Model

Our Model

We work with the xenograft mouse model of acute leukemias: Primary tumor cells from patients suffering from leukemia (either ALL or AML, either pediatric or adult) are
engrafted into immuno-compromised mice. Resulting patient derived xenografted (PDX) cells are then used for in vivo and ex vivo studies, analyzing e.g. resistance mechanisms or stem cell features. This model has major advantages compared to other leukemia models:

 

 

1. Adequate model cells:

As a widely established model system, cell line cells are used to model human malignancies. However, these cells do often not represent the human disease: they have gained multiple non-physiologic genetic changes to enable constant in vitro growth. Furthermore, cell lines do not consist of genetically and functionally diverse subpopulations – however, the heterogeneity of tumor cell populations represents one of the most challenging features of acute leukemias in the clinical setting. And also the heterogeneity between different leukemia patients is another challenge clinicians have to face, but this heterogeneity cannot be covered by cell lines, as the number of available lines is limited.  Therefore, working with primary patient cells is much closer related to the disease than working with cell line cells, to enable the analysis of heterogeneous tumor cells found among and within tumor patients. We have recently shown, that PDX cells resemble the primary sample to a very high extend (PLOS ONE 2012/2015)

2. Survival of primary tumor cells:

primary tumor cells from leukemia patients, especially ALL cells, survive growth in vitro only for short periods of time, and proliferation rate is minimal to absent. However, if cells are injected systemically into immuno-compromised mice, cells proliferate, inducing a leukemia outgrowth comparable to the situation in the human patient. PDX cells can be reisolated and passaged in mice. The mouse is “used as an incubator”.

3. Availability of patient cells and reproducibility of results:

fresh patient cells are isolated at few time points by bone marrow aspiration, and also the quantity is often limited, especially from pediatric patients. Therefore, in vitro analyses using primary patient cells are limited in amount and length. Results cannot be reproduced, as patients will undergo direct treatment after diagnosis, and bone marrow aspirations will be performed only at advanced stages during anti-cancer treatment. By passaging PDX cells in mice, fresh patient-derived cells can be used for repetitive and reproducible in vitro, in vivo and ex vivo analyses.

4. Importance of the right niche:

It has been shown that the bone marrow niche plays an important role for the understanding of disease biology and treatment failure. Apoptosis resistance of tumor cells, e.g., differs dramatically if cells are on a plastic dish or located within the natural microenvironment. The growth of PDX cells in the murine bone marrow niche is therefore much closer related to the disease than in vitro growth conditions.

5. Genetic enineering of PDX cells:

In our lab, we work with the individualized xrenograft mouse model of acute leukemias (see “Models” for details). Within this model, we have established the lentiviral transduction of PDX cells. This enables us to express transgenes within PDX cells, i.e. a luciferase.
Growth of luciferase-expressing PDX cells can be monitored real-time and repetitively in individual mice in a non-invasive way by in vivo bioluminescence imaging, enabling us to follow the systemic growth of the tumor, but also treatment response, in a sensitive and reproducible manner.

 

Genetic engineering in patients' acute leukemia cells growing in mice. Fresh primary tumor cells from ALL or AML patients are injected into immuno-compromised mice. After overt leukemia has developed, patient derived xenografted (PDX) cells are passaged repetitively or used for in vivo or ex vivo studies. PDX cells are lentivirally transduced to express transgenes as luciferase to enable sensitive disease monitoring by in vivo bioluminescence imaging. Image: Group Apoptosis

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