Targeting KDM4 for treating PAX3-FOXO1–driven alveolar rhabdomyosarcoma-Reference-Cited by-同舟云学术

Targeting KDM4 for treating PAX3-FOXO1–driven alveolar rhabdomyosarcoma

Published:2022-07-13 Issue:653 Volume:14 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Singh Shivendra¹^ORCID,Abu-Zaid Ahmed¹^ORCID,Jin Hongjian²^ORCID,Fang Jie¹,Wu Qiong¹^ORCID,Wang Tingting³^ORCID,Feng Helin⁴^ORCID,Quarni Waise¹^ORCID,Shao Ying⁵,Maxham Lily⁵,Abdolvahabi Alireza⁶,Yun Mi-Kyung⁷^ORCID,Vaithiyalingam Sivaraja⁷⁸,Tan Haiyan⁷⁹^ORCID,Bowling John⁶^ORCID,Honnell Victoria¹⁰^ORCID,Young Brandon⁶^ORCID,Guo Yian¹¹^ORCID,Bajpai Richa¹²,Pruett-Miller Shondra M.¹²^ORCID,Grosveld Gerard C.¹³^ORCID,Hatley Mark¹⁴^ORCID,Xu Beisi²^ORCID,Fan Yiping²^ORCID,Wu Gang²^ORCID,Chen Eleanor Y.¹⁵,Chen Taosheng⁶^ORCID,Lewis Peter W.¹⁶^ORCID,Rankovic Zoran⁶,Li Yimei¹¹^ORCID,Murphy Andrew J.¹^ORCID,Easton John⁵^ORCID,Peng Junmin⁷⁹^ORCID,Chen Xiang⁵^ORCID,Wang Ruoning³^ORCID,White Stephen W.⁷¹⁰^ORCID,Davidoff Andrew M.¹^ORCID,Yang Jun¹¹⁰¹⁷^ORCID

Affiliation:

1. Department of Surgery, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

2. Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

3. Center for Childhood Cancer and Blood Disease, Abigail Wexner Research Institute, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA.

4. Department of Orthopedics, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China.

5. Department of Computational Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

6. Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

7. Department of Structural Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

8. Protein Technologies Center, Molecular Interaction Analysis, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

9. Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

10. Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

11. Department of Biostatistics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

12. Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

13. Department of Genetics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

14. Department of Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

15. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.

16. Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.

17. Department of Pathology, College of Medicine, The University of Tennessee Health Science Center, 930 Madison Ave., Suite 500, Memphis, TN 38163, USA.

Abstract

Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3–Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1 + RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1–governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression in preclinical PAX3-FOXO1 + RMS subcutaneous xenograft models. In summary, we identified a targetable mechanism required for maintenance of the PAX3-FOXO1–related transcription factor network, which may translate to a therapeutic approach for fusion-positive RMS.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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