PhD student Leukaemic Fusion Genes Group

Heidenreich Group

Background information about the Leukaemic Fusion Genes Group

Fusion gene-encoded transcriptional regulators such as RUNX1/ETO drive leukaemias by corrupting haematopoietic gene expression. These dysregulated programmes comprise gene products whose continuous expression is required for maintaining leukaemia. This scenario suggests two ways of interfering with fusion genes: directly by inhibiting their expression and indirectly by perturbing their downstream programme. By combining genomic and gene expression data with RNAi and CRISPR screens, we functionally identify crucial “transmitters” of fusion genes that are potentially suitable for indirect targeting (Martinez-Soria et al., 2018, Cancer Cell; Assi et al., 2019, Nat. Genetics). In addition, we have developed a liposomal approach for the in vivo delivery of siRNAs that directly target these fusion transcripts. Moreover, we are refining complex co-culture conditions and immunodeficient mouse transplantation models for the functional interrogation of primary material derived from AML patients (Pal et al., 2016, Leukemia; Elder et al, 2017, Leukemia). Our findings suggest that RUNX1/ETO also controls leukaemic adhesion and migration and affects the interaction between leukaemic cells and the niche including MSCs. Our ultimate aim is to develop more disease-targeted, patient-specific and less toxic treatment options for patients and, in particular, for children with leukaemia.

Project

This work package will harness our liposomal siRNA delivery platform with targeting moieties for improved retention in leukaemic tissues. We have developed a liposomal siRNA delivery approach targeting leukaemic fusion transcripts that also extend median survival in vivo and severely impairs leukaemic self-renewal as judged by serial transplantation assays. In this PhD project, you will refine this approach by decorating lipid nanoplex particles (LNPs) with receptor ligands in order to further improve siRNA delivery to leukaemia-infiltrated tissues. Formulations active in tissue culture will then be tested in vivo using our xenotransplantation models. You will also examine the impact of fusion gene knockdown on the in vivo maintenance of subclonal populations in patient-derived xenograft models. You will perform these studies by applying a wide range of experimental techniques ranging from chemical modification of lipids over 2D and 3D co-culture of patient-derived AML samples to transplantation and treatment of immunodeficient mouse strains. A successful outcome of this project will lay the fundament for novel targeted and more benign treatments of childhood and adult leukaemias.

 

Tasks and responsibilities

We are looking for an enthusiastic candidate enjoying intellectual challenge and out-of-the-box thinking. This position is suitable for biomedical scientists, pharmacists or organic chemists. You will join a newly established research team at the Maxima closely interacting with an established research team at Newcastle University, Newcastle upon Tyne, UK. Both teams are jointly led by Olaf Heidenreich as PI and Josef Vormoor (Clinical Director of Hemato-oncology at the Maxima) as Co-PI.

Skills

  • Master or equivalent degree in biomedical or pharmaceutical sciences or organic chemistry
  • Experience in contemporary cell biology/molecular biology, pharmaceutic techniques or synthetic organic chemistry
  • Excellent analytical and problem-solving skills
  • Team membership skills within multidisciplinary research teams
  • Excellent communication and presentation skills
  • Strong commitment to a research career

Working at the Princess Maxima Center for pediatric Oncology

We offer a full-time position based on 36 hours per week with funding secured for a total of 4 years.

Apply for this position?

You can apply for this position until the 1st of March by pressing the apply button on this screen.

Acquisitie naar aanleiding van deze vacature wordt niet op prijs gesteld.

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