title: C/EBPalpha and C/EBPvarepsilon induce the monocytic differentiation of myelomonocytic cells with the MLL-chimeric fusion gene.
abstract: CCAAT/enhancer binding proteins (C/EBPs) have an important function in granulocytic differentiation, and are also involved in the leukemogenesis of acute myeloid leukemia (AML). Their involvement in myelomonocytic leukemia, however, is still unclear. Therefore, the expression and function of C/EBPs in myelomonocytic cells with MLL-fusion genes were investigated. Retinoic acid (RA) induced monocytic differentiation in the myelomonocytic cell lines with MLL-fusion genes, THP-1, MOLM-14 and HF-6 cells, accompanied by monocytic differentiation with the upregulation of C/EBPalpha and C/EBPepsilon. Monocytic differentiation by RA treatment was confirmed in primary AML cells using a clonogenic assay. When the activity of C/EBPalpha or C/EBPepsilon was introduced into HF-6 cells, their cellular growth was arrested through differentiation into monocytes with the concomitant marked downregulation of Myc. Cebpe mRNA was upregulated by the induction of C/EBPalpha-ER, but not vice versa, thus suggesting that C/EBPepsilon may have an important function in the differentiation process. Introduction of Myc isoforms into HF-6 cells partially antagonized the C/EBPs effects. These findings suggest that the ectopic expression of C/EBPepsilon, as well as C/EBPalpha, can induce the monocytic differentiation of myelomonocytic leukemic cells with MLL-fusion gene through the downregulation of Myc, thus providing insight into the development of novel therapeutic approaches.
authors.affiliation: Department of Laboratory Medicine, Tokai University School of Medicine, Kanagawa, Japan. hmatsu@is.icc.u-tokai.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Matsushita
authors.forename: H
authors.initials: H
authors.lastname: Nakajima
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.forename: H
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.forename: G
authors.initials: G
authors.lastname: Jin
authors.forename: M
authors.initials: M
authors.lastname: Yabe
authors.forename: S
authors.initials: S
authors.lastname: Asai
authors.forename: R
authors.initials: R
authors.lastname: Ono
authors.forename: T
authors.initials: T
authors.lastname: Nosaka
authors.forename: K
authors.initials: K
authors.lastname: Sugita
authors.forename: A
authors.initials: A
authors.lastname: Morimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashi
authors.forename: T
authors.initials: T
authors.lastname: Hotta
authors.forename: K
authors.initials: K
authors.lastname: Ando
authors.forename: H
authors.initials: H
authors.lastname: Miyachi
mesh_terms: D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis* / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015536:Down-Regulation; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000096:biosynthesis* / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D022762:CCAAT-Enhancer-Binding Proteins; C497422:KMT2A protein, human; C489427:MYC protein, human; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C070790:CEBPE protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase