Balanced chromosomal translocations can generate a chimeric gene whose fusion product may have a novel or an altered activity, this condition is typically found in leukemia. B-cell precursor acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer. Despite extensive investigations, the events that trigger initiation and malignant transformation are still ill-known, in part because of the lack of a suitable animal model. The team of Ahmed Amine Khamlichi at the IPBS has generated a mouse model that recapitulates the main steps of the human B-ALL. The study has been published in the Proceedings of the National Academy of Sciences of the USA, on October 9th, 2018.
The investigators inserted a human sequence encoding a fusion protein from a B-ALL patient in a well-defined site of the mouse genome. The human chimeric protein was produced exclusively in B lymphocytes. Analyses of the mice revealed that the fusion protein was an initiating oncogenic event. The oncoprotein led to an altered B cell development at early steps of leukemogenesis. However, malignant transformation involved altered expression profiles of multiple genes and acquisition of additional mutations strikingly similar to those found in B-ALL patients.
This model will be an invaluable tool to further unravel the mechanisms underlying B-ALL and to develop novel therapeutic strategies.
This work was performed in collaboration with Bastien Gerby and Cyril Broccardo, from the team of Eric Delabesse at the Centre de Recherches en Cancérologie de Toulouse, and was funded by Institut National du Cancer (INCa) and Fondation ARC.
Jamrog L#, Chemin G#, Fregona V, Coster L, Pasquet M, Oudinet C, Rouquié N, Prade N, Lagarde S, Cresson C, Hebrard S, Hu NS, Bousquet M, Quelen C, Brousset P, Mancini S, Delabesse E, Khamlichi AA*, Gerby B*, Broccardo C*. PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice. Proc Natl Acad Sci USA 2018 | October 9 | vol. 115 | no. 41 | 10357–10362.
Research: Ahmed Amine Khamlichi
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