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 - Funding Information:
The authors would like to thank the Sequencing and Microarray Core Facility, Flow Cytometry and Cellular Imaging (FCCI) Core Facility, which are supported by the MD Anderson Cancer Center Support Grant 5 P30 CA016672-40. B. N. is supported by an American Cancer Society Postdoctoral Fellowship (PF-17-010-01-CDD) and the Katherine L. and Steven C. Pinard Research Fund. C.C. acknowledges support from CPRIT RP170005, NIEHS CG-CPEH P30 ES030285 and the NCI Cancer Center Support Grant P30CA125123 to the Dan L. Duncan Cancer Center. This research is supported in part by the MD Anderson Cancer Center Leukemia SPORE (P50 CA100632). The authors would like to thank Dr. Nathanael Gray for providing the dTAG-13 compound for the LSD1-FKBP12(F36V)degradation studies in AML cells.
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 -