Most cancer cells share two abnormalities: uncontrolled proliferation and suppressed apoptosis. A direct relationship has been shown between the expression level of nucleophosmin (NPM) and a variety of human cancers including leukemia evolved from Fanconi anemia (FA), a genetic disorder associated with bone marrow failure, clonal proliferation of hematopoietic cells, and transformation to acute leukemia. This suggests a potential role of NPM in cancer development. We identified NPM as a novel cellular inhibitor of the pro-apoptotic protein kinase PKR, and demonstrated that NPM regulates PKR activity and suppresses apoptosis induced by mitogenic inhibitors and therapeutic agents in hematopoietic cells of FA. Our preliminary studies also indicated that NPM is a component of the so-called FA-PKR complex, which functions as a signaling intermediate in cellular responses to apoptotic and survival signals. We hypothesize that NPM suppresses apoptosis and promotes proliferation through inhibiting the pro-apoptotic kinase PKR and accelerating cell-cycle progression and that leukemic evolution in FA and other cancer-prone bone marrow diseases may require increased expression of NPM to maintain survival and proliferation. The long term goals of our study are to utilize FA as an experimental system to examine the role of NPM in hematopoiesis and leukemic evolution. We plan to build on our preliminary characterizations of NPM-PKR interaction and NPM deregulation during FA disease progression to explore in molecular details the biochemical and functional alterations of NPM in the context of NPM expression, NPM-PKR interaction, the integrity of the FA-PKR complex, PKR activity, and apoptosis in BM cells from normal donors and FA patients at different stages of disease progression. We will also investigate whether regulation of PKR by NPM and the FA-PKR protein complex are linked mechanistically in these primary BM cells. We will employ three unique FA cell lines derived from FA patients at different stages of the disease progression to study the mechanism by which NPM promotes proliferation and suppresses apoptosis. To study the role of NPM in clonal proliferation, we will determine effects of NPM expression on proliferation and differentiation of FA evolved leukemic cells and hematopoietic stem/progenitor cells of FA mice. The proposed study will be of fundamental importance in understanding the evolution of bone marrow failure syndromes such as Fanconi anemia to clonal hematologic diseases such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In addition, study of biological consequences of NPM alterations in the context of PKR suppression during FA disease progression may provide rationale for exploiting this molecule for detection and prevention of certain cancers including FA-evolved leukemia.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Mufson, R Allan
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Children's Hospital Med Ctr (Cincinnati)
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Du, Wei; Amarachintha, Surya; Erden, Ozlem et al. (2016) The Fanconi anemia pathway controls oncogenic response in hematopoietic stem and progenitor cells by regulating PRMT5-mediated p53 arginine methylation. Oncotarget 7:60005-60020
Li, Jie; Pang, Qishen (2014) Oxidative stress-associated protein tyrosine kinases and phosphatases in Fanconi anemia. Antioxid Redox Signal 20:2290-301
Li, Jie; Sipple, Jared; Maynard, Suzette et al. (2012) Fanconi anemia links reactive oxygen species to insulin resistance and obesity. Antioxid Redox Signal 17:1083-98
Du, Wei; Li, Xu-E; Sipple, Jared et al. (2011) Overexpression of IL-3R? on CD34+CD38- stem cells defines leukemia-initiating cells in Fanconi anemia AML. Blood 117:4243-52
Du, Wei; Li, Jie; Sipple, Jared et al. (2010) Cytoplasmic FANCA-FANCC complex interacts and stabilizes the cytoplasm-dislocalized leukemic nucleophosmin protein (NPMc). J Biol Chem 285:37436-44
Li, Jie; Du, Wei; Maynard, Suzette et al. (2010) Oxidative stress-specific interaction between FANCD2 and FOXO3a. Blood 115:1545-8
Du, Wei; Zhou, Yun; Pike, Suzette et al. (2010) NPM phosphorylation stimulates Cdk1, overrides G2/M checkpoint and increases leukemic blasts in mice. Carcinogenesis 31:302-10
Rani, Reena; Li, Jie; Pang, Qishen (2008) Differential p53 engagement in response to oxidative and oncogenic stresses in Fanconi anemia mice. Cancer Res 68:9693-702
Zhou, Yun; Du, Wei; Koretsky, Tara et al. (2008) TAT-mediated intracellular delivery of NPM-derived peptide induces apoptosis in leukemic cells and suppresses leukemogenesis in mice. Blood 112:2474-83
Du, Wei; Adam, Zsuzsanna; Rani, Reena et al. (2008) Oxidative stress in Fanconi anemia hematopoiesis and disease progression. Antioxid Redox Signal 10:1909-21

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