Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels

Journal of Hematology & Oncology

David Monk⁶  Reiner Siebert⁵  Franck Court⁶  Mi Kwon⁴  Ismael Buño⁴  María José Calasanz³  Felipe Prósper²  Manel Esteller¹  Albert Catala⁷  Xabi Agirre²  Juan Sandoval⁸  Maria D Odero³  Julia Richter⁵  Amy Guillaumet-Adkins⁶ 

[1] Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain;Division of Cancer and Area of Cell Therapy and Hematology Service, Universidad de Navarra, Pamplona, Spain;Department of Genetics, University of Navarra, Pamplona, Spain;Department of Hematology, Hospital General Universitario Gregorio Maranon, Madrid, Spain;Institute of Human Genetics, Christian-Albrechts University, Kiel, Germany;Imprinting and Cancer group, Cancer Epigenetic and Biology Program, Institut d’Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Av. Gran Via de L’Hospotalet 199-203, 08907 L’Hospitalet de Llobregat, Barcelona, Spain;Servicio de Heamatología, Hospital Sant Joan de Déu, Barcelona, Spain;Cancer Epigenetics group, Cancer Epigenetic and Biology Program, Institut d’Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona, Spain

关键词: Imprinting;    Leukemia;    Epigenetics;    Methylation;    WT1;   

Others  :  802184
DOI  :  10.1186/1756-8722-7-4

 received in 2013-11-15, accepted in 2013-12-19,  发布年份 2014

【 摘 要 】

Background

Wilms tumor 1 (WT1) is over-expressed in numerous cancers with respect to normal cells, and has either a tumor suppressor or oncogenic role depending on cellular context. This gene is associated with numerous alternatively spliced transcripts, which initiate from two different unique first exons within the WT1 and the alternative (A)WT1 promoter intervals. Within the hematological system, WT1 expression is restricted to CD34+/CD38- cells and is undetectable after differentiation. Detectable expression of this gene is an excellent marker for minimal residual disease in acute myeloid leukemia (AML), but the underlying epigenetic alterations are unknown.

Methods

To determine the changes in the underlying epigenetic landscape responsible for this expression, we characterized expression, DNA methylation and histone modification profiles in 28 hematological cancer cell lines and confirmed the methylation signature in 356 cytogenetically well-characterized primary hematological malignancies.

Results

Despite high expression of WT1 and AWT1 transcripts in AML-derived cell lines, we observe robust hypermethylation of the AWT1 promoter and an epigenetic switch from a permissive to repressive chromatin structure between normal cells and AML cell lines. Subsequent methylation analysis in our primary leukemia and lymphoma cohort revealed that the epigenetic signature identified in cell lines is specific to myeloid-lineage malignancies, irrespective of underlying mutational status or translocation. In addition to being a highly specific marker for AML diagnosis (positive predictive value 100%; sensitivity 86.1%; negative predictive value 89.4%), we show that AWT1 hypermethylation also discriminates patients that relapse from those achieving complete remission after hematopoietic stem cell transplantation, with similar efficiency to WT1 expression profiling.

Conclusions

We describe a methylation signature of the AWT1 promoter CpG island that is a promising marker for classifying myeloid-derived leukemias. In addition AWT1 hypermethylation is ideally suited to monitor the recurrence of disease during remission in patients undergoing allogeneic stem cell transfer.

【 授权许可】

   
2014 Guillaumet-Adkins et al.; licensee BioMed Central Ltd.

【 图 表 】

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