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

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, Jie JinGuido Marcucci

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)75-86
Number of pages12
JournalLeukemia
Volume34
Issue number1
DOIs
StatePublished - Jan 1 2020

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ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Wang, H., Zhao, D., Nguyen, L. X., Wu, H., Li, L., Dong, D., Troadec, E., Zhu, Y., Hoang, D. H., Stein, A. S., Al Malki, M., Aldoss, I., Lin, A., Ghoda, L. Y., McDonald, T., Pichiorri, F., Carlesso, N., Kuo, Y. H., Zhang, B., ... Marcucci, G. (2020). Targeting cell membrane HDM2: A novel therapeutic approach for acute myeloid leukemia. Leukemia, 34(1), 75-86. https://doi.org/10.1038/s41375-019-0522-9