Pml and TAp73 interacting at nuclear body mediate imatinib-induced p53-independent apoptosis of chronic myeloid leukemia cells

Authors

  • Jin-Hwang Liu,

    Corresponding author
    1. Division of Hematology and Oncology, Taipei Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China
    • Division of Hematology and Oncology, Taipei Veterans General Hospital, School of Medicine National Yang-Ming University, 201, Shi-Pai Rd, Sec 2, Taipei 112, Taiwan, ROC
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    • Fax: 886-2-28710659.

  • Chin-Cheng Liu,

    1. Institute of Biochemistry, National Yang-Ming University, Taipei, Taiwan, Republic of China
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  • Chueh-Chuan Yen,

    1. Division of Hematology and Oncology, Taipei Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China
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  • Jyh-Pyng Gau,

    1. Division of Hematology and Oncology, Taipei Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China
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  • Wei-Shu Wang,

    1. School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China
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  • Cheng-Hwai Tzeng

    1. Division of Hematology and Oncology, Taipei Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China
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Abstract

Bcr-abl signals for leukemogenesis of chronic myeloid leukemia (CML) and activates ras. Since the function of promyelocytic leukemia protein (pml) is provoked by ras to promote apoptosis and senescence in untransformed cells, the function is probably masked in CML. Imatinib specifically inhibits bcr-abl and induces apoptosis of CML cells. As reported previously, p53wild CML was more resistant to imatinib than that lacking p53. Here, we searched for an imatinib-induced p53 independent proapoptotic mechanism. We found imatinib up-regulated phosphorylation of p38 mitogen-activated protein kinase (MAPK), checkpoint kinase 2 (chk2) and transactivation-competent (TA) p73; expression of pml and bax; formation of PML-nuclear body (NB); and co-localization of TAp73/PML-NB in p53-nonfunctioning K562 and p53mutant Meg-01 CML cells, but not in BCR-ABL- HL60 cells. In K562 cells, with short interfering RNAs (siRNAs), knockdown of pml led to dephosphorylation of TAp73. Knockdown of either pml or TAp73 abolished the imatinib-induced apoptosis. Inhibition of p38 MAPK with SB203580 led to dephosphorylation of TAp73, abolishment of TAp73/PML-NB co-localization, and the subsequent apoptosis. Conversely, interferon α-2a (IFNα), which increased phosphrylated TAp73 and TAp73/PML-NB co-localization, increased additively apoptosis with imatinib. The imatinib-induced TAp73/PML-NB co-localization was accompanied by co-immpunoprecipitation of TAp73 with pml. The imatinib-induced co-localization was also found in primary CML cells from 3 of 6 patients, including 2 with p53mutant and one with p53wild. A novel p53-independent proapoptotic mechanism using p38 MAPK /pml/TAp73 axis with a step processing at PML-NB and probably with chk2 and bax being involved is hereby evident in some imatinib-treated CML cells. © 2009 UICC

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