POU2AF1, an amplification target at 11q23, promotes growth of multiple myeloma cells by directly regulating expression of a B-cell maturation factor, TNFRSF17.
Multiple myeloma (MM), a progressive hematological neoplasm, is thought to result from multiple genetic events affecting the terminal plasma cell. However, genetic aberrations related to MM are seldom reported. Using our in-house array-based comparative genomic hybridization system to locate candidate target genes with following their expression analysis, we identified POU2AF1 at 11q23.1 as a probable amplification target in MM cell lines. POU2AF1 is a B-cell-specific transcriptional co-activator, which interacts with octamer-binding transcription factors Oct-1 and Oct-2, and augments their function. Downregulation of POU2AF1 expression by specific small-interfering RNA (siRNA) inhibited MM cell growth, whereas ectopic expression of POU2AF1 promoted growth of MM cells. Among putative transcriptional targets for POU2AF1, B-cell maturation factor, TNFRSF17, enhanced its transcription by POU2AF1, and POU2AF1 directly bound to an octamer site within the 5' region of TNFRSF17. Expression level of TNFRSF17 was closely correlated with that of POU2AF1 in cell lines and primary samples of MM, and decreasing TNFRSF17 expression by means of TNFRSF17 siRNA inhibited MM cell growth. Taken together, our results suggest that POU2AF1, when activated by amplification or other mechanisms, may contribute to progression of MM by accelerating growth of MM cells through direct transactivation of one of its target genes, TNFRSF17.
Zhao
C
C
Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo, Japan.
Inoue
J
J
Imoto
I
I
Otsuki
T
T
Iida
S
S
Ueda
R
R
Inazawa
J
J
D053301:B-Cell Maturation Antigen / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D005784:Gene Amplification / Q000235:genetics*; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D018390:Gene Targeting; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
D053301:B-Cell Maturation Antigen; C091546:POU2AF1 protein, human; C086966:TNFRSF17 protein, human; D015534:Trans-Activators