Tumor heterogeneity

We are conducting studies to resolve tumor heterogeneity and the links between aberrant chromatin/epigenome and transcriptome features in blood cancers. B cells from patients with chronic lymphocytic leukemia (CLL) were compared to their non-malignant counterparts for a comprehensive set of histone modifications and DNA methylation marks to reveal how the underlying gene regulatory networks are deregulated in CLL. Furthermore, we are identifying novel epigenetic biomarkers by understanding how BCR signaling impacts on the deregulated transcriptional and epigenetic landscape in CLL patient cells.

In collaborations with the group of Marc Raab and coworkers at the Clinical Cooperation Unit Molecular Hematology/Oncology (DKFZ Research Topic Cell and Tumor Biology) and the Myeloma Center of the University Hospital Heidelberg we apply single cell multi-omics to resolve tumor heterogeneity and treatment response in multiple myeloma. Interactions with the bone marrow microenvironment and molecular changes during the emergence of treatment resistance were revealed in relapsed/refractory multiple myeloma. By calling copy number aberrations from single cell RNA sequencing data in conjunction with whole genome sequencing data, the intra-patient tumor heterogeneity can be dissected so that the evolution of tumor subclones is revealed.

Resolving intra-tumor heterogeneity from copy number aberrations. The plot shows the assignment of 10,007 individual cells from a patient sample into 5 different tumor subclones based on single cell RNA sequencing.

This work is currently extended to include an integrative analysis with single cell ATAC-seq data and T cell hyperexpansion in multiple myeloma studied by single cell T/B-cell receptor sequencing.

Key references

Poos AM, Prokoph N, Przybilla MJ, Mallm J-P, Steiger S, Lander I, John L, Tirier SM, Bauer K, Baumann A, Munawar U, Rasche L, Kortuem M, Giesen N, Huhn S, Mueller-Tidow C, Goldschmidt H, Stegle O, Raab MS, Rippe K, Weinhold N (2022) Single-Cell Multi-Omics Reveal Longitudinal Dynamics of Clonal Architecture and Microenvironment Interactions in Relapsed-Refractory Myeloma (ASH 2022 Abstract). Blood 140 (Supplement 1), 9987–9988. doi: 10.1182/blood-2022-166105 | Abstract | Reprint

Tirier SM, Mallm J-P, Steiger S, Poos AM, Awwad M, Giesen N, Casiraghi N, Susak H, Bauer K, Baumann A, John L, Seckinger A, Hose D, Müller-Tidow C, Goldschmidt H, Stegle O, Hundemer M, Weinhold N, Raab MS, Rippe K (2021) Subclone specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single cell transcriptomics. Nat Commun 12, 6960. doi: 10.1038/s41467-021-26951-z | Abstract | Reprint | Article metrics

Mallm JP, Iskar M, Ishaque N, Klett LC, Kugler SJ, Muino JM, Teif VB, Poos AM, Großmann S, Erdel F, Tavernari D, Koser SD, Schumacher S, Brors B, König R, Remondini D, Vingron M, Stilgenbauer S, Lichter P, Zapatka M, Mertens D & Rippe K (2019) Linking aberrant chromatin features in chronic lymphocytic leukemia to deregulated transcription factor networks. Mol Syst Biol 15, e8339. doi: 10.15252/msb.20188339 | Abstract | Reprint | Appendix | Additional data | Article metrics