Exploring the role of PAX5P80R mutation in B-cell leukemia.

B-cell acute lymphoblastic leukemia;

PAX5 alterations;

primary oncogenic event;

PAX5P80R mutation;

leukemia initiation;

oncogenic transformation;

Hif2alpha;

Acriflavine.

Bastien Gerby – IGAALD – Impact of genetic alterations on acute leukemia development.

The gene PAX5 is a major target of genetic alterations in B-cell acute lymphoblastic leukemia (B-ALL). Among these alterations, the P80R mutation affects the DNA binding domain of PAX5 and induces a unique molecular program in patients. Our study recently published in the journal Cancer Research aims to decipher the biological mechanisms by which PAX5P80R mutation leads to B-ALL development. Using mouse modeling, the work indicates that PAX5P80R mutation perturbs the differentiation of normal B-cells during the first steps of the disease, and triggers the acquisition of secondary mutations leading to tumoral transformation. Moreover, molecular analyses of leukemic cells, combined with pharmacological investigations identified the transcription factor Hif2a as a key player in the leukemic process. This work therefore provides new insight into the mechanisms involved in the emergence of this pathology, which particularly affects children.

Major efforts in fundamental and translational research are devoted to the discovery of new therapies targeting specifically the biological mechanisms involved in leukemia initiation and resistance. This study provides a new strategy to model the multistep process of B-ALL and sheds light on the biological mechanisms by which the PAX5P80R mutation leads to leukemia. Moreover, this study highlights for the first time the role of Hif2a in the leukemic process, and offers new prospects for the use of pharmacological inhibitors targeting Hif2a in the treatment of B-cell leukemias.

Discover the published article

Cancer Res. 2025 May 12.doi: 10.1158/0008-5472.CAN-24-1698. Online ahead of print.
Modeling the PAX5P80R Mutation Reveals HIF2α Activation as a Common Feature and Therapeutic Target in B-Cell Acute Lymphoblastic Leukemia
Manon Bayet, Vincent Fregona, Mathieu Bouttier, Clémence Rouzier, Jérémy Bigot, Laura Jamrog, Sylvie Hebrard, Naïs Prade, Stéphanie Lagarde, Christine Didier, Stéphanie Gachet, Marie Passet, Laetitia Largeaud, Marlène Pasquet, Ahmed Amine Khamlichi, Emmanuelle Clappier, Eric Delabesse, Cyril Broccardo, Bastien Gerby

Collaborations and Partnerships

Collaborations :

Pr. Emmanuelle Clappier : INSERM U944, CNRS UMR 7212 GenCellDis, Institut de Recherche Saint-Louis (IRSL), Université Paris Cité, Paris, France.
Dr. Ahmed Amine Khamlichi : Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III – Paul Sabatier (UT3), Toulouse, France.

Founding :

Institut National de la Santé et de la Recherche Médicale (INSERM, France).
National Centre for Scientific Research (CNRS, France).
National Cancer Institute, France (INCa-2020-096, France).
French National Research Agency (ANR-18-CE13-0002-01, France).
ARC Foundation for Cancer Research (PJA-20181207977, France).
Ligue Nationale Contre le Cancer (labellised team)
Institut Carnot OPALE (labellised team)
Associations ‘Laurette Fugain’, ‘111 des arts’, “Cassandra” and ‘Constance la petite guerrière astronaute’.

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