Project 1: Exploring DNA methylation/gene silencing patterns in MDS/AML for potential therapeutic Targets
The role of epigenetic abnormalities (DNMT3A, TET1/2…) as drivers of tumorigenesis has been increasingly recognized in recent years, especially in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These epigenetic alterations are accompanied by hundreds of genes known to be differentially silenced in association with DNA hypermethylation of CpG islands in promoter regions. A key group of these specific loci are known to function as tumor suppressor genes (TSG). Targeted reversal of gene silencing by epigenetic drugs (like DNA methyltransferase inhibitors) is an attractive strategy for cancer prevention and therapy but currently remains limited in MDS/AML due to the lack of reliable TSG biomarkers and poor pharmacodynamics and -kinetics of current FDA/EMA-approved hypomethylating compounds. More importantly, recent findings demonstrate that epigenetic therapy can induce an innate immune activation in MDS/AML cells which might prime cancer cells for an immune response, highlighting the potential to combine epigenetic therapy with immunotherapy.
By using in silico and preclinical analysis approach based on DNA methylation/gene expression data sets, our lab aims to identify potential biomarkers or targets that are highly silenced across different MDS and AML mutational landscapes. We will analyze the re-expression of these gene candidates and assess their potential as therapeutic targets or modulators of metabolic and/or immune response. Similarly, we are also developing novel reporter MDS/AML cell lines using Crispr/Cas9 technology to help understand the contribution of these silenced genes in drug resistance. Furthermore, these cell lines will be used in functional and drug screening assays to develop novel epigenetic regimens that may be broadly applicable to enhance the efficacy of current radiotherapy, chemotherapy or immunotherapy therapies.
[Funding 2018-2022: Deutsches Konsortium für Translationale Krebsforschung (DKTK)]
[Funding 2019-2021: Deutsche José Carreras Leukämie-Stiftung (DJCLS)]
[Funding 2020-2022: Mainzer Wissenschaftsstiftung (MWS)]
Project 2: Stromal profiling of bone marrow micro-environment in Clonal hematopoiesis and Myelodysplasia
With aging, the number of somatic mutations in the hematopoietic compartment constantly increases, leading to a progressive loss of polyclonal hematopoiesis and the evolution of a pre-malignant condition termed clonal hematopoiesis of indeterminate potential (CHIP). In some patients, CHIP progresses towards stem cell driven neoplasms such as myelodysplastic syndromes (MDS). However, the precise mechanisms that drive this process have not been defined and the possible involvement of the osteo-hematopoietic niche in CHIP/MDS propagation remains poorly understood.
By using Next-Generation Sequencing (NGS) technology and high-content imaging analysis, our lab will study the stromal profiles and molecular alterations present in bone marrow populations from CHIP/MDS patients. Specifically, our group aims to characterize the cellular components of the osteo-hematopoietic niche in trephine BM core biopsies from CHIP and MDS clinical cases compared to healthy individuals (DKTK CHOICE Consortium). By using 3D BM co-culture models, we also aim to comprehensively analyze how specific cellular and molecular pathways within the aging osteo-hematopoietic niche contribute to the pathogenesis and differential progression of CHIP and MDS. Overall, this analysis could reveal potential biomarkers useful in predicting disease progression and/or survival prognosis.