Functional Genomics of Acute Leukemias - Baldus’ Lab
Our work is focused on the genomic and functional characterization of acute leukemias with the aim to identify new actionable vulnerabilities. We perform integrative high-throughput analyses in the genomic and epigenetic context of the disease and the regulatory consequences in gene expression and distinct clinical phenotypes. Genome editing (CRISPR/Cas9, cloning) and RNA interference are used to obtain models of candidate genomic alterations, enabling functional characterization and pharmacogenomic screening.
With this approach we identified the novel molecular subtype of acute lymphoblastic leukemia (ALL). The subtype is defined by bi-allelic genomic alterations in the B lymphoid transcription factor PAX5 and a distinct pattern of co-occurring events (Bastian L et al. Leukemia, 2019). Further, we described the acquisition of mutations in epigenetic regulators and deregulation of energy metabolism as signatures of ALL relapse (Schroder MP et al. Sci Rep, 2019). Distinct lncRNA expression patterns characterize molecular ALL subtypes at initial diagnosis and relapse (James AR et al, J Hematol Oncol, 2019). Comprehensive mutation profiling of adult T-cell ALL has yielded a complex alteration landscape, enriched for mutations in epigenetic regulators and JAK/STAT signaling alterations (Neumann M. et al Oncotarget, 2015 and Blood, 2013).
Based on these data, we develop a high throughput data analysis pipeline to provide molecular subgroup allocation and identification of potential treatment targets for patients with newly diagnosed ALL. Subclonal composition of the disease and evolutionary trajectories are studied on single cell resolution levels using sequencing techniques and Cytof. We characterize the functional role of circular RNAs in different molecular ALL subtypes, linking circRNA expression to epigenetic regulations and oncogene dependencies. Based on our pharmacogenomic studies we are developing a clinical trial to explore the efficacy of the BCL-2 inhibitor Venetoclax combined with Blinatumomab in relapsed / refractory ALL.
Our analyses have linked enrichment of mutations in epigenetic regulators (DNMT3A, IDH1/2) in elderly acute myeloid leukemia (AML) patients to altered epigenetic states (Silva P et al. Leukemia 2017). We are now exploring the effect of IDH mutations on long-distance chromatin interactions in AML cell lines and primary patient samples to provide new metabolic treatment strategies.
Leukemogenesis as well as effective disease control after chemo- or immunotherapeutic strategies result from interplay of leukemic blasts with cell-intrinsic oncogenic functions, the local bone marrow environment and systemic immune control. Analyzing bone marrow stroma cells from AML patients and healthy donors, we have observed distinct genetic abnormalities (Blau O et al, Blood, 2011) and deregulation of cell adhesion and metabolic functions in diseased bone marrow (von der Heide EK et al, Leukemia, 2017). We are now exploring the abundance and complexity of lymphoid repertoires as well as immune-related gene expression signatures in transcriptome sequencing data of bone marrow samples from ALL diagnosis and relapse.
Since January 2022, we are part of the clinical research group CATCH ALL which has been funded by the DFG with around five million euros for four years. Together with teams from research and clinic we want to understand how the immune system interacts with the acute lymphoblastic leukemia in different age groups. Furthermore, we aim to translate our results into novel tailored immunotherapy approaches to improve the outcomes for patients of all ages. Find out more about CATCH ALL here .
If you are interested in our work or if you wish to apply for a position, do not hesitate to contact us!