Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia

Tyrone Ryba, Dana Battaglia, Bill Chang, James W. Shirley, Quinton Buckley, Benjamin D. Pope, Meenakshi Devidas, Brian Druker, David M. Gilbert

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Abnormal replication timing has been observed in cancer but no study has comprehensively evaluated this misregulation. We generated genome-wide replication-timing profiles for pediatric leukemias from 17 patients and three cell lines, as well as normal B and T cells. Nonleukemic EBV-transformed lymphoblastoid cell lines displayed highly stable replication-timing profiles that were more similar to normal T cells than to leukemias. Leukemias were more similar to each other than to B and T cells but were considerably more heterogeneous than nonleukemic controls. Some differences were patient specific, while others were found in all leukemic samples, potentially representing early epigenetic events. Differences encompassed large segments of chromosomes and included genes implicated in other types of cancer. Remarkably, differences that distinguished leukemias aligned in register to the boundaries of developmentally regulated replication-timing domains that distinguish normal cell types. Most changes did not coincide with copy-number variation or translocations. However, many of the changes that were associated with translocations in some leukemias were also shared between all leukemic samples independent of the genetic lesion, suggesting that they precede and possibly predispose chromosomes to the translocation. Altogether, our results identify sites of abnormal developmental control of DNA replication in cancer that reveal the significance of replication-timing boundaries to chromosome structure and function and support the replication domain model of replication-timing regulation. They also open new avenues of investigation into the chromosomal basis of cancer and provide a potential novel source of epigenetic cancer biomarkers.

Original languageEnglish (US)
Pages (from-to)1833-1844
Number of pages12
JournalGenome Research
Volume22
Issue number10
DOIs
StatePublished - Oct 2012

Fingerprint

Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia
Pediatrics
Epigenomics
Neoplasms
B-Lymphocytes
Chromosomes
Chromosome Structures
T-Lymphocytes
T-Cell Leukemia
Transformed Cell Line
Tumor Biomarkers
DNA Replication
Human Herpesvirus 4
Genome
Cell Line
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Ryba, T., Battaglia, D., Chang, B., Shirley, J. W., Buckley, Q., Pope, B. D., ... Gilbert, D. M. (2012). Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia. Genome Research, 22(10), 1833-1844. https://doi.org/10.1101/gr.138511.112

Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia. / Ryba, Tyrone; Battaglia, Dana; Chang, Bill; Shirley, James W.; Buckley, Quinton; Pope, Benjamin D.; Devidas, Meenakshi; Druker, Brian; Gilbert, David M.

In: Genome Research, Vol. 22, No. 10, 10.2012, p. 1833-1844.

Research output: Contribution to journalArticle

Ryba, T, Battaglia, D, Chang, B, Shirley, JW, Buckley, Q, Pope, BD, Devidas, M, Druker, B & Gilbert, DM 2012, 'Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia', Genome Research, vol. 22, no. 10, pp. 1833-1844. https://doi.org/10.1101/gr.138511.112
Ryba, Tyrone ; Battaglia, Dana ; Chang, Bill ; Shirley, James W. ; Buckley, Quinton ; Pope, Benjamin D. ; Devidas, Meenakshi ; Druker, Brian ; Gilbert, David M. / Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia. In: Genome Research. 2012 ; Vol. 22, No. 10. pp. 1833-1844.
@article{2d07e05ccb12443fbd1bcee0540ee6f2,
title = "Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia",
abstract = "Abnormal replication timing has been observed in cancer but no study has comprehensively evaluated this misregulation. We generated genome-wide replication-timing profiles for pediatric leukemias from 17 patients and three cell lines, as well as normal B and T cells. Nonleukemic EBV-transformed lymphoblastoid cell lines displayed highly stable replication-timing profiles that were more similar to normal T cells than to leukemias. Leukemias were more similar to each other than to B and T cells but were considerably more heterogeneous than nonleukemic controls. Some differences were patient specific, while others were found in all leukemic samples, potentially representing early epigenetic events. Differences encompassed large segments of chromosomes and included genes implicated in other types of cancer. Remarkably, differences that distinguished leukemias aligned in register to the boundaries of developmentally regulated replication-timing domains that distinguish normal cell types. Most changes did not coincide with copy-number variation or translocations. However, many of the changes that were associated with translocations in some leukemias were also shared between all leukemic samples independent of the genetic lesion, suggesting that they precede and possibly predispose chromosomes to the translocation. Altogether, our results identify sites of abnormal developmental control of DNA replication in cancer that reveal the significance of replication-timing boundaries to chromosome structure and function and support the replication domain model of replication-timing regulation. They also open new avenues of investigation into the chromosomal basis of cancer and provide a potential novel source of epigenetic cancer biomarkers.",
author = "Tyrone Ryba and Dana Battaglia and Bill Chang and Shirley, {James W.} and Quinton Buckley and Pope, {Benjamin D.} and Meenakshi Devidas and Brian Druker and Gilbert, {David M.}",
year = "2012",
month = "10",
doi = "10.1101/gr.138511.112",
language = "English (US)",
volume = "22",
pages = "1833--1844",
journal = "PCR Methods and Applications",
issn = "1088-9051",
publisher = "Cold Spring Harbor Laboratory Press",
number = "10",

