Down-regulation of Thanatos-associated protein 11 by BCR-ABL promotes CML cell proliferation through c-Myc expression
Corresponding Author
Satoki Nakamura
Department of Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
S.N. and D.Y. contributed equally to this work.
Tel.: 81-53-435-2267, Fax: 81-53-434-2910
Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, JapanSearch for more papers by this authorDaisuke Yokota
Cancer Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
S.N. and D.Y. contributed equally to this work.
Search for more papers by this authorLin Tan
Cancer Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorYasuyuki Nagata
Cancer Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorTomonari Takemura
Cancer Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorIsao Hirano
Cancer Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorKazuyuki Shigeno
Department of Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorKiyoshi Shibata
Equipment Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorShinya Fujisawa
Division of Hematology, Hamamatsu Medical Center, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorKazunori Ohnishi
Department of Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Cancer Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorCorresponding Author
Satoki Nakamura
Department of Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
S.N. and D.Y. contributed equally to this work.
Tel.: 81-53-435-2267, Fax: 81-53-434-2910
Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, JapanSearch for more papers by this authorDaisuke Yokota
Cancer Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
S.N. and D.Y. contributed equally to this work.
Search for more papers by this authorLin Tan
Cancer Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorYasuyuki Nagata
Cancer Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorTomonari Takemura
Cancer Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorIsao Hirano
Cancer Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorKazuyuki Shigeno
Department of Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorKiyoshi Shibata
Equipment Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorShinya Fujisawa
Division of Hematology, Hamamatsu Medical Center, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorKazunori Ohnishi
Department of Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Cancer Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Search for more papers by this authorTel.: 81-53-435-2267, Fax: 81-53-434-2910
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 p21Cip1. The depletion of THAP11 inhibited JAK2 or STAT5 inactivation-mediated c-Myc reduction in ALDHhi/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.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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| IJC_26065_sm_suppinfoFigureS1.tif899.8 KB | Supporting Information Figure 1 |
| IJC_26065_sm_suppinfoFigureS2.tif923.1 KB | Supporting Information Figure 2 |
| IJC_26065_sm_suppinfoFigureS3.tif708.2 KB | Supporting Information Figure 3 |
| IJC_26065_sm_suppinfoFigureS4.tif706.9 KB | Supporting Information Figure 4 |
| IJC_26065_sm_suppinfoFigureS5.tif825.1 KB | Supporting Information Figure 5 |
| IJC_26065_sm_suppinfo.doc30 KB | Supporting Information |
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