Cilloni D, Messa F, Rosso V, Arruga F, Defilippi I, Carturan S, Catalano R, Pautasso M, Panuzzo C, Nicoli P, Messa E, Morotti A, Iacobucci I, Martinelli G, Bracco E, Saglio G
Division of Hematology and Internal Medicine, Department of Clinical and Biological Sciences of the University of Turin, Turin, Italy.
Leukemia. 2008 Jun;22(6):1234-40. doi: 10.1038/leu.2008.68. Epub 2008 Apr 10.
Mutations in nucleophosmin (NPM) exon 12 and the resulting delocalization of NPM into the cytoplasm are the most specific and frequent cellular events in acute myeloid leukemia patients (AML) with normal karyotype. Cytoplasmatic NPM (NPMc+) is associated with responsiveness to chemotherapy and better prognosis. The activation of nuclear factor-kappaB (NF-kappaB) has been demonstrated to occur in a subset of AML patients and is thought to induce resistance to many chemotherapeutical agents. In this study, we demonstrate the increased in vitro sensitivity of NPMc+ cells to chemotherapeutical agents and their reduced NF-kappaB activity. Furthermore, we provide evidence of the interaction between NPMc+ and NF-kappaB in the cytoplasm, resulting in the sequestration and inactivation of NF-kappaB. The cytosolic localization and consequent inactivation of NF-kappaB justifies the reduced NF-kappaB DNA-binding activity observed in NPMc+ patients. These data, taken together, may provide a possible explanation for the increased rate of chemosensitivity observed among the NPMc+ patients.
核仁磷酸蛋白（NPM）外显子12的突变以及由此导致的NPM在细胞质中的重新定位，是核型正常的急性髓系白血病（AML）患者中最具特异性且最为常见的细胞事件。细胞质中的NPM（NPMc+）与化疗反应性及较好的预后相关。核因子κB（NF-κB）的激活已在部分AML患者中得到证实，并且被认为会诱导对多种化疗药物产生耐药性。在本研究中，我们证明了NPMc+细胞在体外对化疗药物的敏感性增加以及其NF-κB活性降低。此外，我们提供了NPMc+与NF-κB在细胞质中相互作用的证据，这导致了NF-κB的隔离和失活。NF-κB的胞质定位及随之而来的失活，解释了在NPMc+患者中观察到的NF-κB DNA结合活性降低的现象。综合这些数据，可能为NPMc+患者中化疗敏感性增加的发生率提供一种可能的解释。
