title: Down-regulation of Thanatos-associated protein 11 by BCR-ABL promotes CML cell proliferation through c-Myc expression.
abstract: Bcr-Abl activates various signaling pathways in chronic myelogenous leukemia (CML) cells. The proliferation of Bcr-Abl transformed cells is promoted by c-Myc through the activation of Akt, JAK2 and NF-κB. However, the mechanism by which c-Myc regulates CML cell proliferation is unclear. In our study, we investigated the role of Thanatos-associated protein 11 (THAP11), which inhibits c-Myc transcription, in CML cell lines and in hematopoietic progenitor cells derived from CML patients. The induction of THAP11 expression by Abl kinase inhibitors in CML cell lines and in CML-derived hematopoietic progenitor cells resulted in the suppression of c-Myc. In addition, over-expression of THAP11 inhibited CML cell proliferation. In colony forming cells derived from CML-aldehyde dehydrogenase (ALDH)(hi) /CD34(+)  cells, treatment with Abl kinase inhibitors and siRNA depletion of Bcr-Abl induced THAP11 expression and reduced c-Myc expression, resulting in inhibited colony formation. Moreover, overexpression of THAP11 significantly decreased the colony numbers, and also inhibited the expression of c-myc target genes such as Cyclin D1, ODC and induced the expression of p21(Cip1) . The depletion of THAP11 inhibited JAK2 or STAT5 inactivation-mediated c-Myc reduction in ALDH(hi) /CD34(+)  CML cells. Thus, the induced THAP11 might be one of transcriptional regulators of c-Myc expression in CML cell. Therefore, the induction of THAP11 has a potential possibility as a target for the inhibition of CML cell proliferation.
authors.affiliation: Department of Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan. satonaka@hama-med.ac.jp
authors.forename: Satoki
authors.initials: S
authors.lastname: Nakamura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yokota
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: Isao
authors.initials: I
authors.lastname: Hirano
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shigeno
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: D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D016259:Genes, myc; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012097:Repressor Proteins / Q000502:physiology*
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012097:Repressor Proteins; C498470:THAP11 protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl