title: JmjC-domain containing histone demethylase 1B-mediated p15(Ink4b) suppression promotes the proliferation of leukemic progenitor cells through modulation of cell cycle progression in acute myeloid leukemia.
abstract: The histone demethylase JHDM1B has been implicated in cell cycle regulation and tumorigenesis. In addition, it has been reported that JHDM1B is highly expressed in various human tumors, including leukemias. However, it is not clearly understood how JHDM1B contributes to acute myeloid leukemia (AML) cell proliferation. In this study, we investigated the cellular and molecular function of JHDM1B in AML cells. In AML cell lines and AML-derived ALDH(hi) (high aldehyde dehydrogenase activity)/CD34(+) cells, the levels of JHDM1B mRNA were significantly higher than in normal ALDH(hi) /CD34(+) cells. Reduction of JHDM1B expression in AML cells inhibited cell proliferation compared to control cells, through induction of G1 cell cycle arrest, an increase in the p15(Ink4b) mRNA and protein expression. JHDM1B mRNA was overexpressed in all 133 AML clinical specimens tested (n = 22, 57, 34, and 20 for M1, 2, 4, and 5 subtypes respectively). Compared to normal ALDH(hi) /CD34(+) cells, JHDM1B gene expression was 1.57- to 1.87-fold higher in AML-derived ALDH(hi) /CD34(+) cells. Moreover, the JHDM1B protein was more strongly expressed in AML-derived ALDH(hi) /CD34(+) cells from compared to normal ALDH(hi) /CD34(+) cells. In addition, depletion of JHDM1B reduced colony formation of AML-derived ALDH(hi) /CD34(+) cells due to induction of p15(Ink4b) expression through direct binding to p15(Ink4b) promoter and loss of demethylation of H3K36me2. In summary, we found that JHDM1B mRNA is predominantly expressed in AML-derived ALDH(hi) /CD34(+) cells, and that aberrant expression of JHDM1B induces AML cell proliferation through modulation of cell cycle progression. Thus, inhibition of JHDM1B expression represents an attractive target for AML therapy.
authors.affiliation: Department of Internal Medicine III, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Satoki
authors.initials: S
authors.lastname: Nakamura
authors.forename: Lin
authors.initials: L
authors.lastname: Tan
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nagata
authors.forename: Tomonari
authors.initials: T
authors.lastname: Takemura
authors.forename: Aya
authors.initials: A
authors.lastname: Asahina
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yokota
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yagyu
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Shibata
authors.forename: Shinya
authors.initials: S
authors.lastname: Fujisawa
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ohnishi
mesh_terms: D000328:Adult; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D018952:Antigens, CD34 / Q000032:analysis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism*; D044783:F-Box Proteins / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000378:metabolism*
chemical_list: D018952:Antigens, CD34; D050762:Cyclin-Dependent Kinase Inhibitor p15; D044783:F-Box Proteins; D047428:Protein Kinase Inhibitors; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; D000444:Aldehyde Dehydrogenase; D010089:Oxidoreductases, N-Demethylating