TY - JOUR
T1 - CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas
AU - Veazey, Kylee J.
AU - Cheng, Donghang
AU - Lin, Kevin
AU - Villarreal, Oscar D.
AU - Gao, Guozhen
AU - Perez-Oquendo, Mabel
AU - Van, Hieu T.
AU - Stratton, Sabrina A.
AU - Green, Michael
AU - Xu, Han
AU - Lu, Yue
AU - Bedford, Mark T.
AU - Santos, Margarida Almeida
N1 - Funding Information:
Acknowledgements We thank Manu Sebastian Ph.D., Abhinav Jain Ph.D., Michelle Barton Ph.D., Carlos Perez, and members of the MAS laboratory for technical support and helpful discussions. Core facilities were supported by the NIH Grant P30CA16672 and Cancer Prevention Research Institute of Texas (CPRIT) Grants RP120348, RP170002, and RP170628. This work was supported by CPRIT Recruitment of First-time Tenure-Track Faculty award RR160097 (to HX), NIH grant GM126421 (to MTB), Andrew Sabin Family Fellow Award, American Society of Hematology Junior Faculty Scholar Award, and CPRIT First-time Tenure-Track Faculty award RR150039 (to MAS). MAS and HX are CPRIT scholars in cancer research.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/12
Y1 - 2020/12
N2 - Somatic mutations affecting CREBBP and EP300 are a hallmark of diffuse large B-cell lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway, and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth, and that the levels of sensitivity are positively correlated with the CREBBP/EP300 mutation load. Conversely, treatment of DLBCLs that do not have CREBBP/EP300 mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP-target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of CREBBP/EP300 as a biomarker for the use of small-molecule inhibitors of CARM1 in DLBCL and other cancers.
AB - Somatic mutations affecting CREBBP and EP300 are a hallmark of diffuse large B-cell lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway, and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth, and that the levels of sensitivity are positively correlated with the CREBBP/EP300 mutation load. Conversely, treatment of DLBCLs that do not have CREBBP/EP300 mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP-target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of CREBBP/EP300 as a biomarker for the use of small-molecule inhibitors of CARM1 in DLBCL and other cancers.
UR - http://www.scopus.com/inward/record.url?scp=85096587707&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85096587707&partnerID=8YFLogxK
U2 - 10.1038/s41375-020-0908-8
DO - 10.1038/s41375-020-0908-8
M3 - Article
C2 - 32576962
AN - SCOPUS:85096587707
SN - 0887-6924
VL - 34
SP - 3269
EP - 3285
JO - Leukemia
JF - Leukemia
IS - 12
ER -