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Griffin, Gabriel

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Griffin

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Gabriel

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Griffin, Gabriel

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2016 - 201912020 - 20211

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Author's Publications: search.filters.isAuthorOfPublication.68de944f-fdc2-4033-b12a-7b4fffcfe43b

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    Blastic Plasmacytoid Dendritic Cell Neoplasm Is Dependent on BCL2 and Sensitive to Venetoclax
    (American Association for Cancer Research (AACR), 2016) Montero, Juan; Stephansky, Jason; Cai, Tianyu; Griffin, Gabriel; Cabal-Hierro, Lucia; Togami, Katsuhiro; Hogdal, Leah J.; Galinsky, Ilene; Morgan, Elizabeth; Aster, Jon; Davids, Matthew; Leboeuf, Nicole; Stone, Richard; Konopleva, Marina; Pemmaraju, Naveen; Letai, Anthony; Lane, Andrew
    Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with dismal outcomes for which no standard therapy exists. We found that primary BPDCN cells were dependent on the anti-apoptotic protein BCL-2 and were uniformly sensitive to the BCL-2 inhibitor venetoclax, as measured by direct cytotoxicity, apoptosis assays, and dynamic BH3 profiling. Animals bearing BPDCN patient-derived xenografts had disease responses and improved survival after venetoclax treatment in vivo. Finally, we report on two patients with relapsed/refractory BPDCN who received venetoclax off-label and experienced significant disease responses. We propose that venetoclax or other BCL-2 inhibitors undergo expedited clinical evaluation in BPDCN, alone or in combination with other therapies. In addition, these data illustrate an example of precision medicine to predict treatment response using ex vivo functional assessment of primary tumor tissue, without requiring a genetic biomarker.
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    Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity
    (Springer Science and Business Media LLC, 2021-05-05) Griffin, Gabriel; Wu, Jingyi; Iracheta-Vellve, Arvin; Patti, James C.; Hsu, Jeffrey; Davis, Thomas; Dele-Oni, Deborah; Du, Peter P.; Halawi, Aya G.; Ishizuka, Jeffrey J.; Kim, Sarah Y.; Klaeger, Susan; Knudsen, Nelson H.; Miller, Brian C.; Nguyen, Tung H.; Olander, Kira E.; Papanastasiou, Malvina; Rachimi, Suzanna; Robitschek, Emily J.; Schneider, Emily; Yeary, Mitchell D.; Zimmer, Margaret; Jaffe, Jacob D.; Carr, Steven A.; Doench, John G.; Haining, William; Yates, Kathleen; Manguso, Robert T.; Bernstein, Bradley
    Epigenetic dysregulation is a defining feature of tumorigenesis that has been implicated in immune escape1,2. To identify epigenetic factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumor models treated with immune checkpoint blockade (ICB). We identified the H3K9-methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape in tumor cells3–5. We also found that amplification of SETDB1 (1q21.3) in human tumors is associated with immune exclusion and resistance to ICB. SETDB1 represses broad genomic domains, many of which reside within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune gene clusters associated with segmental duplication events, a central mechanism of genome evolution6. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and TE-encoded retroviral antigens in these regions, and triggers TE-specific cytotoxic T-cell responses in vivo. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses tumor cell immunogenicity by silencing TEs and evolving genomic loci, and thus represents a candidate target for immunotherapy.