The tumor suppressor phosphatase PP2A-56a regulates stemness and promotes the initiation of malignancies in a novel murine model

dProtein phosphatase 2A (PP2A) is a ubiquitously expressed Serine-Threonine phosphatase mediating 30-50% of protein phosphatase activity. PP2A functions as a heterotrimeric complex, with the B subunits directing target specificity to regulate the activity of many key pathways that control cellular phenotypes. PP2A-B56 alpha has been shown to play a tumor suppressor role and to negatively control c-MYC stability and activity. Loss of B56 alpha promotes cellular transformation, likely at least in part through its regulation of c-MYC. Here we report generation of a B56 alpha hypomorph mouse with very low B56 alpha expression that we used to study the physiologic activity of the PP2A-B56 alpha phosphatase. The predominant phenotype we observed in mice with B56 alpha deficiency in the whole body was spontaneous skin lesion formation with hyperproliferation of the epidermis, hair follicles and sebaceous glands. Increased levels of c-MYC phosphorylation on Serine62 and c-MYC activity were observed in the skin lesions of the B56 alpha(hm/hm) mice. B56 alpha deficiency was found to increase the number of skin stem cells, and consistent with this, papilloma initiation was accelerated in a carcinogenesis model. Further analysis of additional tissues revealed increased inflammation in spleen, liver, lung, and intestinal lymph nodes as well as in the skin lesions, resembling elevated extramedullary hematopoiesis phenotypes in the B56 alpha(hm/hm) mice. We also observed an increase in the clonogenicity of bone marrow stem cells in B56 alpha(hm/hm) mice. Overall, this model suggests that B56 alpha is important for stem cells to maintain homeostasis and that B56 alpha loss leading to increased activity of important oncogenes, including c-MYC, can result in aberrant cell growth and increased stem cells that can contribute to the initiation of malignancy.