Open AccessCRISPR-suppressor scanning reveals a nonenzymatic role of LSD1 in AML
Author(s) -
Michael Vinyard,
Cindy Su,
Allison P. Siegenfeld,
Amanda L. Waterbury,
Allyson M. Freedy,
Pallavi M. Gosavi,
Yongho Park,
Eugene E. Kwan,
Benjamin D. Senzer,
John G. Doench,
Daniel E. Bauer,
Luca Pinello,
Brian B. Liau
Publication year - 2019
Publication title -
nature chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.412
H-Index - 216
eISSN - 1552-4469
pISSN - 1552-4450
DOI - 10.1038/s41589-019-0263-0
Subject(s) - crispr , myeloid leukemia , demethylase , small molecule , drug discovery , transcription factor , biology , computational biology , mechanism of action , mechanism (biology) , function (biology) , suppressor , context (archaeology) , histone , microbiology and biotechnology , genetics , biochemistry , cancer research , gene , in vitro , paleontology , philosophy , epistemology
Understanding the mechanism of small molecules is a critical challenge in chemical biology and drug discovery. Medicinal chemistry is essential for elucidating drug mechanism, enabling variation of small molecule structure to gain structure-activity relationships (SARs). However, the development of complementary approaches that systematically vary target protein structure could provide equally informative SARs for investigating drug mechanism and protein function. Here we explore the ability of CRISPR-Cas9 mutagenesis to profile the interactions between lysine-specific histone demethylase 1 (LSD1) and chemical inhibitors in the context of acute myeloid leukemia (AML). Through this approach, termed CRISPR-suppressor scanning, we elucidate drug mechanism of action by showing that LSD1 enzyme activity is not required for AML survival and that LSD1 inhibitors instead function by disrupting interactions between LSD1 and the transcription factor GFI1B on chromatin. Our studies clarify how LSD1 inhibitors mechanistically operate in AML and demonstrate how CRISPR-suppressor scanning can uncover novel aspects of target biology.