DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding

Till Schoofs; Christian Rohde; Katja Hebestreit; Hans-Ulrich Klein; Stefanie Göllner; Isabell Schulze; Mads Lerdrup; Nikolaj Dietrich; Shuchi Agrawal-Singh; Anika Witten; Monika Stoll; Eva Lengfelder; Wolf-Karsten Hofmann; Peter Schlenke; Thomas Büchner; Klaus Hansen; Wolfgang E Berdel; Frank Rosenbauer; Martin Dugas; Carsten Müller-Tidow

doi:10.1182/blood-2012-08-448860

DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding

Till Schoofs, Christian Rohde, Katja Hebestreit, Hans-Ulrich Klein, Stefanie Göllner, Isabell Schulze, Mads Lerdrup, Nikolaj Dietrich, Shuchi Agrawal-Singh, Anika Witten, Monika Stoll, Eva Lengfelder, Wolf-Karsten Hofmann, Peter Schlenke, Thomas Büchner, Klaus Hansen, Wolfgang E Berdel, Frank Rosenbauer, Martin Dugas, Carsten Müller-Tidow

52 Citationer (Scopus)

Abstract

The origin of aberrant DNA methylation in cancer remains largely unknown. In the present study, we elucidated the DNA methylome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia-retinoic acid receptor α (PML-RARα) in establishing these patterns. Cells from APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34(+) cells, promyelocytes, and remission BM cells. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score, and Flt3-mutation status characterized methylation subtypes. Transcription factor-binding sites (eg, the c-myc-binding sites) were associated with low methylation. However, SUZ12- and REST-binding sites identified in embryonic stem cells were preferentially DNA hypermethylated in APL cells. Unexpectedly, PML-RARα-binding sites were also protected from aberrant DNA methylation in APL cells. Consistent with this, myeloid cells from preleukemic PML-RARα knock-in mice did not show altered DNA methylation and the expression of PML-RARα in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. Treatment of APL blasts with all-trans retinoic acid also did not result in immediate DNA methylation changes. The results of the present study suggest that aberrant DNA methylation is associated with leukemia phenotype but is not required for PML-RARα-mediated initiation of leukemogenesis.

Originalsprog	Engelsk
Tidsskrift	Blood
Vol/bind	121
Udgave nummer	1
Sider (fra-til)	178-87
Antal sider	10
ISSN	0006-4971
DOI	https://doi.org/10.1182/blood-2012-08-448860
Status	Udgivet - 3 jan. 2013

FN’s Verdensmål

Dette resultat bidrager til følgende verdensmål

Adgang til dokumentet

10.1182/blood-2012-08-448860

Citationsformater

Schoofs, T., Rohde, C., Hebestreit, K., Klein, H-U., Göllner, S., Schulze, I., Lerdrup, M., Dietrich, N., Agrawal-Singh, S., Witten, A., Stoll, M., Lengfelder, E., Hofmann, W-K., Schlenke, P., Büchner, T., Hansen, K., Berdel, W. E., Rosenbauer, F., Dugas, M., & Müller-Tidow, C. (2013). DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding. Blood, 121(1), 178-87. https://doi.org/10.1182/blood-2012-08-448860

Schoofs, T, Rohde, C, Hebestreit, K, Klein, H-U, Göllner, S, Schulze, I, Lerdrup, M, Dietrich, N, Agrawal-Singh, S, Witten, A, Stoll, M, Lengfelder, E, Hofmann, W-K, Schlenke, P, Büchner, T, Hansen, K, Berdel, WE, Rosenbauer, F, Dugas, M & Müller-Tidow, C 2013, 'DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding', Blood, bind 121, nr. 1, s. 178-87. https://doi.org/10.1182/blood-2012-08-448860

@article{2bb4ead4f6f747c1bfd7ce7626ae1118,

title = "DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding",

abstract = "The origin of aberrant DNA methylation in cancer remains largely unknown. In the present study, we elucidated the DNA methylome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia-retinoic acid receptor α (PML-RARα) in establishing these patterns. Cells from APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34(+) cells, promyelocytes, and remission BM cells. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score, and Flt3-mutation status characterized methylation subtypes. Transcription factor-binding sites (eg, the c-myc-binding sites) were associated with low methylation. However, SUZ12- and REST-binding sites identified in embryonic stem cells were preferentially DNA hypermethylated in APL cells. Unexpectedly, PML-RARα-binding sites were also protected from aberrant DNA methylation in APL cells. Consistent with this, myeloid cells from preleukemic PML-RARα knock-in mice did not show altered DNA methylation and the expression of PML-RARα in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. Treatment of APL blasts with all-trans retinoic acid also did not result in immediate DNA methylation changes. The results of the present study suggest that aberrant DNA methylation is associated with leukemia phenotype but is not required for PML-RARα-mediated initiation of leukemogenesis.",

