Nucleophosmin (Npm) In Cancer And The Aberrant Ribosome Hypothesis
Nucleophosmin (NPM) is a multifunctional nucleolar protein strongly implicated in cancer, where its expression and gene integrity are frequently altered. NPM cytoplasmic mutation (NPMc+) was recently discovered as the single most frequent mutation in acute myeloid leukemia to date. There is significant debate on whether NPM is an oncogene or tumor suppressor. To directly study the role of NPM in cancer, I helped characterize a mouse knockout model of Npm. We have shown that Npm+/mouse embryonic fibroblasts are more susceptible to oncogenic transformation, and Npm+/- mice develop features of human myelodysplastic syndrome which eventually progress to myeloid and lymphoid malignancies. These data demonstrate that Npm is a tumor suppressor in vitro and in vivo. Furthermore, since relatively little is known about NPMc+, I carried out classical transformation assays and generated a transgenic mouse model to assess the oncogenic potential of NPMc+. I find that NPMc+ transforms primary mouse embryonic fibroblasts when its senescence response is evaded, and transgenic mice of NPMc+ develop features of myeloproliferation and other tumors but not acute myeloid leukemia. These data suggest that NPMc+ can act as an oncogene only in the appropriate genetic milieu. In addition, this transgenic model can serve as a tool to identify mutations that cooperate with NPMc+ in leukemogenesis and therapeutic regimens that target NPMc+. To further elucidate the molecular mechanisms of NPM in tumorigenesis, I tested whether aberrant ribosome function could contribute to the increased cancer susceptibility found in Npm+/- cells. Using polysome microarray and a method of determining ribosome composition, my data suggest that aberrant ribosome stoichiometry and cap-independent differential translation of growth promoting mRNAs precedes oncogenisis in Npm+/- mouse embryonic fibroblasts. These findings open a novel paradigm for investigating whether aberrant ribosome quality could lead to cancer.
Dissertation or Thesis