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Acute myeloid leukemia

Targeting cell membrane HDM2: A novel therapeutic approach for acute myeloid leukemia

Leukemia volume 34, pages 75–86 (2020)Cite this article

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Abstract

The E3 ligase human double minute 2 (HDM2) regulates the activity of the tumor suppressor protein p53. A p53-independent HDM2 expression has been reported on the membrane of cancer cells but not on that of normal cells. Herein, we first showed that membrane HDM2 (mHDM2) is exclusively expressed on human and mouse AML blasts, including leukemia stem cell (LSC)-enriched subpopulations, but not on normal hematopoietic stem cells (HSCs). Higher mHDM2 levels in AML blasts were associated with leukemia-initiating capacity, quiescence, and chemoresistance. We also showed that a synthetic peptide PNC-27 binds to mHDM2 and enhances the interaction of mHDM2 and E-cadherin on the cell membrane; in turn, E-cadherin ubiquitination and degradation lead to membrane damage and cell death of AML blasts by necrobiosis. PNC-27 treatment in vivo resulted in a significant killing of both AML “bulk” blasts and LSCs, as demonstrated respectively in primary and secondary transplant experiments, using both human and murine AML models. Notably, PNC-27 spares normal HSC activity, as demonstrated in primary and secondary BM transplant experiments of wild-type mice. We concluded that mHDM2 represents a novel and unique therapeutic target, and targeting mHDM2 using PNC-27 selectively kills AML cells, including LSCs, with minimal off-target hematopoietic toxicity.

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Acknowledgements

This work was supported in part by National Cancer Institute grants: CA102031 (GM), CA201184 (GM), CA180861 (GM), and CA158350 (GM); the Gehr Family Foundation; Youth Natural Science Foundation of Zhejiang Province, China (LQ18H080001); National Natural Science Foundation of China (no. 81370643); Oncolyze, Inc. (drug supply). Research reported in this publication included work performed in the Animal Resources Center, Analytical Cytometry, Hematopoietic Tissue Bank Core, and Electron Microscopy and Light Microscopy Cores at City of Hope Comprehensive Cancer Center supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We are grateful to COH Comprehensive Cancer Center, the patients, and their physicians for providing primary patient material for this study.

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Authors and Affiliations

  1. Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China

    Huafeng Wang & Jie Jin

  2. Hematologic Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA

    Huafeng Wang, Dandan Zhao, Le Xuan Nguyen, Herman Wu, Ling Li, Dan Dong, Estelle Troadec, Yinghui Zhu, Dinh Hoa Hoang, Anthony S. Stein, Monzr Al Malki, Ibrahim Aldoss, Allen Lin, Lucy Y. Ghoda, Tinisha McDonald, Flavia Pichiorri, Nadia Carlesso, Ya-Huei Kuo, Bin Zhang & Guido Marcucci

  3. Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China

    Huafeng Wang & Jie Jin

  4. Department of Medical Biotechnology, Biotechnology Center of Ho Chi Minh City, Ho Chi Minh, Vietnam

    Le Xuan Nguyen

  5. Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, PR China

    Dan Dong

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  1. Huafeng Wang
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Contributions

HFW designed and conducted experiments, analyzed the data, and wrote the paper; DDZ, LXN, HW, LL, DD, ET, YHZ, DHH, and WXM conducted experiments; ASS, MAM, IA, AL, LYG, and TM provided samples and reviewed the patients’ data; FP, NC, and Y-HK designed experiments and reviewed the paper; BZ designed and conducted experiments, analyzed the data, and wrote paper; JJ and GM designed experiments, analyzed the data, wrote the paper, and provided administrative support.

Corresponding authors

Correspondence to Bin Zhang, Jie Jin or Guido Marcucci.

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Conflict of interest

Oncolyze, Inc. provided PNC-27, PNC-26, and PNC-29 for this study. The authors declare that they have no conflict of interest.

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Wang, H., Zhao, D., Nguyen, L.X. et al. Targeting cell membrane HDM2: A novel therapeutic approach for acute myeloid leukemia. Leukemia 34, 75–86 (2020). https://doi.org/10.1038/s41375-019-0522-9

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