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c-Myc plays a critical role in the antileukemic activity of the Mcl-1-selective inhibitor AZD5991 in acute myeloid leukemia

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Abstract

Acute myeloid leukemia (AML) is an aggressive disease with a low 5-year overall survival rate of 29.5%. Thus, more effective therapies are in need to prolong survival of AML patients. Mcl-1 is overexpressed in AML and is associated with poor prognosis, representing a promising therapeutic target. The oncoprotein c-Myc is also overexpressed in AML and is a significant prognostic factor. In addition, Mcl-1 is required for c-Myc induced AML, indicating that c-Myc-driven AML harbors a Mcl-1 dependency and co-targeting of Mcl-1 and c-Myc represents a promising strategy to eradicate AML. In this study, we investigated the role of c-Myc in the antileukemic activity of Mcl-1 selective inhibitor AZD5991 and the antileukemic activity of co-targeting of Mcl-1 and c-Myc in preclinical models of AML. We found that c-Myc protein levels negatively correlated with AZD5991 EC50s in AML cell lines and primary patient samples. AZD5991 combined with inhibition of c-Myc synergistically induced apoptosis in AML cell lines and primary patient samples, and cooperatively targeted leukemia progenitor cells. AML cells with acquired resistance to AZD5991 were resensitized to AZD5991 when c-Myc was inhibited. The combination also showed promising and synergistic antileukemic activity in vitro against AML cell lines with acquired resistance to the main chemotherapeutic drug AraC and primary AML cells derived from a patient at relapse post chemotherapy. The oncoprotein c-Myc represents a potential biomarker of AZD5991 sensitivity and inhibition of c-Myc synergistically enhances the antileukemic activity of AZD5991 against AML.

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Data Availability

All data generated or analyzed during this study are included in this published article or are available upon request to either Yubin Ge (gey@karmanos.org) or Guan Wang (wg10@jlu.edu.cn).

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Funding

This study was supported by grants from the National Natural Science Foundation of China (NSFC81800154 to Guan Wang), Children’s Foundation, LaFontaine Family/U Can CerVive Foundation, Kids Without Cancer, Decerchio/Guisewite Family, Justin’s Gift, Elana Fund, Ginopolis/Karmanos Endowment, the Ring Screw Textron Endowed Chair for Pediatric Cancer Research. The funders had no role in study design, data collection, analysis and interpretation of data, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, P.R. China

    Shuang Liu, Xinan Qiao, Shuangshuang Wu, Yuqinq Gai & Guan Wang

  2. Department of Pediatric Hematology and Oncology, The First Hospital of Jilin University, Changchun, China

    Shuangshuang Wu & Yue Wang

  3. Department of Oncology, Wayne State University School of Medicine, 421 E. Canfield, 48201, Detroit, MI, USA

    Yongwei Su, Holly Edwards & Yubin Ge

  4. Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

    Yongwei Su, Holly Edwards & Yubin Ge

  5. Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, China

    Hai Lin

  6. Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA

    Jeffrey W. Taub

  7. Division of Pediatric Hematology and Oncology, Department of Pediatrics, Children’s Hospital of Michigan, Detroit, MI, USA

    Jeffrey W. Taub

  8. Central Michigan University College of Medicine, Mt. Pleasant, MI, USA

    Jeffrey W. Taub

Authors
  1. Shuang Liu
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  2. Xinan Qiao
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  6. Holly Edwards
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  7. Yue Wang
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  8. Hai Lin
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  9. Jeffrey W. Taub
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  10. Guan Wang
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  11. Yubin Ge
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Contributions

Conceptualization, Yubin Ge; Formal analysis, Shuang Liu, Xinan Qiao, Shuangshuang Wu, Yuqin Gai, Yongwei Su, Holly Edwards, Yue Wang, Jeffrey W. Taub, Guan Wang and Yubin Ge; Funding acquisition, Jeffrey W. Taub, Guan Wang and Yubin Ge; Investiga-tion, Shuang Liu, Xinan Qiao, Shuangshuang Wu and Yongwei Su; Methodology, Yubin Ge; Pro-ject administration, Guan Wang and Yubin Ge; Resources, Yue Wang and Hai Lin; Supervision, Guan Wang and Yubin Ge; Visualization, Shuang Liu, Holly Edwards, Guan Wang and Yubin Ge; Writing – original draft, Holly Edwards and Yubin Ge; Writing – review & editing, Shuang Liu, Xinan Qiao, Shuangshuang Wu, Yuqin Gai, Yongwei Su, Holly Edwards, Yue Wang, Hai Lin, Jeffrey W. Taub, Guan Wang and Yubin Ge. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Guan Wang or Yubin Ge.

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The authors declare no competing financial interests or other competing interests.

Ethical approval

Diagnostic blast samples were obtained from the First Hospital of Jilin University, Changchun, China. Normal peripheral blood mononuclear cells (PBMCs) were donated by healthy individuals. Written informed consent was provided according to the Declaration of Helsinki. The study was approved by the Human Ethics Committee of the First Hospital of Jilin University (Ethical code # 2019 − 128).

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Liu, S., Qiao, X., Wu, S. et al. c-Myc plays a critical role in the antileukemic activity of the Mcl-1-selective inhibitor AZD5991 in acute myeloid leukemia. Apoptosis 27, 913–928 (2022). https://doi.org/10.1007/s10495-022-01756-7

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