Characterization of the molecular basis for combined epigenetic treatment and BCL2 inhibition in myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML)

• Applicant: Dr. Stephan Bohl
• Subject Area: Hematology, Oncology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 406044709

Myelodysplastic syndrome (MDS) is a clonal disorder arising from transformed hematopoietic stem cells. MDS tends to evolve into secondary acute myeloid leukemia (sAML) which is often resistant to chemotherapy and therefore associated with a very short life expectancy. Due to the primary older age at diagnosis most patient are only eligible for hypomethylating agents (HMA) treatment like azacitidine (AZA) and decitabine. However the response rates are low and even patients achieving a complete response in general relapse over time despite continuous HMA maintenance treatment. So far, the development of rational HMA combination therapies has been limited by a lack of precise understanding of mechanisms underlying treatment response and drug resistance. However, since expression of mitochondrial BCL2 proteins, protecting cells from diverse stress challenges including chemotherapy, seems to be relevant for HMA response, BCL2 inhibiting drugs like venetoclax may provide a promising therapeutic addition for outcome improvement. Interestingly the balance between proapoptotic and antiapoptotic BCL2 family proteins shifts in patients that progress from low-risk to high-risk MDS and sAML. However, it remains unclear how certain genetic and epigenetic aberrations in myeloid malignancies influence mitochondrial mediated apoptosis.Therefore the major aim of the proposed study is to better characterize the molecular basis for combined epigenetic and antiapoptotic treatment in myeloid malignancies. In the first part we will study the molecular basis of sensitivity to BCL2 antagonism in MDS/sAML cell lines and in primary patient samples by BH3 profiling and how this sensitivity can be modulated by AZA. This will potentially give us further insights into the alterations of the mitochondrial apoptotic pathway induced by venetoclax, AZA and the combination of both drugs. Next, we will examine the impact of individual MDS/sAML associated genetic aberrations on mitochondrial priming and sensitivity to BCL2 inhibition. In order to clarify the potential synergistic effect of AZA and venetoclax we will study the differently expressed genes prior and after treatment with AZA in several cell lines and determine how these genes influence BCL2 inhibition. These experiments together with the data obtained in the first aim will possibly inform us about the influence of specific gene mutations on mitochondrial priming and sensitivity to venetoclax and AZA. Later on, we will assess whether dynamic BH3 profiling can predict response to venetoclax and AZA in patients. For that purpose, profiling will be performed in samples from patients treated within two clinical trials investigating AZA +/- venetoclax in high-risk MDS patients.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Anthony G. Letai