title: Down-regulation of PU.1 by methylation of distal regulatory elements and the promoter is required for myeloma cell growth.
abstract: The transcription factor PU.1 is essential for myeloid and B-cell development. Down-regulation of PU.1 by disruption of its 14-kb 5' upstream regulatory element induced acute myeloid leukemia, T-cell lymphoma, and chronic lymphocytic leukemia-like disease in murine models. In the present study, we found that PU.1 was down-regulated in the majority of human myeloma cell lines and a subset of freshly isolated myeloma cells, in contrast to relatively high expression of PU.1 in normal plasma cells. Patients in this low PU.1 expression subset may have a poor prognosis. In human myeloma cell lines, the 17-kb 5' upstream enhancer and the promoter region of the PU.1 gene were highly methylated, and this is consistent with disappearance of DNase I-hypersensitive sites in these regions. To elucidate the significance of down-regulation of PU.1, we generated stable myeloma cell lines with an inducible PU.1 expression system. Exogenous expression of PU.1 in PU.1 null myeloma cell lines, U266 and KMS12PE, induced complete growth arrest and cell death. Up-regulation of PU.1 by 5-aza-2'-deoxycytidine also induced growth arrest of KMS12PE and KHM11 myeloma cells. These data suggest that down-regulation of PU.1 is an essential step for the survival of a subset of myeloma cells and that up-regulation of PU.1 by demethylation agents or other types of agents may represent a new therapeutic strategy for treatment of multiple myeloma patients.
authors.affiliation: Department of Hematology, Kumamoto University of Medicine, Kumamoto, Japan.
authors.forename: Hiro
authors.initials: H
authors.lastname: Tatetsu
authors.forename: Shikiko
authors.initials: S
authors.lastname: Ueno
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hata
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okuno
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000077209:Decitabine; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D001374:Azacitidine; D000077209:Decitabine; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1