J Cancer 2023; 14(7):1182-1194. doi:10.7150/jca.83219 This issue Cite

Research Paper

Differentiation of imatinib -resistant chronic myeloid leukemia cells with BCR-ABL-T315I mutation induced by Jiyuan Oridonin A

Yun Xu1†, Ziting Wang1†, Lei Zhang1†, Congying Gao1, Fahui Li1, Xueming Li1, Yu Ke2, Hong-Min Liu2, Zhenbo Hu3, Liuya Wei1✉, Zhe-Sheng Chen4✉

1. School of Pharmacy, Weifang Medical University, Weifang, 261053, China;
2. School of Pharmacy, Zhengzhou University, Zhengzhou, 450052, China;
3. Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang 261042, China;
4. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
† These authors contributed equally to this work.

Citation:
Xu Y, Wang Z, Zhang L, Gao C, Li F, Li X, Ke Y, Liu HM, Hu Z, Wei L, Chen ZS. Differentiation of imatinib -resistant chronic myeloid leukemia cells with BCR-ABL-T315I mutation induced by Jiyuan Oridonin A. J Cancer 2023; 14(7):1182-1194. doi:10.7150/jca.83219. https://www.jcancer.org/v14p1182.htm
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Abstract

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Chronic myeloid leukemia (CML) results from BCR-ABL oncogene, which blocks CML cells differentiation and protects these cells from apoptosis. T315I mutated BCR-ABL is the main cause of the resistance mediated by imatinib and second generation BCR-ABL inhibitor. CML with the T315I mutation has been considered to have poor prognosis. Here, we determined the effect of Jiyuan oridonin A (JOA), an ent-kaurene diterpenoid compound, on the differentiation blockade in imatinib-sensitive, particularly, imatinib-resistant CML cells with BCR-ABL-T315I mutation by cell proliferation assay, apoptosis analysis, cell differentiation analysis, cell cycle analysis and colony formation assay. We also investigated the possible molecular mechanism by mRNA sequencing, qRT-PCR and Western blotting. We found that JOA at lower concentration significantly inhibited the proliferation of CML cells expressing mutant BCR-ABL (T315I mutation included) and wild-type BCR-ABL, which was due to that JOA induced the cell differentiation and the cell cycle arrest at G0/G1 phase. Interestingly, JOA possessed stronger anti-leukemia activity than its analogues such as OGP46 and Oridonin, which has been investigated extensively. Mechanistically, the cell differentiation mediated by JOA may be originated from the inhibition of BCR-ABL/c-MYC signaling in CML cells expressing wild-type BCR-ABL and BCR-ABL-T315I. JOA displayed the activity of inhibiting the BCR-ABL and promoted differentiation of not only imatinib -sensitive but also imatinib -resistant cells with BCR-ABL mutation, which could become a potent lead compound to overcome the imatinib -resistant induced by inhibitors of BCR-ABL tyrosine kinase in CML therapy.

Keywords: Chronic myeloid leukemia, BCR-ABL oncogene, T315I mutation, imatinib-resistant BCR-ABL mutations, cell differentiation


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APA
Xu, Y., Wang, Z., Zhang, L., Gao, C., Li, F., Li, X., Ke, Y., Liu, H.M., Hu, Z., Wei, L., Chen, Z.S. (2023). Differentiation of imatinib -resistant chronic myeloid leukemia cells with BCR-ABL-T315I mutation induced by Jiyuan Oridonin A. Journal of Cancer, 14(7), 1182-1194. https://doi.org/10.7150/jca.83219.

ACS
Xu, Y.; Wang, Z.; Zhang, L.; Gao, C.; Li, F.; Li, X.; Ke, Y.; Liu, H.M.; Hu, Z.; Wei, L.; Chen, Z.S. Differentiation of imatinib -resistant chronic myeloid leukemia cells with BCR-ABL-T315I mutation induced by Jiyuan Oridonin A. J. Cancer 2023, 14 (7), 1182-1194. DOI: 10.7150/jca.83219.

NLM
Xu Y, Wang Z, Zhang L, Gao C, Li F, Li X, Ke Y, Liu HM, Hu Z, Wei L, Chen ZS. Differentiation of imatinib -resistant chronic myeloid leukemia cells with BCR-ABL-T315I mutation induced by Jiyuan Oridonin A. J Cancer 2023; 14(7):1182-1194. doi:10.7150/jca.83219. https://www.jcancer.org/v14p1182.htm

CSE
Xu Y, Wang Z, Zhang L, Gao C, Li F, Li X, Ke Y, Liu HM, Hu Z, Wei L, Chen ZS. 2023. Differentiation of imatinib -resistant chronic myeloid leukemia cells with BCR-ABL-T315I mutation induced by Jiyuan Oridonin A. J Cancer. 14(7):1182-1194.

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