Postdoc position KiTZ Máxima

The vast majority of pediatric acute leukemias is driven by a genomic translocation and resulting fusion oncogenes are known for their important role, both in oncogenesis and in maintaining established tumors alive. Fusion gene-encoded transcriptional regulators such as RUNX1/ETO or MLL/AF4 drive leukaemias by corrupting haematopoietic gene expression, with the continuous expression of such fusion genes being required for maintaining leukaemia. Consequently, an elegant vision for future anti-cancer therapy is to target and downregulate fusion oncogenes, e.g., by RNA interference, as tumor cell specific approach. For instance, the as MLL/AF4 is the single most frequent gene fusion in infant ALL.

For this two-year project, the Jeremias group located at the Kindertumorzentrum Heidelberg (KiTZ) and the Heidenreich group at the Princess Maxima Center for Pediatric Oncology have joined forces for developing lipid nanoparticle (LNP) formulations that allow targeting the MLL/AF4 gene fusion in preclinical mouse models for infant ALL. The Heidenreich group has developed liposomal formulations which enable to deliver small interfering RNAs to the bone marrow; the group could show that targeting the RUNX1/ETO fusion oncogene impaired engraftment of RUNX1/ETO-positive AML cells in mice. The Jeremias group has shown that lentiviral expression of an MLL/AF4-specific shRNA diminished tumour load in mice carrying MLL/AF4 rearranged PDX ALL models. While the Heidenreich group will optimize siRNA sequences and LNP design for targeting the MLL/AF4 fusion, the Jeremias group will use the Heidenreich LNP to perform the preclinical treatment trials. They have established several serially transplantable PDX ALL models carrying the identical MLL/AF4 gene fusion mRNA. The effect of LNP treatment will be tested on these models, monitored by repetitive bioluminescence in vivo imaging as a highly sensitive and reliable readout. To elucidate underlying mechanisms in PDX and primary ALL samples, you will use state of the art co-culture and mouse transplantation models and system based on RUNX1/ETO patient-derived xenograft material generated from AML patients. Applied techniques will include lentiviral transduction of PDX, LNP-siRNA-mediated gene knockdown and performing and analysing next generation sequencing experiments including scRNA-seq.

The proposed work fits into the strategic program KiTZ and Máxima as it aims at developing a new strategy to treat pediatric cancer and addresses a translocation with high prevalence in infants. The feasibility of the present work is high as all techniques are established and have been successfully used in other projects before. Of major impact, direct genetic targeting of the MLL/AF4 fusion transcript may offer new options. The LNP-siRNA treatment is strictly tumor specific as it does not alter expression of neither of the two genes involved, suggesting low adverse effects. The work is of high clinical significance as MLL/AF4 rearranged leukaemias suffer a poor prognosis and novel treatment options are intensively needed. As an expected follow-up and if we succeed in targeting the MLL/AF4 fusion, we will apply for further resources to systematically target additional leukaemia fusion genes in the future. Furthermore, a successful outcome of this study will set a paradigm for targeting other fusion gene drivers of paediatric malignancies well beyond leukaemias, including those currently investigated by Maxima and KiTZ teams in solid and brain tumours.

Tasks and responsibilities

We are looking for an enthusiastic candidate enjoying intellectual challenge and out-of-the-box thinking. You have substantial skills in molecular biology and cell biology. Expertise in animal models, in particular immunodeficient mouse models, or basic bioinformatics skills are a strong plus. This project will take place both at the Maxima (year 1) and the KiTZ (year 2) with the employment located at the KiTZ.

Skills

  • PhD or equivalent doctoral degree in a relevant scientific area
  • Experience in contemporary cell biology/molecular biology techniques
  • Experience in the ex vivo culture of primary cells
  • Experience in the analysis of gene function
  • Excellent publication record in peer-reviewed journals
  • Experience in in vivo work, particularly in PDX transplantation of immunodeficient mice
  • Excellent analytical and problem-solving skills
  • Team membership skills within multidisciplinary research teams
  • Excellent communication and presentation skills
  • Ability to demonstrate commitment to a research career and evidence of development towards group leadership

Working at the KiTZ and the Maxima

We offer a full-time position based on 36 hours per week for the duration of two years. Salary is based on German postdoc salary scales depending on years of experience.

Apply for this position?

You can apply for this position until the 31st of December 2022 by pressing the apply button on this screen.

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