Determining the contribution of NPM1 heterozygosity to NPM-ALK-induced lymphomagenesis.
Mduff, Fiona KE
Tooze, Reuben M
Pandolfi, Pier Paolo
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Mduff, F. K., Hook, C., Tooze, R. M., Huntly, B., Pandolfi, P. P., & Turner, S. (2011). Determining the contribution of NPM1 heterozygosity to NPM-ALK-induced lymphomagenesis.. Laboratory Investigation, 91 (9), 1298-1303. https://doi.org/10.1038/labinvest.2011.96
Heterozygous expression of Nucleophosmin (NPM1) predisposes to hematological malignancies in the mouse and cooperates with Myc in lymphomagenesis. NPM1 is therefore regarded as a haploinsufficient tumor suppressor. Heterozygous loss of NPM1 occurs as a result of the t(2;5), which generates the oncogenic fusion tyrosine kinase, NPM-anaplastic lymphoma kinase (ALK), a molecule underlying the pathogenesis of anaplastic large cell lymphoma (ALCL). Given the aforementioned role of NPM1 as a tumor suppressor, we hypothesized that NPM1 heterozygosity would cooperate with NPM-ALK in lymphomagenesis. In the event, we observed no difference in tumor latency, incidence or phenotype in NPM-ALK-transgenic mice heterozygous for NPM1 relative to transgenic mice expressing both NPM1 alleles. We propose that although the t(2;5) simultaneously reduces NPM1 allelic dosage and creates the NPM-ALK fusion protein, the two events do not cooperate in the pathogenesis of ALCL in our mouse model. These data indicate that a tumor-suppressive role for NPM1 may depend on cellular and/or genetic context.
Anaplastic Lymphoma Kinase, Animals, Heterozygote, Humans, Lymphoma, Mice, Mice, Knockout, Nuclear Proteins, Receptor Protein-Tyrosine Kinases
This work was supported by Cancer Research UK (C19666 to SDT) and the Wellcome Trust (studentship to FKEM). SDT is a Leukaemia and Lymphoma Research Bennett Fellow (07006 to SDT), RT is a Cancer Research UK Senior Clinical Fellow and BJH is a Medical Research Council Senior Clinical Research Fellow.
Cancer Research Uk (None)
Medical Research Council (G0800784)
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External DOI: https://doi.org/10.1038/labinvest.2011.96
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266261