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Open AccessArticle

DNA Methylation Clusters and Their Relation to Cytogenetic Features in Pediatric AML

1
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32608, USA
2
Department of Acute and Tertiary Care, University of Tennessee Health Science Center, Memphis, TN 38163, USA
3
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
4
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
5
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
6
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(10), 3024; https://doi.org/10.3390/cancers12103024
Received: 26 September 2020 / Accepted: 15 October 2020 / Published: 17 October 2020
(This article belongs to the Section Cancer Biomarkers)
Acute myeloid leukemia is a heterogenous disease with dismal outcome. In order to improve currently used therapeutic strategies it is important to get a in depth understanding of the molecular and genomic landscape of AML. Adult AML studies have established the significant of mutational profile of epigenetic genes as well as epigenetic deregulation DNA methylation signatures. In the current study we focused on establishing the DNA methylation profile in pediatric AML. Our result show that in pediatric AML patients the risk group and cytogenetic features have distinctive epigenetic signatures. Additionally, we observed that distinctive epigenetic hotspots co-occur complementary to the known genomic lesions and contribute towards leukemogenesis.
Acute Myeloid Leukemia (AML) is characterized by recurrent genetic and cytogenetic lesions that are utilized for risk stratification and for making treatment decisions. In recent years, methylation dysregulation has been extensively studied and associated with risk groups and prognosis in adult AML, however, such studies in pediatric AML are limited. Moreover, the mutations in epigenetic genes such as DNMT3A, IDH1 or IDH2 are almost absent or rare in pediatric patients as compared to their abundance in adult AML. In the current study, we evaluated methylation patterns that occur with or independent of the well-defined cytogenetic features in pediatric AML patients enrolled on multi-site AML02 clinical trial (NCT00136084). Our results demonstrate that unlike adult AML, cytosine DNA methylation does not result in significant unique clusters in pediatric AML, however, DNA methylation signatures correlated significantly with the most common and recurrent cytogenetic features. Paired evaluation of DNA methylation and expression identified genes and pathways of biological relevance that hold promise for novel therapeutic strategies. Our results further demonstrate that epigenetic signatures occur complimentary to the well-established chromosomal/mutational landscape, implying that dysregulation of oncogenes or tumor suppressors might be leveraging both genetic and epigenetic mechanisms to impact biological pathways critical for leukemogenesis.
Keywords: acute myeloid leukemia; DNA methylation; cytogenetics; pediatrics acute myeloid leukemia; DNA methylation; cytogenetics; pediatrics
MDPI and ACS Style

Lamba, J.K.; Cao, X.; Raimondi, S.; Downing, J.; Ribeiro, R.; Gruber, T.A.; Rubnitz, J.; Pounds, S. DNA Methylation Clusters and Their Relation to Cytogenetic Features in Pediatric AML. Cancers 2020, 12, 3024.

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