Epigenetic deregulation in pediatric acute lymphoblastic leukemia

Zac Chatterton; Leah Morenos; Francoise Mechinaud; David M. Ashley; Jeffrey M. Craig; Alexandra Sexton-Oates; Minhee S. Halemba; Mandy Parkinson-Bates; Jane Ng; Debra Morrison; William L. Carroll; Richard Saffery; Nicholas C. Wong

doi:10.4161/epi.27585

Epigenetic deregulation in pediatric acute lymphoblastic leukemia

Zac Chatterton, Leah Morenos, Francoise Mechinaud, David M. Ashley, Jeffrey M. Craig, Alexandra Sexton-Oates, Minhee S. Halemba, Mandy Parkinson-Bates, Jane Ng, Debra Morrison, William L. Carroll, Richard Saffery, Nicholas C. Wong

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

Similar to most cancers, genome-wide DNA methylation profiles are commonly altered in pediatric acute lymphoblastic leukemia (ALL); however, recent observations highlight that a large portion of malignancy-associated DNA methylation alterations are not accompanied by related gene expression changes. By analyzing and integrating the methylome and transcriptome profiles of pediatric B-cell ALL cases and primary tissue controls, we report 325 genes hypermethylated and downregulated and 45 genes hypomethylated and upregulated in pediatric B-cell ALL, irrespective of subtype. Repressed cation channel subunits and cAMP signaling activators and transducers are overrepresented, potentially indicating a reduced cellular potential to receive and propagate apoptotic signals. Furthermore, we report specific DNA methylation alterations with concurrent gene expression changes within individual ALL subtypes. The ETV6-RUNX1 translocation was associated with downregulation of ASNS and upregulation of the EPO-receptor, while Hyperdiploid patients (>50 chr) displayed upregulation of B-cell lymphoma (BCL) members and repression of PTPRG and FHIT. In combination, these data indicate genetically distinct B-cell ALL subtypes contain cooperative epimutations and genome-wide epigenetic deregulation is common across all B-cell ALL subtypes.

Original language	English
Pages (from-to)	459-467
Number of pages	9
Journal	Epigenetics
Volume	9
Issue number	3
DOIs	https://doi.org/10.4161/epi.27585
State	Published - 6 Jan 2014
Externally published	Yes

Keywords

ALL
Acute lymphoblastic leukemia
B-cell
DNA methylation
Epigenetics
Hematology
Leukemia

Access to Document

10.4161/epi.27585

Cite this

@article{199ebe189a4341828d8e79236c6d3c53,

title = "Epigenetic deregulation in pediatric acute lymphoblastic leukemia",

abstract = "Similar to most cancers, genome-wide DNA methylation profiles are commonly altered in pediatric acute lymphoblastic leukemia (ALL); however, recent observations highlight that a large portion of malignancy-associated DNA methylation alterations are not accompanied by related gene expression changes. By analyzing and integrating the methylome and transcriptome profiles of pediatric B-cell ALL cases and primary tissue controls, we report 325 genes hypermethylated and downregulated and 45 genes hypomethylated and upregulated in pediatric B-cell ALL, irrespective of subtype. Repressed cation channel subunits and cAMP signaling activators and transducers are overrepresented, potentially indicating a reduced cellular potential to receive and propagate apoptotic signals. Furthermore, we report specific DNA methylation alterations with concurrent gene expression changes within individual ALL subtypes. The ETV6-RUNX1 translocation was associated with downregulation of ASNS and upregulation of the EPO-receptor, while Hyperdiploid patients (>50 chr) displayed upregulation of B-cell lymphoma (BCL) members and repression of PTPRG and FHIT. In combination, these data indicate genetically distinct B-cell ALL subtypes contain cooperative epimutations and genome-wide epigenetic deregulation is common across all B-cell ALL subtypes.",

keywords = "ALL, Acute lymphoblastic leukemia, B-cell, DNA methylation, Epigenetics, Hematology, Leukemia",

author = "Zac Chatterton and Leah Morenos and Francoise Mechinaud and Ashley, {David M.} and Craig, {Jeffrey M.} and Alexandra Sexton-Oates and Halemba, {Minhee S.} and Mandy Parkinson-Bates and Jane Ng and Debra Morrison and Carroll, {William L.} and Richard Saffery and Wong, {Nicholas C.}",

note = "Funding Information: The Leukaemia Foundation of Australia supported this work through a Philip Desbrow Postdoctoral Fellowship (Wong N) and a Grant-in-Aid (Ashley DM, Wong N, Saffery R, and Craig JM). This work was funded by a National Health and Medical Research Project grant (Wong N, Craig JM, and Ashley DM) a Victorian Cancer Agency Grant. Wong N was also supported by My Room and the Children{\textquoteright}s Cancer Centre Foundation. Funding Information: Support was also obtained from the National Institutes of Health (R01 CA140729; Carroll WL) and New York University Cancer Centre (support grant 5 P30 CA16087). MCRI was supported by the Victorian Government{\textquoteright}s Operational Infrastructure Support Program. Morenos L is also supported by the NHMRC Dora Lush Postgraduate Research Scholarship and Saffery R by a NHMRC Senior Research Fellowship.",

year = "2014",

month = jan,

day = "6",

doi = "10.4161/epi.27585",

language = "English",

volume = "9",

pages = "459--467",

journal = "Epigenetics",

issn = "1559-2294",

publisher = "Landes Bioscience",

number = "3",

}

TY - JOUR

T1 - Epigenetic deregulation in pediatric acute lymphoblastic leukemia

AU - Chatterton, Zac

AU - Morenos, Leah

AU - Mechinaud, Francoise

AU - Ashley, David M.

