Identification of novel tumor suppressor genes in acute myeloid leukemia by global methylome analysis in a mouse model

Blood smear of an evolving AML

Dieter Weichenhan, Rainer Claus, Christoph Plass
in cooperation with
Frank Rosenbauer (Universität Münster) and Michael Rehli (Universität Regensburg)

Acute myeloid leukemia (AML) is the most frequent type of leukemia in adults. It is a heterogeneous, rather aggressive malignancy and associated with a poor prognosis. Epigenetic abnormalities like hypermethylation of CpG islands in promoter regions of tumor suppressor genes contribute to the different developmental stages and the progression of AML.

The aim of this project is to identify novel tumor suppressor genes associated with AML in an inbred mouse model. Compared to human studies, advantages of the model are that i) animals at different developmental stages enable to study disease development from early onset over progression to end-stage, ii) genetic background differences between affected and non-affected control individuals can be excluded, and iii) environmental differences which may entail epigenetic differences can be largely diminished.

Hypermethylated DNA enriched by methyl-CpG immunoprecipitation (MCIp) from normal and malignant leukocytes will be used in an unbiased whole genome differential screening applying microarray hybridization and next-generation sequencing. Novel candidate genes will be validated by MassArray analysis, bisulfite sequencing, expression and functional studies.

Positively validated candidates will provide a valuable resource for exploring the epigenetic pathways involved in AML initiation and progression. Our study will enable the development of new concepts to target AML at its different stages of progression, from early onset to the fully developed disease.

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