Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Lamba JK

PROVIDER: S-EPMC7603219 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Lamba Jatinder K JK Cao Xueyuan X Raimondi Susana S Downing James J Ribeiro Raul R Gruber Tanja A TA Rubnitz Jeffrey J Pounds Stanley S

Cancers 20201017 10

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 co ...[more]

PMID: 33080932

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Project description:microRNAs, important regulators of cell proliferation and apoptosis, have been shown to be involved in the pathogenesis of acute myeloid leukemia in adulthood AML. However, comprehensive studies in AML of children and adolescents are missing so far. We investigated the miRNA expression profiles of different AML subtypes from 102 pediatric patients in comparison to CD34+ cells from healthy donors and adult AML patients, in order to identify differentially expressed miRNAs. Pediatric samples with core factor binding acute myeloid leukemia and promyelocytic leukemia could be distinguished from each other and MLL rearranged AML subtypes by 9 and 18 miRNAs, respectively. miR-126, -146a, -181a/b, -100, and miR-125b were identified as highest differentially expressed with marked difference of expression between pediatric and adulthood samples of the same cytogenetic subgroup. We next isolated the miRNA targeting complex from t(8;21) and t(15;17) cell line models and comprehensively identified bound miRNAs and targeted mRNAs by a newly devised immunoprecipitation assay followed by rapid microarray detection. Our findings indicate separate binding preferences for the four human Argonaute proteins. Subsequent bioinformatic analysis revealed a concerted action of different Ago proteins in the regulation of AML-relevant pathways, providing an experimental based database of miRNA-mRNA target interaction in Argonaute proteins. Ago-associated microRNAs: Co-immunoprecipitation in the acute myeloid leukemia cell line models, KASUMI-1 and NB4, of the four human Argonaute complexes using monoclonal antibodies and stringent washing conditions. We performed photo-activated UV cross-linking using 4M-bM-^@M-^Y-thioruidine before cell lysis. Unspecific binding to the bead matrix and to the Fc part of the monoclonal rat antibody were recorded and corrected by empty bead controls and an antibody isotype control. Argonaute-associated miRNAs/mRNAs and unspecific bound miRNAs/mRNAs of the isotype control were identified by microarray hybridization. These experiments were performed in triplicates. Ago-associated mRNAs: Co-immunoprecipitation in the acute myeloid leukemia cell line models, KASUMI-1 and NB4, of the four human Argonaute complexes using monoclonal antibodies and stringent washing conditions. We performed photo-activated UV cross-linking using 4M-bM-^@M-^Y-thioruidine before cell lysis. Unspecific binding to the bead matrix and to the Fc part of the monoclonal rat antibody were recorded and corrected by empty bead controls and an antibody isotype control. Argonaute-associated miRNAs/mRNAs and unspecific bound miRNAs/mRNAs of the isotype control were identified by microarray hybridization. These experiments were performed in triplicates. AML-patient microRNAs: RNA extraction using the TRIzol protocol (Invitrogen), labeling of RNA with Cy3- (universal reference) and Cy5-Dyes (samples) using a truncated and mutated RNA ligase, hybridization of miRNAs over night at 42M-BM-0C using miRXplore microarrays and the a-Hyb Hybridization Station (MACS molecular Miltenyi Biotec)

Dataset Information

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

Publications

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

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