AU - Craig, Jeffrey M.

AU - Sexton-Oates, Alexandra

AU - Halemba, Minhee S.

AU - Parkinson-Bates, Mandy

AU - Ng, Jane

AU - Morrison, Debra

AU - Carroll, William L.

AU - Saffery, Richard

AU - Wong, Nicholas C.

N1 - Funding Information: The Leukaemia Foundation of Australia supported this work through a Philip Desbrow Postdoctoral Fellowship (Wong N) and a Grant-in-Aid (Ashley DM, Wong N, Saffery R, and Craig JM). This work was funded by a National Health and Medical Research Project grant (Wong N, Craig JM, and Ashley DM) a Victorian Cancer Agency Grant. Wong N was also supported by My Room and the Children’s Cancer Centre Foundation. Funding Information: Support was also obtained from the National Institutes of Health (R01 CA140729; Carroll WL) and New York University Cancer Centre (support grant 5 P30 CA16087). MCRI was supported by the Victorian Government’s Operational Infrastructure Support Program. Morenos L is also supported by the NHMRC Dora Lush Postgraduate Research Scholarship and Saffery R by a NHMRC Senior Research Fellowship.

PY - 2014/1/6

Y1 - 2014/1/6

N2 - Similar to most cancers, genome-wide DNA methylation profiles are commonly altered in pediatric acute lymphoblastic leukemia (ALL); however, recent observations highlight that a large portion of malignancy-associated DNA methylation alterations are not accompanied by related gene expression changes. By analyzing and integrating the methylome and transcriptome profiles of pediatric B-cell ALL cases and primary tissue controls, we report 325 genes hypermethylated and downregulated and 45 genes hypomethylated and upregulated in pediatric B-cell ALL, irrespective of subtype. Repressed cation channel subunits and cAMP signaling activators and transducers are overrepresented, potentially indicating a reduced cellular potential to receive and propagate apoptotic signals. Furthermore, we report specific DNA methylation alterations with concurrent gene expression changes within individual ALL subtypes. The ETV6-RUNX1 translocation was associated with downregulation of ASNS and upregulation of the EPO-receptor, while Hyperdiploid patients (>50 chr) displayed upregulation of B-cell lymphoma (BCL) members and repression of PTPRG and FHIT. In combination, these data indicate genetically distinct B-cell ALL subtypes contain cooperative epimutations and genome-wide epigenetic deregulation is common across all B-cell ALL subtypes.

AB - Similar to most cancers, genome-wide DNA methylation profiles are commonly altered in pediatric acute lymphoblastic leukemia (ALL); however, recent observations highlight that a large portion of malignancy-associated DNA methylation alterations are not accompanied by related gene expression changes. By analyzing and integrating the methylome and transcriptome profiles of pediatric B-cell ALL cases and primary tissue controls, we report 325 genes hypermethylated and downregulated and 45 genes hypomethylated and upregulated in pediatric B-cell ALL, irrespective of subtype. Repressed cation channel subunits and cAMP signaling activators and transducers are overrepresented, potentially indicating a reduced cellular potential to receive and propagate apoptotic signals. Furthermore, we report specific DNA methylation alterations with concurrent gene expression changes within individual ALL subtypes. The ETV6-RUNX1 translocation was associated with downregulation of ASNS and upregulation of the EPO-receptor, while Hyperdiploid patients (>50 chr) displayed upregulation of B-cell lymphoma (BCL) members and repression of PTPRG and FHIT. In combination, these data indicate genetically distinct B-cell ALL subtypes contain cooperative epimutations and genome-wide epigenetic deregulation is common across all B-cell ALL subtypes.

KW - ALL

KW - Acute lymphoblastic leukemia

KW - B-cell

KW - DNA methylation

KW - Epigenetics

KW - Hematology

KW - Leukemia

UR - http://www.scopus.com/inward/record.url?scp=84899141186&partnerID=8YFLogxK

U2 - 10.4161/epi.27585

DO - 10.4161/epi.27585

M3 - Article

C2 - 24394348

AN - SCOPUS:84899141186

SN - 1559-2294

VL - 9

SP - 459

EP - 467

JO - Epigenetics

JF - Epigenetics

IS - 3

ER -

Epigenetic deregulation in pediatric acute lymphoblastic leukemia

Abstract

Keywords

Access to Document

Fingerprint

Cite this