2. Academic Validation
  3. Intracellular angiopoietin-1 promotes TKI-resistance via activation of JAK/STAT5 pathway in chronic myeloid leukemia

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

  • Oncogene. 2023 Jan;42(2):124-137. doi: 10.1038/s41388-022-02536-y.
Dan Ma 1 2,  Ping Liu 1,  Chujiao Hu 2,  Zhen Zhou 3,  Ping Wang 1,  Yan Wang 1,  Yaming Zhang 1,  Yunsheng Ran 2,  Pinghao Li 4,  Jiangyuan Zhao 1,  Jishi Wang 5,  Chengliang Zhang 6,  Lei Tang 7
Affiliations

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.
  • 2 Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China.
  • 3 Department of Pharmacy, Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang, 550014, China.
  • 4 Department of Pathology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
  • 5 Department of Hematology, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China. wangjishi96461@163.com.
  • 6 Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. clzhang@tjh.tjmu.edu.cn.
  • 7 Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China. tlei1974@163.com.
PMID: 36385374 DOI: 10.1038/s41388-022-02536-y
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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