A novel network pharmacology approach for leukaemia differentiation therapy using Mogrify®

Oncogene. 2022 Oct 21. doi: 10.1038/s41388-022-02505-5.

Lin Ming Lee ^# ¹, Eleni G Christodoulou ^# ² ³, Pavithra Shyamsunder ¹, Bei Jun Chen ² ³, Kian Leong Lee ¹, Tsz Kan Fung ⁴ ⁵, Chi Wai Eric So ⁴ ⁵, Gee Chuan Wong ⁶, Enrico Petretto ⁷ ⁸ ⁹ ¹⁰, Owen J L Rackham ¹¹ ¹² ¹³, S Tiong Ong ¹⁴ ¹⁵ ¹⁶ ¹⁷

Affiliations

1 Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
2 Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore.
3 Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore.
4 Comprehensive Cancer Centre, King's College London, London, UK.
5 Department of Haematological Medicine, King's College Hospital, London, UK.
6 Department of Haematology, Singapore General Hospital, Singapore, Singapore.
7 Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore. enrico.petretto@duke-nus.edu.sg.
8 Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore. enrico.petretto@duke-nus.edu.sg.
9 MRC London Institute of Medical Sciences (LMC), Imperial College London, Faculty of Medicine, London, UK. enrico.petretto@duke-nus.edu.sg.
10 Institute for Big Data and Artificial Intelligence in Medicine, School of Science, China Pharmaceutical University (CPU), Nanjing, China. enrico.petretto@duke-nus.edu.sg.
11 Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore. owen.rackham@duke-nus.edu.sg.
12 Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore. owen.rackham@duke-nus.edu.sg.
13 School of Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK. owen.rackham@duke-nus.edu.sg.
14 Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore. sintiong.ong@duke-nus.edu.sg.
15 Department of Haematology, Singapore General Hospital, Singapore, Singapore. sintiong.ong@duke-nus.edu.sg.
16 Department of Medical Oncology, National Cancer Centre, Singapore, Singapore. sintiong.ong@duke-nus.edu.sg.
17 Department of Medicine, Duke University Medical Center, Durham, NC, USA. sintiong.ong@duke-nus.edu.sg.
# Contributed equally.

PMID: 36271030 DOI: 10.1038/s41388-022-02505-5

Abstract

Acute myeloid leukaemia (AML) is a rapidly fatal blood Cancer that is characterised by the accumulation of immature myeloid cells in the blood and bone marrow as a result of blocked differentiation. Methods which identify master transcriptional regulators of AML subtype-specific leukaemia cell states and their combinations could be critical for discovering novel differentiation-inducing therapies. In this proof-of-concept study, we demonstrate a novel utility of the Mogrify^® algorithm in identifying combinations of transcription factors (TFs) and drugs, which recapitulate granulocytic differentiation of the NB4 acute promyelocytic leukaemia (APL) cell line, using two different approaches. In the first approach, Connectivity Map (CMAP) analysis of these TFs and their target networks outperformed standard approaches, retrieving ATRA as the top hit. We identify dimaprit and mebendazole as a drug combination which induces myeloid differentiation. In the second approach, we show that genetic manipulation of specific Mogrify^®-identified TFs (MYC and IRF1) leads to co-operative induction of APL differentiation, as does pharmacological targeting of these TFs using currently available compounds. We also show that loss of IRF1 blunts ATRA-mediated differentiation, and that MYC represses IRF1 expression through recruitment of PML-RARα, the driver fusion oncoprotein in APL, to the IRF1 promoter. Finally, we demonstrate that these drug combinations can also induce differentiation of primary patient-derived APL cells, and highlight the potential of targeting MYC and IRF1 in high-risk APL. Thus, these results suggest that Mogrify^® could be used for drug discovery or repositioning in leukaemia differentiation therapy for other subtypes of leukaemia or cancers.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-111411

IZCZ-3

98.13%, c-MYC Transcription Inhibitor

c-Myc; Autophagy

Cancer

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