PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice

PAX5 is a well-known haploinsufficient tumor suppressor gene in human B-cell precursor acute lymphoblastic leukemia (B-ALL) and is involved in various chromosomal translocations that fuse a part of PAX5 with other partners. However, the role of PAX5 fusion proteins in B-ALL initiation and transforma...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2018-10, Vol.115 (41), p.10357-10362
Main Authors: Jamrog, Laura, Chemin, Guillaume, Fregona, Vincent, Coster, Lucie, Pasquet, Marlène, Oudinet, Chloé, Rouquié, Nelly, Prade, Naïs, Lagarde, Stéphanie, Cresson, Charlotte, Hébrard, Sylvie, Huu, Ngoc Sa Nguyen, Bousquet, Marina, Quelen, Cathy, Brousset, Pierre, Mancini, Stéphane J. C., Delabesse, Eric, Khamlichi, Ahmed Amine, Gerby, Bastien, Broccardo, Cyril
Format: Article
Language:English
Subjects:
Acute lymphoblastic leukemia
Animals
B-Lymphocytes - pathology
B-Lymphocytes - physiology
Biological Sciences
Cancer
Cell proliferation
Cells
Chromosome translocations
Computer applications
Elastin
Elastin - genetics
Elastin - metabolism
Fusion protein
Gene Expression Regulation, Leukemic
Gene Knock-In Techniques
Genetic transformation
In vivo methods and tests
Janus Kinase 3 - genetics
Leukemia
Life Sciences
Lymphatic leukemia
Lymphocytes B
Mice
Mice, Transgenic
Mutation
Neoplasms, Experimental
Oncogene Proteins, Fusion - genetics
Oncogene Proteins, Fusion - metabolism
Oncoproteins
Pax5 protein
PAX5 Transcription Factor - genetics
PAX5 Transcription Factor - metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology
Protein expression
Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics
Proteins
Proto-Oncogene Proteins p21(ras) - genetics
Translocation
Tumor suppressor genes
Tumorigenesis
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Summary:PAX5 is a well-known haploinsufficient tumor suppressor gene in human B-cell precursor acute lymphoblastic leukemia (B-ALL) and is involved in various chromosomal translocations that fuse a part of PAX5 with other partners. However, the role of PAX5 fusion proteins in B-ALL initiation and transformation is ill-known. We previously reported a new recurrent t(7;9)(q11;p13) chromosomal translocation in human B-ALL that juxtaposed PAX5 to the coding sequence of elastin (ELN). To study the function of the resulting PAX5-ELN fusion protein in B-ALL development, we generated a knockin mouse model in which the PAX5-ELN transgene is expressed specifically in B cells. PAX5-ELN–expressing mice efficiently developed B-ALL with an incidence of 80%. Leukemic transformation was associated with recurrent secondary mutations on Ptpn11, Kras, Pax5, and Jak3 genes affecting key signaling pathways required for cell proliferation. Our functional studies demonstrate that PAX5-ELN affected B-cell development in vitro and in vivo featuring an aberrant expansion of the pro-B cell compartment at the preleukemic stage. Finally, our molecular and computational approaches identified PAX5-ELN–regulated gene candidates that establish the molecular bases of the preleukemic state to drive B-ALL initiation. Hence, our study provides a new in vivo model of human B-ALL and strongly implicates PAX5 fusion proteins as potent oncoproteins in leukemia development.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1721678115