IL-6-induced activation of MYC is responsible for the down-regulation of CD33 expression in CD33+ myeloma cells.
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.
Shamsasenjan
Karim
K
Laboratory of Cellular Signal Analysis, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, 755-8505, Japan.
Otsuyama
Ken-Ichiro
KI
Laboratory of Cellular Signal Analysis, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, 755-8505, Japan.
Abroun
Saeid
S
Laboratory of Cellular Signal Analysis, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, 755-8505, Japan.
Iqbal
Mohd S
MS
Laboratory of Cellular Signal Analysis, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, 755-8505, Japan.
Mahmoud
Maged S
MS
Department of Clinical Pathology, Assiut University Hospital, Assiut, Egypt.
Asaoku
Hideki
H
Hiroshima Red Cross Hospital, Hiroshima, 730-0052, Japan.
Kawano
Michio M
MM
Laboratory of Cellular Signal Analysis, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, 755-8505, Japan. mkawano@yamaguchi-u.ac.jp.
D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000276:immunology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor / Q000378:metabolism; D063268:Sialic Acid Binding Ig-like Lectin 3; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D022762:CCAAT-Enhancer-Binding Proteins; C571163:CD33 protein, human; C515848:CEBPA protein, human; D015850:Interleukin-6; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3