Linking CDK6 to the epigenome in AML

Acute myeloid leukemia (AML) is a disease with poor outcomes, due to disease relapse. Leukemic stem cells (LSCs), which are capable of giving rise to identical daughter cells as well as more mature leukemic cells, are important in disease initiation and progression. LSCs have different properties than the bulk AML population, making them difficult to eliminate which is considered to be the root of drug resistance. One hallmark of AML is aberrant DNA methylation patterns. The mechanisms underlying the generation of genomic methylation patterns are still poorly understood. However, a recent study showed rst evidence of epigenetic differences between patient LSCs and their nonstem cell progeny. Hypomethylating agents are on the forerun. However rational combinations can offer the greatest benefit. Preliminary data from our group led us hypothesize a role for the cyclin dependent kinase CDK6 in regulating the epigenetic landscape and that CDK6 kinase activity alters therapeutic responsiveness towards epigenetic agents. CDK6 has been recognized not only as a typical CDK kinase phosphorylating its most prominent target the retinoblastoma protein but as a transcriptional regulator. For this project we aim to use a murine hematopoietic progenitor cell (HPCLSK) model to mimic cell state heterogeneity in a genetically defined setting of AML subtypes. This model allows us to analyze LSCs as well as their non- stem cell progeny. We will analyze in detail how CDK6 regulates DNA methylation patterns in different AML subtypes and what are the critical players dependent on CDK6. Furthermore we will determine if these changes account for novel therapeutic vulnerabilities for epigenetic drugs. Therefore we will perform combinatorial drug treatments using a CDK4/6 inhibitor Palbociclib and small molecules targeting CDK6 dependent epigenetic modulators. Palbociclib as well as several epigenetic drugs have been FDA approved and are widely used in clinical studies what makes novel therapeutic combinations very attractive. The proposed project will address two key issues: (i) if LSCs and/or their non-stem cell pool of different AML subtypes show changes in their epigenetic landscape and epigenetic modulators due to CDK6 kinase inhibition and (ii) if these changes lead to novel epigenetic vulnerabilities.