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Acute myeloid leukemia

LG-362B targets PML-RARα and blocks ATRA resistance of acute promyelocytic leukemia

Leukemia volume 30, pages 1465–1474 (2016)Cite this article

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Abstract

Acute promyelocytic leukemia (APL) is a M3 subtype of acute myeloid leukemia (AML). Promyelocytic leukemia (PML)-retinoic acid receptor α (RARα) translocation generally occurs in APL patients and makes APL unique both for diagnosis and treatment. However, some conventional drugs like all-transretinoic acid (ATRA) and arsenic trioxide (ATO), as the preferred ones for APL therapy, induce irreversible resistance and responsible for clinical failure of complete remission. Herein, we screened a library of novel chemical compounds with structural diversity and discovered a novel synthetic small compound, named LG-362B, specifically inhibited the proliferation of APL and induced apoptosis. Notably, the differentiation arrest was also relieved by LG-362B in cultured APL cells and APL mouse models. Moreover, LG-362B overcame the ATRA resistance on cellular differentiation and transplantable APL mice. These positive effects were driven by caspases-mediated degradation of PML-RARα when treated with LG-362B, making it specific to APL and reasonable for ATRA resistance relief. We propose that LG-362B would be a potential candidate agent for the treatment of the relapsed APL with ATRA resistance in the future.

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Acknowledgements

This study was partially supported by Major State Basic Research Development Program of China (2015CB910400 and 2012CB910404), National Natural Science Foundation of China (81472788, 81272463, 81202407 and 81330049), National Major Scientific and Technological Special Project for ‘Significant New Drugs Development’ (2013ZX09507001), Innovation Program of Shanghai Municipal Education Commission (13zz034), the Science and Technology Commission of Shanghai Municipality (15431902200) and the Youth Innovation Promotion Association (CAS 2015224).

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  1. X Wang and Q Lin: These authors contributed equally to this work.

Authors and Affiliations

  1. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China

    X Wang, Q Lin, F Lv, N Liu, M Liu, Y Chen & Z Yi

  2. Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM, Shanghai, China

    Y Xu

  3. Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA

    M Liu

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Wang, X., Lin, Q., Lv, F. et al. LG-362B targets PML-RARα and blocks ATRA resistance of acute promyelocytic leukemia. Leukemia 30, 1465–1474 (2016). https://doi.org/10.1038/leu.2016.50

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