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Binomial mitotic segregation of MYCN-carrying double minutes in neuroblastoma illustrates the role of randomness in oncogene amplification.

Lundberg, Gisela LU ; Rosengren, Anders LU ; Håkanson, Ulf LU ; Stewenius, Henrik LU ; Jin, Yuesheng LU ; Stewénius, Ylva LU ; Påhlman, Sven LU and Gisselsson Nord, David LU (2008) In PLoS One 3(8).
Abstract
BACKGROUND: Amplification of the oncogene MYCN in double minutes (DMs) is a common finding in neuroblastoma (NB). Because DMs lack centromeric sequences it has been unclear how NB cells retain and amplify extrachromosomal MYCN copies during tumour development. PRINCIPAL FINDINGS: We show that MYCN-carrying DMs in NB cells translocate from the nuclear interior to the periphery of the condensing chromatin at transition from interphase to prophase and are preferentially located adjacent to the telomere repeat sequences of the chromosomes throughout cell division. However, DM segregation was not affected by disruption of the telosome nucleoprotein complex and DMs readily migrated from human to murine chromatin in human/mouse cell hybrids,... (More)
BACKGROUND: Amplification of the oncogene MYCN in double minutes (DMs) is a common finding in neuroblastoma (NB). Because DMs lack centromeric sequences it has been unclear how NB cells retain and amplify extrachromosomal MYCN copies during tumour development. PRINCIPAL FINDINGS: We show that MYCN-carrying DMs in NB cells translocate from the nuclear interior to the periphery of the condensing chromatin at transition from interphase to prophase and are preferentially located adjacent to the telomere repeat sequences of the chromosomes throughout cell division. However, DM segregation was not affected by disruption of the telosome nucleoprotein complex and DMs readily migrated from human to murine chromatin in human/mouse cell hybrids, indicating that they do not bind to specific positional elements in human chromosomes. Scoring DM copy-numbers in ana/telophase cells revealed that DM segregation could be closely approximated by a binomial random distribution. Colony-forming assay demonstrated a strong growth-advantage for NB cells with high DM (MYCN) copy-numbers, compared to NB cells with lower copy-numbers. In fact, the overall distribution of DMs in growing NB cell populations could be readily reproduced by a mathematical model assuming binomial segregation at cell division combined with a proliferative advantage for cells with high DM copy-numbers. CONCLUSION: Binomial segregation at cell division explains the high degree of MYCN copy-number variability in NB. Our findings also provide a proof-of-principle for oncogene amplification through creation of genetic diversity by random events followed by Darwinian selection. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS One
volume
3
issue
8
publisher
Public Library of Science
external identifiers
  • WOS:000264796800006
  • PMID:18769732
  • Scopus:51849083862
ISSN
1932-6203
DOI
10.1371/journal.pone.0003099
language
English
LU publication?
yes
id
a79126ce-8c3f-4240-92bc-4c1d5c93f29b (old id 1243390)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18769732?dopt=Abstract
date added to LUP
2008-10-03 15:53:22
date last changed
2016-10-13 04:30:09
@misc{a79126ce-8c3f-4240-92bc-4c1d5c93f29b,
  abstract     = {BACKGROUND: Amplification of the oncogene MYCN in double minutes (DMs) is a common finding in neuroblastoma (NB). Because DMs lack centromeric sequences it has been unclear how NB cells retain and amplify extrachromosomal MYCN copies during tumour development. PRINCIPAL FINDINGS: We show that MYCN-carrying DMs in NB cells translocate from the nuclear interior to the periphery of the condensing chromatin at transition from interphase to prophase and are preferentially located adjacent to the telomere repeat sequences of the chromosomes throughout cell division. However, DM segregation was not affected by disruption of the telosome nucleoprotein complex and DMs readily migrated from human to murine chromatin in human/mouse cell hybrids, indicating that they do not bind to specific positional elements in human chromosomes. Scoring DM copy-numbers in ana/telophase cells revealed that DM segregation could be closely approximated by a binomial random distribution. Colony-forming assay demonstrated a strong growth-advantage for NB cells with high DM (MYCN) copy-numbers, compared to NB cells with lower copy-numbers. In fact, the overall distribution of DMs in growing NB cell populations could be readily reproduced by a mathematical model assuming binomial segregation at cell division combined with a proliferative advantage for cells with high DM copy-numbers. CONCLUSION: Binomial segregation at cell division explains the high degree of MYCN copy-number variability in NB. Our findings also provide a proof-of-principle for oncogene amplification through creation of genetic diversity by random events followed by Darwinian selection.},
  author       = {Lundberg, Gisela and Rosengren, Anders and Håkanson, Ulf and Stewenius, Henrik and Jin, Yuesheng and Stewénius, Ylva and Påhlman, Sven and Gisselsson Nord, David},
  issn         = {1932-6203},
  language     = {eng},
  number       = {8},
  publisher    = {ARRAY(0xaab1e70)},
  series       = {PLoS One},
  title        = {Binomial mitotic segregation of MYCN-carrying double minutes in neuroblastoma illustrates the role of randomness in oncogene amplification.},
  url          = {http://dx.doi.org/10.1371/journal.pone.0003099},
  volume       = {3},
  year         = {2008},
}