2. Academic Validation
  3. Targeting cell membrane HDM2: A novel therapeutic approach for acute myeloid leukemia

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

  • Leukemia. 2020 Jan;34(1):75-86. doi: 10.1038/s41375-019-0522-9.
Huafeng Wang 1 2 3,  Dandan Zhao 2,  Le Xuan Nguyen 2 4,  Herman Wu 2,  Ling Li 2,  Dan Dong 2 5,  Estelle Troadec 2,  Yinghui Zhu 2,  Dinh Hoa Hoang 2,  Anthony S Stein 2,  Monzr Al Malki 2,  Ibrahim Aldoss 2,  Allen Lin 2,  Lucy Y Ghoda 2,  Tinisha McDonald 2,  Flavia Pichiorri 2,  Nadia Carlesso 2,  Ya-Huei Kuo 2,  Bin Zhang 6,  Jie Jin 7 8,  Guido Marcucci 9
Affiliations

Affiliations

  • 1 Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.
  • 2 Hematologic Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA.
  • 3 Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China.
  • 4 Department of Medical Biotechnology, Biotechnology Center of Ho Chi Minh City, Ho Chi Minh, Vietnam.
  • 5 Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, PR China.
  • 6 Hematologic Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA. bzhang@coh.org.
  • 7 Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China. jiej0503@zju.edu.cn.
  • 8 Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China. jiej0503@zju.edu.cn.
  • 9 Hematologic Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA. gmarcucci@coh.org.
PMID: 31337857 DOI: 10.1038/s41375-019-0522-9
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.

Figures
Products