MYC-containing amplicons in acute myeloid leukemia: genomic structures, evolution, and transcriptional consequences

Leukemia
Alberto L'AbbateClelia Tiziana Storlazzi

Abstract

Double minutes (dmin), homogeneously staining regions, and ring chromosomes are vehicles of gene amplification in cancer. The underlying mechanism leading to their formation as well as their structure and function in acute myeloid leukemia (AML) remain mysterious. We combined a range of high-resolution genomic methods to investigate the architecture and expression pattern of amplicons involving chromosome band 8q24 in 23 cases of AML (AML-amp). This revealed that different MYC-dmin architectures can coexist within the same leukemic cell population, indicating a step-wise evolution rather than a single event origin, such as through chromothripsis. This was supported also by the analysis of the chromothripsis criteria, that poorly matched the model in our samples. Furthermore, we found that dmin could evolve toward ring chromosomes stabilized by neocentromeres. Surprisingly, amplified genes (mainly PVT1) frequently participated in fusion transcripts lacking a corresponding DNA template. We also detected a significant overexpression of the circular RNA of PVT1 (circPVT1) in AML-amp cases versus AML with a normal karyotype. Our results show that 8q24 amplicons in AML are surprisingly plastic DNA structures with an unexpected associ...Continue Reading

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Jul 7, 2018·Leukemia & Lymphoma·Katherine L B Knorr, Martin S Tallman
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Datasets Mentioned

BETA
MF125224
MF125228
E-MTAB-5372
PRJNA386992

Methods Mentioned

BETA
RNA-seq
PCR

Software Mentioned

DAVID
DESeq2 Bioconductor
R
GSEA
ToppGene
REST
FusionMap ( FM )
DELLY
MSigDB
ChimeraScan ( CS )

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