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ACY-1215 suppresses the proliferation and induces apoptosis of chronic myeloid leukemia cells via the ROS/PTEN/Akt pathway

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Cell Stress and Chaperones Aims and scope

Abstract

Chronic myeloid leukemia (CML) is a hematological tumor marked by the bcr-abl fusion gene formed by t (9;22) (q34; q11), which translated into the BCR-ABL protein. Tyrosine kinase inhibitors (TKIs) have been widely used to cure CML patients. Nevertheless, the emergence of TKI resistance has become the problem to the outcome of CML patients. Histone deacetylase 6 (HDAC6), a kind of Hsp90α deacetylase, was detected to be overexpressed in chronic myeloid leukemia stem cells. Besides, the loss of HDAC6 enzymatic activity can result in the degradation of Hsp90α’s client proteins, such as BCR-ABL, the oncoprotein of CML. Here, we explored the expression of HDAC6 and discovered that it was upregulated compared with control in CML. Then we explored the effect of Rocilinostat (ACY-1215), a specific HDAC6 inhibitor, on CML cells. Our results proved that ACY-1215 could induce apoptosis and cell cycle arrest in a ROS-dependent manner. Moreover, we detected a downregulation of the BCR-ABL signaling pathway in the ACY-1215 treatment group. Mechanistically, we noted that the upregulation of PTEN was induced after being treated by ACY-1215 and its downstream protein p-Akt was decreased. The Akt activator SC79 can partially reverse the influence of ACY-1215 on CML cells. Besides, our results also proved that ACY-1215 can synergize with imatinib to suppress chronic myeloid leukemia in vitro and in vivo. On the whole, our study revealed that HDAC6 is a possible therapeutic target in CML, and the combination therapy of TKI and HDAC6 inhibitor may improve the outcome of CML patients.

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  1. Yuefeng Qin and Yang Liang contributed equally to this work.

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  1. Key Laboratory of Laboratory Medical Diagnostics Designated By the Ministry of Education, Department of Clinical Hematology, Chongqing Medical University, Chongqing, China

    Yuefeng Qin, Yang Liang, Guoyun Jiang, Yuhang Peng & Wenli Feng

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  1. Yuefeng Qin
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The idea for this study was proposed by YQ. YQ and YL designed the experiments. YQ, YL, GJ and YP conducted the experiments. YQ drew the all figures and wrote the manuscript. WF revised this manuscript. All authors contributed to the article and approved the submitted version.

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Correspondence to Wenli Feng.

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Qin, Y., Liang, Y., Jiang, G. et al. ACY-1215 suppresses the proliferation and induces apoptosis of chronic myeloid leukemia cells via the ROS/PTEN/Akt pathway. Cell Stress and Chaperones 27, 383–396 (2022). https://doi.org/10.1007/s12192-022-01280-2

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