TY - JOUR
T1 - Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells
AU - Fiskus, Warren
AU - Mill, Christopher P.
AU - Nabet, Behnam
AU - Perera, Dimuthu
AU - Birdwell, Christine
AU - Manshouri, Taghi
AU - Lara, Bernardo
AU - Kadia, Tapan M.
AU - DiNardo, Courtney
AU - Takahashi, Koichi
AU - Daver, Naval
AU - Bose, Prithviraj
AU - Masarova, Lucia
AU - Pemmaraju, Naveen
AU - Kornblau, Steven
AU - Borthakur, Gautam
AU - Montalban-Bravo, Guillermo
AU - Manero, Guillermo Garcia
AU - Sharma, Sunil
AU - Stubbs, Matthew
AU - Su, Xiaoping
AU - Green, Michael R.
AU - Coarfa, Cristian
AU - Verstovsek, Srdan
AU - Khoury, Joseph D.
AU - Vakoc, Christopher R.
AU - Bhalla, Kapil N.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
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U2 - 10.1038/s41408-021-00487-3
DO - 10.1038/s41408-021-00487-3
M3 - Article
C2 - 34016956
AN - SCOPUS:85106277040
SN - 2044-5385
VL - 11
JO - Blood Cancer Journal
JF - Blood Cancer Journal
IS - 5
M1 - 98
ER -