Contributions
Abstract: EP422
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
Cyclin-dependent kinase (CDK) 4 and CDK6 are key players mediating G1 progression. In addition, CDK6 - but not CDK4 - has been implicated in gene transcription. High CDK6 levels are frequently observed in human malignancies and CDK4/6 inhibitors show promising efficacy against different types of tumors, including hematopoietic malignancies. One hallmark of leukemia is aberrant DNA methylation patterns. The molecular mechanisms underlying these aberrant genomic methylation patterns are poorly understood. We here provide evidence for a role of CDK6 in epigenetic alterations in leukemia.
Aims
We aim at understanding how CDK6 interferes with the epigenetic landscape and which leukemic subtypes will have an advantage from combinatorial drug treatment with CDK6 inhibitors and drugs interfering with epigenetic players.
Methods
To study the interplay between CDK6 and the epigenome, we use a murine Bcr/Abl p185 ALL model and murine hematopoietic progenitor cells (HPCLSK) transformed with different AML oncogenes generated from wildtype and Cdk6 knockout mice and/or treated with CDK4/6 inhibitors. We performed RNA-Seq, Chip-Seq, Phosphoproteomics and RRBS as well as in vitro assays to investigate proliferation, apoptosis and differentiation.
Results
CDK6 activity is associated with specific changes in CpG methylation. ChIP-seq revealed that CDK6 binds to genomic regions of DNMTs. Phosphoproteomic studies and RNA-Seq analysis uncover the regulation of several epigenetic factors by CDK6 at different levels. RNA-seq data from human ALL and AML samples assessed the correlation between CDK6 and DNMT expression. Reduced representation bisulfite sequencing analysis uncovers reversible and cell line-specific changes in DNA methylation patterns upon CDK6 loss. As a consequence, CDK6 interferes with the response to epigenetic agents.
Conclusion
We show that CDK6 affects the methylation pattern by altered expression and phosphorylation of several epigenetic modifiers, such as DNMTs and EZH2, in leukemia and therefore enhances the sensitivity towards specific epigenetic agents.
Keyword(s):
Abstract: EP422
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
Cyclin-dependent kinase (CDK) 4 and CDK6 are key players mediating G1 progression. In addition, CDK6 - but not CDK4 - has been implicated in gene transcription. High CDK6 levels are frequently observed in human malignancies and CDK4/6 inhibitors show promising efficacy against different types of tumors, including hematopoietic malignancies. One hallmark of leukemia is aberrant DNA methylation patterns. The molecular mechanisms underlying these aberrant genomic methylation patterns are poorly understood. We here provide evidence for a role of CDK6 in epigenetic alterations in leukemia.
Aims
We aim at understanding how CDK6 interferes with the epigenetic landscape and which leukemic subtypes will have an advantage from combinatorial drug treatment with CDK6 inhibitors and drugs interfering with epigenetic players.
Methods
To study the interplay between CDK6 and the epigenome, we use a murine Bcr/Abl p185 ALL model and murine hematopoietic progenitor cells (HPCLSK) transformed with different AML oncogenes generated from wildtype and Cdk6 knockout mice and/or treated with CDK4/6 inhibitors. We performed RNA-Seq, Chip-Seq, Phosphoproteomics and RRBS as well as in vitro assays to investigate proliferation, apoptosis and differentiation.
Results
CDK6 activity is associated with specific changes in CpG methylation. ChIP-seq revealed that CDK6 binds to genomic regions of DNMTs. Phosphoproteomic studies and RNA-Seq analysis uncover the regulation of several epigenetic factors by CDK6 at different levels. RNA-seq data from human ALL and AML samples assessed the correlation between CDK6 and DNMT expression. Reduced representation bisulfite sequencing analysis uncovers reversible and cell line-specific changes in DNA methylation patterns upon CDK6 loss. As a consequence, CDK6 interferes with the response to epigenetic agents.
Conclusion
We show that CDK6 affects the methylation pattern by altered expression and phosphorylation of several epigenetic modifiers, such as DNMTs and EZH2, in leukemia and therefore enhances the sensitivity towards specific epigenetic agents.
Keyword(s):