Peng Jie, Fu Bin, Fu Gan, Zhao Xielan, Li Xiaolin, Chen Fangping
Pharmazie. 2017 Oct 1;72(10):608-613. doi: 10.1691/ph.2017.7473.
Acute myeloid leukemia (AML) is the most malignant myeloid disorder in adults. AML with mutated nucleophosmin (NPM1) is regarded as an independent leukemia subtype. According to previous studies, the role of NPM1 gene A mutation in AML has been well established; however, another major type, NPM1 gene B type mutation (NPM1 MutB) has been rarely reported. In the present study, we found that overexpression of NPM1 MutB enhanced the proliferation and invasion of THP-1 AML cells through the regulation of TIMP-2, MMP-2, Ang-1, c-myc and CCND1; led to no significant change of apoptosis rate with the absence of chemotherapy agents, while enhanced the chemosensitivity of THP-1 AML cells to chemotherapy agents DNR and Ara-C through the regulation of Bax, Bcl-2 and caspase-3. Further, we revealed that NPM1 MutB overexpression reduced the NF-κB activity of THP-1 cells upon drug treatment. Taken together, we demonstrated the detailed functions of NPM1MutB in THP-1 proliferation, invasion, apoptosis and chemo-sensitivity. We provided a novel understanding of prognosis of patients carrying the NPM1 B mutation.
急性髓系白血病（AML）是成人中最恶性的髓系疾病。核仁磷酸蛋白（NPM1）突变的AML被视为一种独立的白血病亚型。根据以往研究，NPM1基因A突变在AML中的作用已得到充分证实；然而，另一种主要类型，即NPM1基因B型突变（NPM1 MutB）却鲜有报道。在本研究中，我们发现NPM1 MutB的过表达通过调节基质金属蛋白酶组织抑制因子-2（TIMP-2）、基质金属蛋白酶-2（MMP-2）、血管生成素-1（Ang-1）、原癌基因c-myc和细胞周期蛋白D1（CCND1）增强了THP-1 AML细胞的增殖和侵袭能力；在无化疗药物时凋亡率无显著变化，而通过调节凋亡相关蛋白Bax、Bcl-2和半胱天冬酶-3（caspase-3）增强了THP-1 AML细胞对化疗药物柔红霉素（DNR）和阿糖胞苷（Ara-C）的化疗敏感性。此外，我们还发现NPM1 MutB过表达降低了药物处理后THP-1细胞的核因子κB（NF-κB）活性。综上所述，我们阐明了NPM1 MutB在THP-1细胞增殖、侵袭、凋亡及化疗敏感性方面的详细功能。我们为携带NPM1 B突变患者的预后提供了新的认识。
