TY - JOUR
T1 - BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma
AU - Fiskus, Warren
AU - Mill, Christopher P.
AU - Perera, Dimuthu
AU - Birdwell, Christine
AU - Deng, Qing
AU - Yang, Haopeng
AU - Lara, Bernardo H.
AU - Jain, Nitin
AU - Burger, Jan
AU - Ferrajoli, Alessandra
AU - Davis, John A.
AU - Saenz, Dyana T.
AU - Jin, Wendy
AU - Coarfa, Cristian
AU - Crews, Craig M.
AU - Green, Michael R.
AU - Khoury, Joseph D.
AU - Bhalla, Kapil N.
N1 - Funding Information:
Acknowledgements 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. C.C. acknowledges support from CPRIT RP170005, NIEHS CG-CPEH P30 ES030285 and the NCI Cancer Center Support Grant P30 CA125123 to the Dan L. Duncan Cancer Center. C.M.C. acknowledges support from the National Institutes of Health (grant number R35 CA197589) and Arvinas. This research is supported in part by the MD Anderson Cancer Center Leukemia SPORE (P50 CA100632).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/9
Y1 - 2021/9
N2 - Richter Transformation (RT) develops in CLL as an aggressive, therapy-resistant, diffuse large B cell lymphoma (RT-DLBCL), commonly clonally-related (CLR) to the concomitant CLL. Lack of available pre-clinical human models has hampered the development of novel therapies for RT-DLBCL. Here, we report the profiles of genetic alterations, chromatin accessibility and active enhancers, gene-expressions and anti-lymphoma drug-sensitivity of three newly established, patient-derived, xenograft (PDX) models of RT-DLBCLs, including CLR and clonally-unrelated (CLUR) to concomitant CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein expressions of IRF4, TCF4, and BCL2, as well as increased sensitivity to BET protein inhibitors. CRISPR knockout of IRF4 attenuated c-Myc levels and increased sensitivity to a BET protein inhibitor. Co-treatment with BET inhibitor or BET-PROTAC and ibrutinib or venetoclax exerted synergistic in vitro lethality in the RT-DLBCL cells. Finally, as compared to each agent alone, combination therapy with BET-PROTAC and venetoclax significantly reduced lymphoma burden and improved survival of immune-depleted mice engrafted with CLR-RT-DLBCL. These findings highlight a novel, potentially effective therapy for RT-DLBCL.
AB - Richter Transformation (RT) develops in CLL as an aggressive, therapy-resistant, diffuse large B cell lymphoma (RT-DLBCL), commonly clonally-related (CLR) to the concomitant CLL. Lack of available pre-clinical human models has hampered the development of novel therapies for RT-DLBCL. Here, we report the profiles of genetic alterations, chromatin accessibility and active enhancers, gene-expressions and anti-lymphoma drug-sensitivity of three newly established, patient-derived, xenograft (PDX) models of RT-DLBCLs, including CLR and clonally-unrelated (CLUR) to concomitant CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein expressions of IRF4, TCF4, and BCL2, as well as increased sensitivity to BET protein inhibitors. CRISPR knockout of IRF4 attenuated c-Myc levels and increased sensitivity to a BET protein inhibitor. Co-treatment with BET inhibitor or BET-PROTAC and ibrutinib or venetoclax exerted synergistic in vitro lethality in the RT-DLBCL cells. Finally, as compared to each agent alone, combination therapy with BET-PROTAC and venetoclax significantly reduced lymphoma burden and improved survival of immune-depleted mice engrafted with CLR-RT-DLBCL. These findings highlight a novel, potentially effective therapy for RT-DLBCL.
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U2 - 10.1038/s41375-021-01181-w
DO - 10.1038/s41375-021-01181-w
M3 - Article
C2 - 33654205
AN - SCOPUS:85102052721
SN - 0887-6924
VL - 35
SP - 2621
EP - 2634
JO - Leukemia
JF - Leukemia
IS - 9
ER -