International Journal of Hematology

DOI: 10.1007/s12185-009-0256-y Pages: 310-318

IL-6-induced activation of MYC is responsible for the down-regulation of CD33 expression in CD33(+) myeloma cells

1. Yamaguchi University, Laboratory of Cellular Signal Analysis, Graduate School of Medicine

2. Assiut University Hospital, Department of Clinical Pathology

3. Hiroshima Red Cross Hospital

Correspondence to:
Michio M. Kawano
Tel: +81-836-222341
Fax: +81-836-222237
Email: mkawano@yamaguchi-u.ac.jp

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Abstract

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/EBPα). 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.

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