The Roles of MST1/2 in Tumor Suppression and Thymic Seeding

Abstract

Mammalian Hippo signaling pathway has been implicated in development of solid tumors, such as hepatocellular carcinoma. Even though Mst1, the core component of the Hippo signaling pathway, is most highly expressed in hematopoietic cells, whether it suppresses tumorigenesis in blood lineage cells is unknown. Herein, I demonstrate that loss of Mst1 promotes both chemically and genetically induced lymphoma development by inducing chromosomal instability. Mst1-/- mice were more susceptible to development of ENU-induced T-cell acute lymphoblastic leukemia. Pre-transformed Mst1-/- thymocytes did not show any alterations in proliferation or apoptosis in vitro and in vivo. Notably, immunofluorescence staining and karyotype analyses revealed that Mst1-/- lymphocytes displayed elevated levels of abnormal mitotic chromosomes (misaligned or lagging) and aneuploidy, likely promoting tumorigenesis. Furthermore, Mst1 deficient mice showed accelerated spontaneous lymphoma formation in p53-null background accompanied by severe aneuploidy. Consistent with these results from mice, microarray data showed that MST1 expression was downregulated in various human lymphoma and leukemia samples. These data reveal a new tumor suppressive mechanism of Mst1, in which Mst1 prevents chromosomal instability at least in lymphocytes. In addition to increased susceptibility to tumor development, Mst1-/- mice exhibit dramatic lymphopenia in peripheral blood and secondary lymphoid organs (SLOs). Lymphopenia in lymph nodes was explained by the fact that Mst1-/- lymphocytes do not firmly attach to blood vessels of lymph nodes. More precisely, LFA-1 integrin activation (clustering) was impaired in the absence of Mst1 in T or B lymphocytes. However, lymphopenia in spleen could not be explained by the same mechanism, since it does not depend on integrin-mediated attachment. On the other hand, reduction in peripheral blood T cells was thought to be caused by increased apoptosis and/or defect in thymic ...