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急性髓系白血病中含有 MYC 的扩增子：基因组结构、进化和转录后果。

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

机构信息

Department of Biology, University of Bari "Aldo Moro", Bari, Italy.

Institute for Biomedical Technologies (ITB), CNR, Segrate, Italy.

出版信息

Leukemia. 2018 Oct;32(10):2152-2166. doi: 10.1038/s41375-018-0033-0. Epub 2018 Feb 22.

DOI:10.1038/s41375-018-0033-0
PMID:29467491
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6170393/
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 association to novel fusion transcripts and circular RNAs.

摘要

双微体（dmin）、均染区和环状染色体是癌症中基因扩增的载体。导致它们形成的潜在机制，以及它们在急性髓系白血病（AML）中的结构和功能仍然是个谜。我们结合了一系列高分辨率基因组方法，研究了涉及 AML 中的染色体带 8q24 的扩增子的结构和表达模式（AML-amp）。这表明，不同的 MYC-dmin 结构可以在同一白血病细胞群体中共存，表明这是一个逐步进化的过程，而不是单一事件的起源，例如通过染色体重排。这也得到了分析染色体重排标准的支持，这些标准与我们样本中的模型不太匹配。此外，我们发现 dmin 可以向由新着丝粒稳定的环状染色体进化。令人惊讶的是，扩增的基因（主要是 PVT1）经常参与缺乏相应 DNA 模板的融合转录本。我们还检测到 AML-amp 病例中 PVT1 的环状 RNA（circPVT1）的显著过表达，而 AML 具有正常核型。我们的研究结果表明，AML 中的 8q24 扩增子是具有惊人可塑性的 DNA 结构，与新型融合转录本和环状 RNA 具有意想不到的关联。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea36/6170393/7415cef7a54d/41375_2018_33_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea36/6170393/14ea84587496/41375_2018_33_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea36/6170393/aed0a2714cc7/41375_2018_33_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea36/6170393/c8d419cef553/41375_2018_33_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea36/6170393/a415368cf8ad/41375_2018_33_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea36/6170393/7415cef7a54d/41375_2018_33_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea36/6170393/14ea84587496/41375_2018_33_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea36/6170393/aed0a2714cc7/41375_2018_33_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea36/6170393/c8d419cef553/41375_2018_33_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea36/6170393/a415368cf8ad/41375_2018_33_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea36/6170393/7415cef7a54d/41375_2018_33_Fig5_HTML.jpg

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