title: Regulation of cancer stem cell properties by CD9 in human B-acute lymphoblastic leukemia.
abstract: Although the prognosis of acute lymphoblastic leukemia (ALL) has improved considerably in recent years, some of the cases still exhibit therapy-resistant. We have previously reported that CD9 was expressed heterogeneously in B-ALL cell lines and CD9(+) cells exhibited an asymmetric cell division with greater tumorigenic potential than CD9(-) cells. CD9(+) cells were also serially transplantable in immunodeficient mice, indicating that CD9(+) cell possess self-renewal capacity. In the current study, we performed more detailed analysis of CD9 function for the cancer stem cell (CSC) properties. In patient sample, CD9 was expressed in the most cases of B-ALL cells with significant correlation of CD34-expression. Gene expression analysis revealed that leukemogenic fusion proteins and Src family proteins were significantly regulated in the CD9(+) population. Moreover, CD9(+) cells exhibited drug-resistance, but proliferation of bulk cells was inhibited by anti-CD9 monoclonal antibody. Knockdown of CD9 remarkably reduced the leukemogenic potential. Furthermore, gene ablation of CD9 affected the expression and tyrosine-phosphorylation of Src family proteins and reduced the expression of histone-deubiquitinase USP22. Taken together, our results suggest that CD9 links to several signaling pathways and epigenetic modification for regulating the CSC properties of B-ALL.
authors.affiliation: Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Yamazaki
authors.forename: C Wilson
authors.initials: CW
authors.lastname: Xu
authors.forename: Motohiko
authors.initials: M
authors.lastname: Naito
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nishida
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Okamoto
authors.forename: Farhana Ishrat
authors.initials: FI
authors.lastname: Ghani
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inukai
authors.forename: Kanji
authors.initials: K
authors.lastname: Sugita
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D060245:Tetraspanin 29; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018952:Antigens, CD34; C554869:CD9 protein, human; C554870:Cd9 protein, mouse; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D060245:Tetraspanin 29; D019061:src-Family Kinases