Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells.
Warren C FiskusChristopher P MillBehnam NabetDimuthu PereraChristine BirdwellTaghi ManshouriBernardo LaraTapan Mahendra KadiaCourtney D D DiNardoKoichi TakahashiNaval G DaverPrithviraj BoseLucia MasarovaNaveen PemmarajuSteven Mitchell KornblauGautam BorthakurGuillermo Montalban-BravoGuillermo Garcia ManeroSunil SharmaMatthew StubbsXiaoping SuMichael R GreenCristian CoarfaSrdan VerstovsekJoseph D KhouryChristopher R VakocKapil N BhallaPublished in: Blood cancer journal (2021)
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.
Keyphrases
- induced apoptosis
- cell cycle arrest
- acute myeloid leukemia
- small molecule
- type diabetes
- signaling pathway
- stem cells
- allogeneic hematopoietic stem cell transplantation
- cell death
- genome wide
- oxidative stress
- gene expression
- endothelial cells
- metabolic syndrome
- cancer therapy
- transcription factor
- weight loss
- acute lymphoblastic leukemia
- mesenchymal stem cells
- binding protein
- cell therapy
- drug induced