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

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.

Citation

Warren Fiskus, Christopher P Mill, Behnam Nabet, Dimuthu Perera, Christine Birdwell, Taghi Manshouri, Bernardo Lara, Tapan M Kadia, Courtney DiNardo, Koichi Takahashi, Naval Daver, Prithviraj Bose, Lucia Masarova, Naveen Pemmaraju, Steven Kornblau, Gautam Borthakur, Guillermo Montalban-Bravo, Guillermo Garcia Manero, Sunil Sharma, Matthew Stubbs, Xiaoping Su, Michael R Green, Cristian Coarfa, Srdan Verstovsek, Joseph D Khoury, Christopher R Vakoc, Kapil N Bhalla. Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells. Blood cancer journal. 2021 May 20;11(5):98

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PMID: 34016956

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