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Publication Detail

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

Authors: 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

Published In Blood Cancer J, (2021 05 20)

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.

PubMed ID: 34016956 Exiting the NIEHS site

MeSH Terms: No MeSH terms associated with this publication

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