2.2.5 CC-122
CC-122 is a next-generation brain E3 ligase regulator, and Zhongying Mo et al 45 performed a genome-wide CRISPR / Cas9 screen for CC-122 in the DLBCL cell line SU-DHL-4, enriched for the CUL4/DDB1/RBX1/CRBN E3 ubiquitin ligase complex or regulator, which induced IKZF1 and IKZF3 proteins ubiquitination and degradation, resulting in enhanced antiproliferative effects of CC-122 in DLBCL cells46. The sgRNAs targeting the NF-κB inhibitory genes CYLD, NFKBIA, TRAF2 and TRAF3 also showed significant enrichment in SU-DHL-4 cells, indicating that inhibition of the NF-κB pathway enhanced the anti-tumor activity of CC-122 in DLBCL. The elimination of CRBN showed more resistance to CC-122 than CYLD, NFKBIA, TRAF2 or TRAF3 inactivation, and the knockdown effect of CYLD and NFKB1A was also more pronounced than TRAF2 and TRAF3. Furthermore, knockdown of KCTD5, RFX7 and AMBRA1 in CRISPR screens abrogated the response to CC-122, and accumulation of the Gβγ subunit GNG5 after KCTD5 depletion reduced the growth inhibitory effect of CC-122 in several DLBCL cell lines. RFX7 and AMBRA1 are key factors in CC-122 apoptosis, RFX7 and Ambra1 loss will lead to V-7-AAD cell loss.