}

TY - JOUR

T1 - Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia

AU - Ryba, Tyrone

AU - Battaglia, Dana

AU - Chang, Bill

AU - Shirley, James W.

AU - Buckley, Quinton

AU - Pope, Benjamin D.

AU - Devidas, Meenakshi

AU - Druker, Brian

AU - Gilbert, David M.

PY - 2012/10

Y1 - 2012/10

N2 - Abnormal replication timing has been observed in cancer but no study has comprehensively evaluated this misregulation. We generated genome-wide replication-timing profiles for pediatric leukemias from 17 patients and three cell lines, as well as normal B and T cells. Nonleukemic EBV-transformed lymphoblastoid cell lines displayed highly stable replication-timing profiles that were more similar to normal T cells than to leukemias. Leukemias were more similar to each other than to B and T cells but were considerably more heterogeneous than nonleukemic controls. Some differences were patient specific, while others were found in all leukemic samples, potentially representing early epigenetic events. Differences encompassed large segments of chromosomes and included genes implicated in other types of cancer. Remarkably, differences that distinguished leukemias aligned in register to the boundaries of developmentally regulated replication-timing domains that distinguish normal cell types. Most changes did not coincide with copy-number variation or translocations. However, many of the changes that were associated with translocations in some leukemias were also shared between all leukemic samples independent of the genetic lesion, suggesting that they precede and possibly predispose chromosomes to the translocation. Altogether, our results identify sites of abnormal developmental control of DNA replication in cancer that reveal the significance of replication-timing boundaries to chromosome structure and function and support the replication domain model of replication-timing regulation. They also open new avenues of investigation into the chromosomal basis of cancer and provide a potential novel source of epigenetic cancer biomarkers.

AB - Abnormal replication timing has been observed in cancer but no study has comprehensively evaluated this misregulation. We generated genome-wide replication-timing profiles for pediatric leukemias from 17 patients and three cell lines, as well as normal B and T cells. Nonleukemic EBV-transformed lymphoblastoid cell lines displayed highly stable replication-timing profiles that were more similar to normal T cells than to leukemias. Leukemias were more similar to each other than to B and T cells but were considerably more heterogeneous than nonleukemic controls. Some differences were patient specific, while others were found in all leukemic samples, potentially representing early epigenetic events. Differences encompassed large segments of chromosomes and included genes implicated in other types of cancer. Remarkably, differences that distinguished leukemias aligned in register to the boundaries of developmentally regulated replication-timing domains that distinguish normal cell types. Most changes did not coincide with copy-number variation or translocations. However, many of the changes that were associated with translocations in some leukemias were also shared between all leukemic samples independent of the genetic lesion, suggesting that they precede and possibly predispose chromosomes to the translocation. Altogether, our results identify sites of abnormal developmental control of DNA replication in cancer that reveal the significance of replication-timing boundaries to chromosome structure and function and support the replication domain model of replication-timing regulation. They also open new avenues of investigation into the chromosomal basis of cancer and provide a potential novel source of epigenetic cancer biomarkers.

UR - http://www.scopus.com/inward/record.url?scp=84866384009&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866384009&partnerID=8YFLogxK

U2 - 10.1101/gr.138511.112

DO - 10.1101/gr.138511.112

M3 - Article

C2 - 22628462

AN - SCOPUS:84866384009

VL - 22

SP - 1833

EP - 1844

JO - PCR Methods and Applications

JF - PCR Methods and Applications

SN - 1088-9051

IS - 10

ER -