Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

Fiskus, Warren, Mill, Christopher P, Nabet, Behnam, Perera, Dimuthu, Birdwell, Christine, Manshouri, Taghi, Lara, Bernardo, Kadia, Tapan M, DiNardo, Courtney, Takahashi, Koichi, Daver, Naval, Bose, Prithviraj, Masarova, Lucia, Pemmaraju, Naveen, Kornblau, Steven, Borthakur, Gautam, Montalban-Bravo, Guillermo, Manero, Guillermo Garcia, Sharma, Sunil, Stubbs, Matthew, Su, Xiaoping, Green, Michael R, Coarfa, Cristian, Verstovsek, Srdan, Khoury, Joseph D, Vakoc, Christopher R, Bhalla, Kapil N (May 2021) Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells. Blood Cancer Journal, 11 (5). p. 98. ISSN 2044-5385

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URL: https://www.ncbi.nlm.nih.gov/pubmed/34016956

DOI: 10.1038/s41408-021-00487-3

Abstract

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification diseases & disorders > cancer > cancer types > acute myeloid leukemia organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > drugs and therapies organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor bioinformatics > genomics and proteomics > genetics & nucleic acid processing > transcriptomes diseases & disorders > cancer > cancer types
CSHL Authors:	Vakoc, Christopher R.
Communities:	CSHL labs > Vakoc lab CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	20 May 2021
Date Deposited:	26 May 2021 15:04
Last Modified:	13 Feb 2024 16:48
PMCID:	PMC8138012
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/40169

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