Theranostics 2022; 12(11):4922-4934. doi:10.7150/thno.71460 This issue

Research Paper

KDM4 inhibitor SD49-7 attenuates leukemia stem cell via KDM4A/MDM2/p21CIP1 axis

Yinghui Li1#, Chaoqun Wang1#, Huier Gao1,2#, Jiali Gu1, Yiran Zhang1, Yingyi Zhang3, Min Xie4, Xuelian Cheng1, Ming Yang1, Wenshan Zhang1, Yafang Li1, Mei He1, Hui Xu1, Hexiao Zhang1, Qing Ji1, Tianhua Ma5,6, Sheng Ding5,6✉, Yu Zhao7✉, Yingdai Gao1✉

1. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
2. Department of Pharmacy, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China.
3. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55901, USA.
4. Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
5. School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
6. Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China.
7. Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Li Y, Wang C, Gao H, Gu J, Zhang Y, Zhang Y, Xie M, Cheng X, Yang M, Zhang W, Li Y, He M, Xu H, Zhang H, Ji Q, Ma T, Ding S, Zhao Y, Gao Y. KDM4 inhibitor SD49-7 attenuates leukemia stem cell via KDM4A/MDM2/p21CIP1 axis. Theranostics 2022; 12(11):4922-4934. doi:10.7150/thno.71460. Available from https://www.thno.org/v12p4922.htm

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Abstract

Graphic abstract

Rationale: Traditional treatments for leukemia fail to address stem cell drug resistance characterized by epigenetic mediators such as histone lysine-specific demethylase 4 (KDM4). The KDM4 family, which acts as epigenetic regulators inducing histone demethylation during the development and progression of leukemia, lacks specific molecular inhibitors.

Methods: The KDM4 inhibitor, SD49-7, was synthesized and purified based on acyl hydrazone Schiff base. The interaction between SD49-7 and KDM4s was monitored in vitro by surface plasma resonance (SPR). In vitro and in vivo biological function experiments were performed to analyze apoptosis, colony-formation, proliferation, differentiation, and cell cycle in cell sub-lines and mice. Molecular mechanisms were demonstrated by RNA-seq, ChIP-seq, RT-qPCR and Western blotting.

Results: We found significantly high KDM4A expression levels in several human leukemia subtypes. The knockdown of KDM4s inhibited leukemogenesis in the MLL-AF9 leukemia mouse model but did not affect the survival of normal human hematopoietic cells. We identified SD49-7 as a selective KDM4 inhibitor that impaired the progression of leukemia stem cells (LSCs) in vitro. SD49-7 suppressed leukemia development in the mouse model and patient-derived xenograft model of leukemia. Depletion of KDM4s activated the apoptosis signaling pathway by suppressing MDM2 expression via modulating H3K9me3 levels on the MDM2 promoter region.

Conclusion: Our study demonstrates a unique KDM4 inhibitor for LSCs to overcome the resistance to traditional treatment and offers KDM4 inhibition as a promising strategy for resistant leukemia therapy.

Keywords: Leukemia stem cells, Lysine-specific demethylase 4, Small molecular compounds