents a genetically heterogeneous disease, this technology might prove helpful, especially for cytogenetically normal AML (CN-AML) cases. Thus, we performed highresolution SNP analyses in 157 adult cases of CN-AML. Regions of acquired UPDs were identified in 12% of cases and in the most frequently affected chromosomes, 6p, 11p and 13q. Notably, acquired UPD was invariably associated with mutations in nucleophosmin 1 (NPM1) or CCAAT/enhancer binding protein-a (CEBPA) that impair hematopoietic differentiation (P ¼ 0.008), suggesting that UPDs may preferentially target genes that are essential for proliferation and survival of hematopoietic progenitors. Acquired copy number alterations (CNAs) were detected in 49% of cases with losses found in two or more cases affecting, for example, chromosome bands 3p13-p14.1 and 12p13. Furthermore, we identified two cases with a cryptic t(6;11) as well as several non-recurrent aberrations pointing to leukemia-relevant regions. With regard to clinical outcome, there seemed to be an association between UPD 11p and UPD 13q cases with overall survival. These data show the potential of high-resolution SNP analysis for identifying genomic regions of potential pathogenic and clinical relevance in AML.

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

“…These abnormalities include many gene mutations (NPM1 (nucleophosmin), FLT3 (fms-like tyrosine kinase receptor-3), CEBPA, MLL, N-RAS, RUNX1 (Runtrelated transcription factor 1), WT1 (Wilms tumor 1) and so on), 1 deregulation of gene expression (EVI1 (Ecotropic Viral Integration Site 1), BAALC (brain and acute leukemia, cytoplasmic), MN1 (meningioma 1), ERG (Ets-related gene), WT1 and so on), 2 --8 as well as acquired copy number variations and regions with loss of heterozygosity. 9,10 Prognostic significance within CN-AML has been well established for FLT3 internal tandem duplication (FLT3-ITD), NPM1 and CEBPA mutations. 11,12 NPM1 mutations confer a relatively favorable clinical outcome in CN-AML in the absence of a concomitant adverse FLT3-ITD.…”

Helicase-like transcription factor is a RUNX1 target whose downregulation promotes genomic instability and correlates with complex cytogenetic features in acute myeloid leukemia

“…These observations suggest broad impacts of HLTF reduction on chromosomal instability across AML subtypes. Previous studies have shown that submicroscopic copy number alterations are present in about half of the cytogenetically normal AML patients, 35 and whether HLTF also impacts on these alterations warrants further investigation. Regarding prognostication, we revealed in this study an inverse correlation between reduced HLTF and CEBPA double mutations in adult AML patients.…”

Pretransplant HLA mistyping in diagnostic samples of acute myeloid leukemia patients due to acquired uniparental disomy

“…A more recent genome-wide single-nucleotide polymorphism analysis of 157 cytogenetically normal AML adult patients also reported a 17% aUPD incidence. 14 We report herein six patients whose HLA typing was performed on peripheral blood lymphocytes obtained from AML patients in acute phase at diagnosis and led to an apparent LOH as determined by PCR sequence-specific oligonucleotide (SSO)/ sequence-based typing (SBT) using locus-specific primers. Comparative genomic hybridization (CGH) on microarrays did not reveal any copy number variation of HLA loci at 6p21 that could account for the loss of haplotypes, and thus allowed to confirm that the HLA homozygosity was due to aUPD.…”