keywords = "Animals, Cell Transformation, Neoplastic, Chromosomes, Human, CpG Islands, DNA Methylation, DNA, Neoplasm, Disease Progression, Gene Expression Regulation, Leukemic, Gene Knock-In Techniques, Hematopoietic Stem Cells, Humans, Leukemia, Promyelocytic, Acute, Mice, Mice, Inbred C57BL, Neoplasm Proteins, Neoplastic Stem Cells, Oncogene Proteins, Fusion, Phenotype, Polycomb Repressive Complex 2, Preleukemia, Recombinant Fusion Proteins, Repressor Proteins, Transcription Factors, Tretinoin",

author = "Till Schoofs and Christian Rohde and Katja Hebestreit and Hans-Ulrich Klein and Stefanie G{\"o}llner and Isabell Schulze and Mads Lerdrup and Nikolaj Dietrich and Shuchi Agrawal-Singh and Anika Witten and Monika Stoll and Eva Lengfelder and Wolf-Karsten Hofmann and Peter Schlenke and Thomas B{\"u}chner and Klaus Hansen and Berdel, {Wolfgang E} and Frank Rosenbauer and Martin Dugas and Carsten M{\"u}ller-Tidow",

year = "2013",

month = jan,

day = "3",

doi = "10.1182/blood-2012-08-448860",

language = "English",

volume = "121",

pages = "178--87",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "1",

}

TY - JOUR

T1 - DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding

AU - Schoofs, Till

AU - Rohde, Christian

AU - Hebestreit, Katja

AU - Klein, Hans-Ulrich

AU - Göllner, Stefanie

AU - Schulze, Isabell

AU - Lerdrup, Mads

AU - Dietrich, Nikolaj

AU - Agrawal-Singh, Shuchi

AU - Witten, Anika

AU - Stoll, Monika

AU - Lengfelder, Eva

AU - Hofmann, Wolf-Karsten

AU - Schlenke, Peter

AU - Büchner, Thomas

AU - Hansen, Klaus

AU - Berdel, Wolfgang E

AU - Rosenbauer, Frank

AU - Dugas, Martin

AU - Müller-Tidow, Carsten

PY - 2013/1/3

Y1 - 2013/1/3

N2 - The origin of aberrant DNA methylation in cancer remains largely unknown. In the present study, we elucidated the DNA methylome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia-retinoic acid receptor α (PML-RARα) in establishing these patterns. Cells from APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34(+) cells, promyelocytes, and remission BM cells. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score, and Flt3-mutation status characterized methylation subtypes. Transcription factor-binding sites (eg, the c-myc-binding sites) were associated with low methylation. However, SUZ12- and REST-binding sites identified in embryonic stem cells were preferentially DNA hypermethylated in APL cells. Unexpectedly, PML-RARα-binding sites were also protected from aberrant DNA methylation in APL cells. Consistent with this, myeloid cells from preleukemic PML-RARα knock-in mice did not show altered DNA methylation and the expression of PML-RARα in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. Treatment of APL blasts with all-trans retinoic acid also did not result in immediate DNA methylation changes. The results of the present study suggest that aberrant DNA methylation is associated with leukemia phenotype but is not required for PML-RARα-mediated initiation of leukemogenesis.

AB - The origin of aberrant DNA methylation in cancer remains largely unknown. In the present study, we elucidated the DNA methylome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia-retinoic acid receptor α (PML-RARα) in establishing these patterns. Cells from APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34(+) cells, promyelocytes, and remission BM cells. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score, and Flt3-mutation status characterized methylation subtypes. Transcription factor-binding sites (eg, the c-myc-binding sites) were associated with low methylation. However, SUZ12- and REST-binding sites identified in embryonic stem cells were preferentially DNA hypermethylated in APL cells. Unexpectedly, PML-RARα-binding sites were also protected from aberrant DNA methylation in APL cells. Consistent with this, myeloid cells from preleukemic PML-RARα knock-in mice did not show altered DNA methylation and the expression of PML-RARα in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. Treatment of APL blasts with all-trans retinoic acid also did not result in immediate DNA methylation changes. The results of the present study suggest that aberrant DNA methylation is associated with leukemia phenotype but is not required for PML-RARα-mediated initiation of leukemogenesis.

KW - Animals

KW - Cell Transformation, Neoplastic

KW - Chromosomes, Human

KW - CpG Islands

KW - DNA Methylation

KW - DNA, Neoplasm

KW - Disease Progression

KW - Gene Expression Regulation, Leukemic

KW - Gene Knock-In Techniques

KW - Hematopoietic Stem Cells

KW - Humans

KW - Leukemia, Promyelocytic, Acute

KW - Mice

KW - Mice, Inbred C57BL

KW - Neoplasm Proteins

KW - Neoplastic Stem Cells

KW - Oncogene Proteins, Fusion

KW - Phenotype

KW - Polycomb Repressive Complex 2

KW - Preleukemia

KW - Recombinant Fusion Proteins

KW - Repressor Proteins

KW - Transcription Factors

KW - Tretinoin

U2 - 10.1182/blood-2012-08-448860

DO - 10.1182/blood-2012-08-448860

M3 - Journal article

C2 - 23152544

SN - 0006-4971

VL - 121

SP - 178

EP - 187

JO - Blood

JF - Blood

IS - 1

ER -

DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding

Abstract

FN’s Verdensmål

Adgang til dokumentet

Fingeraftryk

Citationsformater