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Intracellular angiopoietin-1 promotes TKI-resistance via activation of JAK/STAT5 pathway in chronic myeloid leukemia

Oncogene volume 42, pages 124–137 (2023)Cite this article

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Abstract

Drug resistance from BCR-ABL tyrosine kinase inhibitors (TKIs) and other chemotherapeutics results in treatment failure and disease progression in chronic myeloid leukemia (CML). However, the mechanism is still uncertain. In this study, we investigated the role of angiopoietin-1 (ANG-1) as a potential prognostic factor for drug resistance in CML. Both intracellular and secretory ANG-1 (iANG-1 and sANG-1) were overexpressed in multidrug-resistant CML samples. The IC50 value was higher in primary CD34+ CD38– cells with more ANG-1. Silencing ANG-1significantly sensitized three TKI-resistant CML cell lines to imatinib (IM) while recombinant human ANG-1 failed to retain cell survival in vitro. This indicated the important role of iANG-1 as opposed to sANG-1 in CML drug resistance. Moreover, a similar effect was observed in xenograft mice models bearing ANG-1-silenced CML cells. Subsequently, pathway analysis and protein validation experiments showed activation of the JAK/STAT pathway and augmentation of STAT5a phosphorylation in ANG-1 restored CML cells. Upstream Src phosphorylation, which plays a crucial role in CML drug resistance, was also upregulated as a key event in iANG-1-related JAK/STAT pathway activation. In conclusion, our study elucidated a new BCR-ABL independent molecular mechanism induced by intracytoplasmic ANG-1 overexpression as a potential strategy for overcoming CML resistance.

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Fig. 1: Critical target screening in CML at the transcriptional level using bioinformatics analysis.
Fig. 2: ANGPT1 overexpression and its encoding product ANG-1 in patients with CML and TKI-resistance.
Fig. 3: Modulation of ANG-1 expression significantly affects sensitivity of CML cells to TKIs and inhibits proliferation of CML-LSCs.
Fig. 4: Silencing ANG-1 inhibits invasion and proliferation of CML cell lines in vivo and prolongs the survival time of CML-CDX mice model.
Fig. 5: Inhibition of ANG-1 increases the sensitivity of CML-LSCs to TKI in a CML-PDX mice model.
Fig. 6: Activation of JAK/STAT5 signaling pathway mediated by intracellular ANG-1 plays a crucial role in TKI-response in CML cells.
Fig. 7: SRC phosphorylation mediates activation of JAK/STAT5 pathway induced by iANG-1 overexpression.
Fig. 8: Schematic diagram of molecular mechanism of iANG-1 involved TKI-resistance in CML.

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Acknowledgements

This study was supported, in part, by the National Natural Science Foundation of China (Nos. 82003835, 82160704 and 82160665), Basic Research Program of Guizhou Province Technology Bureau(No. ZK[2021] General-399, No.ZK[2022]General-451 and No. ZK[2021] General-568), Science and Technology Program of Guizhou Province Health Committee(Nos. gzwkj2021-466, Nos. gzwkj2021-158 and Nos. gzwkj2021-442), National-Local Joint EngineeringResearch Center for Innovative & Generic Chemical Drug, Guizhou. High-level Innovative Talents Supporting Program (2016-4015)Guiyang City Technology Bureau Planned Project (No. 2019‐9‐14‐8). And we gratefully appreciated the support from public experimental platform of Department of Pathology of Affiliated Hospital of Guizhou Medical University.

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Authors and Affiliations

  1. Department of Hematology, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China

    Dan Ma, Ping Liu, Ping Wang, Yan Wang, Yaming Zhang, Jiangyuan Zhao & Jishi Wang

  2. Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China

    Dan Ma, Chujiao Hu, Yunsheng Ran & Lei Tang

  3. Department of Pharmacy, Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang, 550014, China

    Zhen Zhou

  4. Department of Pathology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China

    Pinghao Li

  5. Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Chengliang Zhang

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Contributions

DM and CLZ designed the experiments; PL, YW, YMZ and YSR performed experiments; DM and CJH completed bioinformatic analyses; DM, ZZ, PL and PW analyzed data; JSW, JYZ and PHL provided specimens; DM, CLZ and LT wrote and edited the manuscript; DM and CJH provided research reagents and valuable comments; DM, CJH and PL provided funding for the study.

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Correspondence to Jishi Wang, Chengliang Zhang or Lei Tang.

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Ma, D., Liu, P., Hu, C. et al. Intracellular angiopoietin-1 promotes TKI-resistance via activation of JAK/STAT5 pathway in chronic myeloid leukemia. Oncogene 42, 124–137 (2023). https://doi.org/10.1038/s41388-022-02536-y

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