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CBFB-MYH11 hypomethylation signature and PBX3 differential methylation revealed by targeted bisulfite sequencing in patients with acute myeloid leukemia.

Hájková H, Fritz MH, Haškovec C, Schwarz J, Šálek C, Marková J, Krejčík Z, Dostálová Merkerová M, Kostečka A, Vostrý M, Fuchs O, Michalová K, Cetkovský P, Beneš V - J Hematol Oncol (2014)

Bottom Line: Further, by comparing all targeted methylation and microarray expression data, PBX3 differential methylation was found to correlate with its gene expression.We discovered new genomic regions with aberrant DNA methylation that are associated with expression of genes involved in leukemogenesis.Our results demonstrate the potential of the targeted approach for DNA methylation studies to reveal new regulatory regions.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Studying DNA methylation changes in the context of structural rearrangements and point mutations as well as gene expression changes enables the identification of genes that are important for disease onset and progression in different subtypes of acute myeloid leukemia (AML) patients. The aim of this study was to identify differentially methylated genes with potential impact on AML pathogenesis based on the correlation of methylation and expression data.

Methods: The primary method of studying DNA methylation changes was targeted bisulfite sequencing capturing approximately 84 megabases (Mb) of the genome in 14 diagnostic AML patients and a healthy donors' CD34+ pool. Subsequently, selected DNA methylation changes were confirmed by 454 bisulfite pyrosequencing in a larger cohort of samples. Furthermore, we addressed gene expression by microarray profiling and correlated methylation of regions adjacent to transcription start sites with expression of corresponding genes.

Results: Here, we report a novel hypomethylation pattern, specific to CBFB-MYH11 fusion resulting from inv(16) rearrangement that is associated with genes previously described as upregulated in inv(16) AML. We assume that this hypomethylation and corresponding overexpresion occurs in the genes whose function is important in inv(16) leukemogenesis. Further, by comparing all targeted methylation and microarray expression data, PBX3 differential methylation was found to correlate with its gene expression. PBX3 has been recently shown to be a key interaction partner of HOX genes during leukemogenesis and we revealed higher incidence of relapses in PBX3-overexpressing patients.

Conclusions: We discovered new genomic regions with aberrant DNA methylation that are associated with expression of genes involved in leukemogenesis. Our results demonstrate the potential of the targeted approach for DNA methylation studies to reveal new regulatory regions.

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Related in: MedlinePlus

Impact ofPBX3expression levels on prognosis. (A) Kaplan–Meier curves of overall survival (OS) in AML with low versus high expression of PBX3 displaying no significant difference between these two groups of AML patients; (B) Cumulative incidence of relapse showing higher relapse rates in PBX3-overexpressing AML patients (P = 0.004).
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Fig6: Impact ofPBX3expression levels on prognosis. (A) Kaplan–Meier curves of overall survival (OS) in AML with low versus high expression of PBX3 displaying no significant difference between these two groups of AML patients; (B) Cumulative incidence of relapse showing higher relapse rates in PBX3-overexpressing AML patients (P = 0.004).

Mentions: We did not observe any effect of PBX3 expression levels on OS in AML patients (Figure 6A), however we found higher relapse rates in AML patients with overexpressed PBX3 (Figure 6B, P = 0.004).Figure 6


CBFB-MYH11 hypomethylation signature and PBX3 differential methylation revealed by targeted bisulfite sequencing in patients with acute myeloid leukemia.

Hájková H, Fritz MH, Haškovec C, Schwarz J, Šálek C, Marková J, Krejčík Z, Dostálová Merkerová M, Kostečka A, Vostrý M, Fuchs O, Michalová K, Cetkovský P, Beneš V - J Hematol Oncol (2014)

Impact ofPBX3expression levels on prognosis. (A) Kaplan–Meier curves of overall survival (OS) in AML with low versus high expression of PBX3 displaying no significant difference between these two groups of AML patients; (B) Cumulative incidence of relapse showing higher relapse rates in PBX3-overexpressing AML patients (P = 0.004).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4197269&req=5

Fig6: Impact ofPBX3expression levels on prognosis. (A) Kaplan–Meier curves of overall survival (OS) in AML with low versus high expression of PBX3 displaying no significant difference between these two groups of AML patients; (B) Cumulative incidence of relapse showing higher relapse rates in PBX3-overexpressing AML patients (P = 0.004).
Mentions: We did not observe any effect of PBX3 expression levels on OS in AML patients (Figure 6A), however we found higher relapse rates in AML patients with overexpressed PBX3 (Figure 6B, P = 0.004).Figure 6

Bottom Line: Further, by comparing all targeted methylation and microarray expression data, PBX3 differential methylation was found to correlate with its gene expression.We discovered new genomic regions with aberrant DNA methylation that are associated with expression of genes involved in leukemogenesis.Our results demonstrate the potential of the targeted approach for DNA methylation studies to reveal new regulatory regions.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Studying DNA methylation changes in the context of structural rearrangements and point mutations as well as gene expression changes enables the identification of genes that are important for disease onset and progression in different subtypes of acute myeloid leukemia (AML) patients. The aim of this study was to identify differentially methylated genes with potential impact on AML pathogenesis based on the correlation of methylation and expression data.

Methods: The primary method of studying DNA methylation changes was targeted bisulfite sequencing capturing approximately 84 megabases (Mb) of the genome in 14 diagnostic AML patients and a healthy donors' CD34+ pool. Subsequently, selected DNA methylation changes were confirmed by 454 bisulfite pyrosequencing in a larger cohort of samples. Furthermore, we addressed gene expression by microarray profiling and correlated methylation of regions adjacent to transcription start sites with expression of corresponding genes.

Results: Here, we report a novel hypomethylation pattern, specific to CBFB-MYH11 fusion resulting from inv(16) rearrangement that is associated with genes previously described as upregulated in inv(16) AML. We assume that this hypomethylation and corresponding overexpresion occurs in the genes whose function is important in inv(16) leukemogenesis. Further, by comparing all targeted methylation and microarray expression data, PBX3 differential methylation was found to correlate with its gene expression. PBX3 has been recently shown to be a key interaction partner of HOX genes during leukemogenesis and we revealed higher incidence of relapses in PBX3-overexpressing patients.

Conclusions: We discovered new genomic regions with aberrant DNA methylation that are associated with expression of genes involved in leukemogenesis. Our results demonstrate the potential of the targeted approach for DNA methylation studies to reveal new regulatory regions.

Show MeSH
Related in: MedlinePlus