First demonstration in human cells of chromosomal translocations that cause certain cancer

PUBLIC RELEASE DATE:

4-Jun-2014

Contact: Ainhoa Iriberri airiberri@cnic.es 34-610-295-556 Centro Nacional de Investigaciones Cardiovasculares

Scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and the Centro Nacional de Investigaciones Oncolgicas (CNIO) have succeeded in reproducing, in human cells, the chromosomal translocations that cause two types of cancer: acute myeloid leukemia and Ewing's sarcoma. The findings, published today in Nature Communications, open the way to the development of new therapeutic targets for the treatment of these cancers.

The study was led by Juan Carlos Ramrez and Ral Torres, of the CNIC Viral Vectors Unit, and Sandra Rodrguez-Perales, of the Molecular Cytogenetics group at the CNIO, directed by Juan Cruz Cigudosa. The research team used innovative technology to demonstrate that it is possible to reproduce chromosomal modifications in human cells that are identical to the modifications observed in leukemias and other types of cancer.

The new technology, which uses molecular tools to manipulate the genome, has two main advantages. First, it allows researchers to generate previously unavailable cell models for the study of tumor biology. And second, future development will allow the study of new therapeutic targets and therapies.

The development of tumors is caused by multiple changes in cell physiology and particularly in the genome. In leukemias and a group of cancers called sarcomas, large fragments of DNA are exchanged between different chromosomes, a phenomenon known as chromosomal translocation. These translocations are necessary steps in both the generation and the progression of many neoplastic processes.

"Investigation of these kinds of cancers has been impeded until now by the lack of suitable cell and animal models," explains CNIC researcher Juan Carlos Ramrez, who adds that the difficulty in generating these chromosomal translocations in the laboratory has meant that researchers have lacked cell models with which to investigate the effect of a key marker of the disease: the presence of specific chromosomal translocations.

Using RGEN technology (for RNA-guided endonuclease), also known as CRISPR/Cas9, the team of CNIC and CNIO investigators demonstrated that it is possible to engineer cells to undergo these specific chromosomal translocations. Using human hematopoietic and mesenchymal stem cells, the researchers reproduced chromosomal translocations identical to those observed in patients with acute myeloid leukemia (a cancer of the blood and bone marrow) or Ewing's sarcoma (a type of bone cancer that affects children and adolescents).

According to CNIO researcher Sandra Rodrguez-Perales "With this advance it is now possible to generate cell models with the same alterations detected in tumor cells from patients, and this will permit study of how these changes lead to the development of the tumor. Specifically, it will now be possible to experimentally recapitulate the processes subsequent to chromosomal translocation through which the cell transforms into a tumor cell".

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First demonstration in human cells of chromosomal translocations that cause certain cancer