Shamsasenjan Karim, Otsuyama Ken-Ichiro, Abroun Saeid, Iqbal Mohd S, Mahmoud Maged S, Asaoku Hideki, Kawano Michio M
Laboratory of Cellular Signal Analysis, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, 755-8505, Japan.
Department of Clinical Pathology, Assiut University Hospital, Assiut, Egypt.
Int J Hematol. 2009 Apr;89(3):310-318. doi: 10.1007/s12185-009-0256-y. Epub 2009 Mar 4.
Human myeloma cells from about 10% of cases with multiple myeloma expressed CD33 and had monocytoid morphology with convoluted nuclei, and all these patients had no increase in serum CRP values. In CD33(+) myeloma cells as well as myeloma cell lines, CD33 expression levels were correlated with the increased expression levels of CEBPA (C/EBPalpha). This correlation was confirmed by the finding that transfection with the CEBPA gene induced CD33 expression in a CD33(-) myeloma cell line. As suggested by the lack of an increase in serum CRP values in CD33(+) myelomas, IL-6 down-regulated the expression of CD33 in CD33(+) myeloma cell lines along with the down-regulation of CEBPA gene expression. Cucurbitacin I (STAT3 inhibitor), but not U0126 (MAPK inhibitor), could abolish the effect of IL-6. Furthermore, IL-6 up-regulated the expression of MYC via STAT3 phosphorylation and MYC bound to the promoter region of the CEBPA gene followed by the down-regulation of CEBPA expression. It was confirmed that introduction of shRNA for MYC into a CD33(+) myeloma cell line blocked the IL-6-induced down-regulation of CD33 and CEBPA expression. Therefore, these results indicate that IL-6 can reverse the expression level of CD33 by up-regulating MYC followed by the down-regulation of CEBPA expression.
约10%的多发性骨髓瘤患者的人骨髓瘤细胞表达CD33，具有单核细胞样形态且细胞核呈卷曲状，所有这些患者的血清CRP值均未升高。在CD33(+)骨髓瘤细胞以及骨髓瘤细胞系中，CD33表达水平与CEBPA（C/EBPα）表达水平的升高相关。用CEBPA基因转染可在CD33(-)骨髓瘤细胞系中诱导CD33表达，这一发现证实了这种相关性。正如CD33(+)骨髓瘤患者血清CRP值未升高所提示的，IL-6下调了CD33(+)骨髓瘤细胞系中CD33的表达以及CEBPA基因的表达。葫芦素I（STAT3抑制剂）而非U0126（MAPK抑制剂）可消除IL-6的作用。此外，IL-6通过STAT3磷酸化上调MYC的表达，MYC与CEBPA基因的启动子区域结合，随后下调CEBPA的表达。已证实，将针对MYC的shRNA导入CD33(+)骨髓瘤细胞系可阻断IL-6诱导的CD33和CEBPA表达下调。因此，这些结果表明，IL-6可通过上调MYC继而下调CEBPA表达来逆转CD33的表达水平。
