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 language | English |
|---|---|
| Pages (from-to) | 1-15 |
| Number of pages | 15 |
| Journal | Leukemia |
| DOIs | |
| Publication status | Accepted/In press - Feb 22 2018 |
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ASJC Scopus subject areas
- Hematology
- Cancer Research
- Anesthesiology and Pain Medicine
Cite this
MYC-containing amplicons in acute myeloid leukemia : genomic structures, evolution, and transcriptional consequences. / L´Abbate, Alberto; Tolomeo, Doron; Cifola, Ingrid; Severgnini, Marco; Turchiano, Antonella; Augello, Bartolomeo; Squeo, Gabriella; D´Addabbo, Pietro; Traversa, Debora; Daniele, Giulia; Lonoce, Angelo; Pafundi, Mariella; Carella, Massimo; Palumbo, Orazio; Dolnik, Anna; Muehlematter, Dominique; Schoumans, Jacqueline; van Roy, Nadine; de Bellis, Gianluca; Martinelli, Giovanni; Merla, Giuseppe; Bullinger, Lars; Haferlach, Claudia; Storlazzi, Clelia Tiziana.
In: Leukemia, 22.02.2018, p. 1-15.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MYC-containing amplicons in acute myeloid leukemia
T2 - genomic structures, evolution, and transcriptional consequences
AU - L´Abbate, Alberto
AU - Tolomeo, Doron
AU - Cifola, Ingrid
AU - Severgnini, Marco
AU - Turchiano, Antonella
AU - Augello, Bartolomeo
AU - Squeo, Gabriella
AU - D´Addabbo, Pietro
AU - Traversa, Debora
AU - Daniele, Giulia
AU - Lonoce, Angelo
AU - Pafundi, Mariella
AU - Carella, Massimo
AU - Palumbo, Orazio
AU - Dolnik, Anna
AU - Muehlematter, Dominique
AU - Schoumans, Jacqueline
AU - van Roy, Nadine
AU - de Bellis, Gianluca
AU - Martinelli, Giovanni
AU - Merla, Giuseppe
AU - Bullinger, Lars
AU - Haferlach, Claudia
AU - Storlazzi, Clelia Tiziana
PY - 2018/2/22
Y1 - 2018/2/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85042218005&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85042218005&partnerID=8YFLogxK
U2 - 10.1038/s41375-018-0033-0
DO - 10.1038/s41375-018-0033-0
M3 - Article
AN - SCOPUS:85042218005
SP - 1
EP - 15
JO - Leukemia
JF - Leukemia
SN - 0887-6924
ER -