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

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 StubbsXiaoping Su, Michael R. Green, Cristian Coarfa, Srdan Verstovsek, Joseph D. Khoury, Christopher R. Vakoc, Kapil N. Bhalla

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish (US)
Article number98
JournalBlood Cancer Journal
Volume11
Issue number5
DOIs
StatePublished - May 2021
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Oncology

Fingerprint

Dive into the research topics of 'Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells'. Together they form a unique fingerprint.

Cite this