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Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells

  • Authors:
    • Limengmeng Wang
    • Haowen Xiao
    • Xing Zhang
    • Weichao Liao
    • Shan Fu
    • He Huang
  • View Affiliations / Copyright

    Affiliations: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1685-1695
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    Published online on: September 14, 2015
       https://doi.org/10.3892/ijo.2015.3163
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Abstract

All-trans retinoic acid (ATRA) is one of the first line agents in differentiation therapy for acute promyelocytic leukemia (APL). However, drug resistance is a major problem influencing the efficacy of ATRA. Identification of mechanisms of ATRA resistance are urgenly needed. In the present study, we found that expression of C/EBPα, an important transcription factor for myeloid differentiation, was significantly suppressed in ATRA resistant APL cell line NB4-R1 compared with ATRA sensitive NB4 cells. Moreover, two forms of C/EBPα were unequally suppressed in NB4-R1 cells. Suppression of the full-length form P42 was more pronounced than the truncated form P30. Inhibition of PI3K/Akt/mTOR pathway was also observed in NB4-R1 cells. Moreover, C/EBPα expression was reduced by PI3K inhibitor LY294002 and mTOR inhibitor RAD001 in NB4 cells, suggesting that inactivation of the PI3K/Akt/mTOR pathway was responsible for C/EBPα suppression in APL cells. We restored C/EBPα P42 and P30 by lentivirus vectors in NB4-R1 cells, respectively, and found C/EBPα P42, but not P30, could increase CD11b, CD14, G-CSFR and GM-CSFR expression, which indicated the occurrence of myeloid differentiation. Further upregulating of CD11b expression and differential morphological changes were found in NB4-R1 cells with restored C/EBPα P42 after ATRA treatment. However, CD11b expression and differential morphological changes could not be induced by ATRA in NB4-R1 cells infected with P30 expressing or control vector. Thus, we inferred that ATRA sensitivity of NB4-R1 cells was enhanced by restoration of C/EBPα P42. In addition, we used histone deacetylase inhibitor trichostatin (TSA) to restore C/EBPα expression in NB4-R1 cells. Similar enhancement of myeloid differentiation and cell growth arrest were detected. Together, the present study demonstrated that suppression of C/EBPα P42 induced by PI3K/Akt/mTOR inhibition impaired the differentiation and ATRA sensitivity of APL cells. Restoring C/EBPα P42 is an attractive approach for differentiation therapy in ATRA resistant APL.
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Copy and paste a formatted citation
Spandidos Publications style
Wang L, Xiao H, Zhang X, Liao W, Fu S and Huang H: Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells. Int J Oncol 47: 1685-1695, 2015.
APA
Wang, L., Xiao, H., Zhang, X., Liao, W., Fu, S., & Huang, H. (2015). Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells. International Journal of Oncology, 47, 1685-1695. https://doi.org/10.3892/ijo.2015.3163
MLA
Wang, L., Xiao, H., Zhang, X., Liao, W., Fu, S., Huang, H."Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells". International Journal of Oncology 47.5 (2015): 1685-1695.
Chicago
Wang, L., Xiao, H., Zhang, X., Liao, W., Fu, S., Huang, H."Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells". International Journal of Oncology 47, no. 5 (2015): 1685-1695. https://doi.org/10.3892/ijo.2015.3163
Copy and paste a formatted citation
x
Spandidos Publications style
Wang L, Xiao H, Zhang X, Liao W, Fu S and Huang H: Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells. Int J Oncol 47: 1685-1695, 2015.
APA
Wang, L., Xiao, H., Zhang, X., Liao, W., Fu, S., & Huang, H. (2015). Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells. International Journal of Oncology, 47, 1685-1695. https://doi.org/10.3892/ijo.2015.3163
MLA
Wang, L., Xiao, H., Zhang, X., Liao, W., Fu, S., Huang, H."Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells". International Journal of Oncology 47.5 (2015): 1685-1695.
Chicago
Wang, L., Xiao, H., Zhang, X., Liao, W., Fu, S., Huang, H."Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells". International Journal of Oncology 47, no. 5 (2015): 1685-1695. https://doi.org/10.3892/ijo.2015.3163
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