Heidenreich group

Group leader: Prof. dr. Olaf Heidenreich

Functional dissection of leukaemic transcriptional networks

Fusion gene-encoded transcriptional regulators such as RUNX1/ETO or MLL/AF4 drive leukaemia by corrupting haematopoietic gene expression programmes (Ptasinska et al., 2012, 2014). These deregulated programmes include gene products whose continuous expression is required for maintaining leukaemia (stemness). By combining genomic and gene expression analyses with RNAi and CRISPR screens, we functionally identify crucial “transmitters” of fusion genes followed by examination and validation of target genes in tissue culture and in vivo. In subsequent steps, we explore and develop drug combinations that target these validated mediators and pathways. Here, we focus on testing efficacy and selectivity in patient-derived xenograft (PDX) cells both in tissue culture (see also topic 3) and in immunodeficient mouse strains.  

"Fusion genes hold the key for the elimination of leukaemia." Prof. dr. Olaf Heidenreich - Group leader

Therapeutic targeting of fusion genes by siRNA delivery

We have developed siRNA delivery approaches to target leukaemic fusion transcripts (van Asbeck et al., 2013). For instance, liposomal treatment of mice xenotransplanted with t(8;21) AML cells expressing the RUNX1/ETO fusion gene substantially extends median survival and severely impairs leukaemic self-renewal as judged by serial transplantation assays. We are exploring the decoration of liposomes with receptor ligands in order to enhance their association, in vivo retention and uptake by leukaemic cells and tissues. Furthermore, direct perturbation of fusion genes also generates novel vulnerabilities potentially amenable for drug targeting. We are, thus, exploring possible combinations of liposomal siRNA formulations with small molecular weight compounds (i.e. “classical” drugs) in PDX both in tissue culture (see also topic 3) and in immunodeficient mice.

An ex vivo platform for determining patient-specific treatment responses

Unlike leukaemic cell lines, patient-derived leukaemic cells still represent the clonal heterogeneity present in a patient and, thus, would represent superior models for examining drug efficacy in tissue culture and predicting drug responses in patients. However, the major bottleneck for a more general application of patient-derived cells in drug testing is their low viability in tissue culture. We have addressed this challenge by establishing a human bone marrow-derived MSC platform for prolonged ex vivo culture and expansion of patient material and patient-derived xenografts (PDXs) (Pal et al., 2016). To minimize donor-related heterogeneity of MSCs, we established several MSC-derived iPSC lines that can be differentiated into different niche components including MSC-associated lineages and endothelial cells. We are currently employing these platforms for establishing novel drug combinations in PDX in tissue culture (see topics 1 and 2). One additional important goal of this project is the development of a platform to rapidly validate patient-specific drug sensitivities predicted by genome or transcriptome sequencing results but also to explore and therapeutically exploit the communication of the leukaemic cells with their microenvrionment.