DNA Methylation Profiles and Their Relationship with Cytogenetic Status in Adult Acute Myeloid Leukemia

被引：61

作者：

Alvarez, Sara ^{[1
]}

Suela, Javier ^{[1
]}

Valencia, Ana ^{[2
]}

Fernandez, Agustin ^{[3
]}

Wunderlich, Mark ^{[4
]}

Agirre, Xabier ^{[5
,6
,7
]}

Prosper, Felipe ^{[5
,6
,7
]}

Ignacio Martin-Subero, Jose ^{[3
,10
]}

Maiques, Alba ^{[1
]}

Acquadro, Francesco ^{[1
]}

Rodriguez Perales, Sandra ^{[1
]}

Jose Calasanz, Maria ^{[8
]}

Roman-Gomez, Jose ^{[9
]}

Siebert, Reiner ^{[10
]}

Mulloy, James C. ^{[4
]}

Cervera, Jose ^{[2
]}

Angel Sanz, Miguel ^{[2
]}

Esteller, Manel ^{[3
]}

Cigudosa, Juan C. ^{[1
]}

机构：

[1] Ctr Invest Enfermedades Raras CIBERER, CNIO, Mol Cytogenet Grp, Madrid, Spain

[2] Hosp Univ La Fe, Hematol Serv, Valencia, Spain

[3] Bellvitge Inst Biomed Res Catalan Inst Oncol IDIB, Canc Epigenet & Biol Program, Barcelona, Spain

[4] Univ Cincinnati, Coll Med, Div Expt Hematol, Cincinnati Childrens Hosp,Med Ctr, Cincinnati, OH USA

[5] Univ Navarra, Clin Univ, Fdn Appl Med Res, Div Canc, E-31080 Pamplona, Spain

[6] Univ Navarra, Clin Univ, Fdn Appl Med Res, Area Cell Therapy, E-31080 Pamplona, Spain

[7] Univ Navarra, Clin Univ, Fdn Appl Med Res, Hematol Serv, E-31080 Pamplona, Spain

[8] Univ Navarra, Dept Genet, E-31080 Pamplona, Spain

[9] Hosp Univ Reina Sofia, Hematol Serv, Cordoba, Spain

[10] Univ Kiel, Inst Human Genet, Univ Hosp Schleswig Holstein, Kiel, Germany

来源：

PLOS ONE | 2010年 / 5卷 / 08期

关键词：

CPG ISLAND METHYLATION; PREDICTS SURVIVAL; GENE DBCCR1; CELLS; MALIGNANCIES; CANCER; EXPRESSION; DBC1; EPIGENETICS; NEOPLASMS;

D O I：

10.1371/journal.pone.0012197

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Background: Aberrant promoter DNA methylation has been shown to play a role in acute myeloid leukemia (AML) pathophysiology. However, further studies to discuss the prognostic value and the relationship of the epigenetic signatures with defined genomic rearrangements in acute myeloid leukemia are required. Methodology/Principal Findings: We carried out high-throughput methylation profiling on 116 de novo AML cases and we validated the significant biomarkers in an independent cohort of 244 AML cases. Methylation signatures were associated with the presence of a specific cytogenetic status. In normal karyotype cases, aberrant methylation of the promoter of DBC1 was validated as a predictor of the disease-free and overall survival. Furthermore, DBC1 expression was significantly silenced in the aberrantly methylated samples. Patients with chromosome rearrangements showed distinct methylation signatures. To establish the role of fusion proteins in the epigenetic profiles, 20 additional samples of human hematopoietic stem/progenitor cells (HSPC) transduced with common fusion genes were studied and compared with patient samples carrying the same rearrangements. The presence of MLL rearrangements in HSPC induced the methylation profile observed in the MLL-positive primary samples. In contrast, fusion genes such as AML1/ETO or CBFB/MYH11 failed to reproduce the epigenetic signature observed in the patients. Conclusions/Significance: Our study provides a comprehensive epigenetic profiling of AML, identifies new clinical markers for cases with a normal karyotype, and reveals relevant biological information related to the role of fusion proteins on the methylation signature.

引用

页数：12

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