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

Alberto L´Abbate, Doron Tolomeo, Ingrid Cifola, Marco Severgnini, Antonella Turchiano, Bartolomeo Augello, Gabriella Squeo, Pietro D´Addabbo, Debora Traversa, Giulia Daniele, Angelo Lonoce, Mariella Pafundi, Massimo Carella, Orazio Palumbo, Anna Dolnik, Dominique Muehlematter, Jacqueline Schoumans, Nadine van Roy, Gianluca de Bellis, Giovanni MartinelliGiuseppe Merla, Lars Bullinger, Claudia Haferlach, Clelia Tiziana Storlazzi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalLeukemia
DOIs
Publication statusAccepted/In press - Feb 22 2018

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

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    L´Abbate, A., Tolomeo, D., Cifola, I., Severgnini, M., Turchiano, A., Augello, B., Squeo, G., D´Addabbo, P., Traversa, D., Daniele, G., Lonoce, A., Pafundi, M., Carella, M., Palumbo, O., Dolnik, A., Muehlematter, D., Schoumans, J., van Roy, N., de Bellis, G., ... Storlazzi, C. T. (Accepted/In press). MYC-containing amplicons in acute myeloid leukemia: genomic structures, evolution, and transcriptional consequences. Leukemia, 1-15. https://doi.org/10.1038/s41375-018-0033-0