| First Author | McCarter AC | Year | 2020 |
| Journal | Blood Cancer Discov | Volume | 1 |
| Issue | 2 | Pages | 178-197 |
| PubMed ID | 32924017 | Mgi Jnum | J:334571 |
| Mgi Id | MGI:7461369 | Doi | 10.1158/2643-3230.BCD-20-0026 |
| Citation | McCarter AC, et al. (2020) Combinatorial ETS1-dependent control of oncogenic NOTCH1 enhancers in T-cell leukemia. Blood Cancer Discov 1(2):178-197 |
| abstractText | Notch activation is highly prevalent among cancers, in particular T-cell acute lymphoblastic leukemia (T-ALL). However, the use of pan-Notch inhibitors to treat cancers has been hampered by adverse effects, particularly intestinal toxicities. To circumvent this barrier in T-ALL, we aimed to inhibit ETS1, a developmentally important T-cell transcription factor previously shown to co-bind Notch response elements. Using complementary genetic approaches in mouse models, we show that ablation of Ets1 leads to strong Notch-mediated suppressive effects on T-cell development and leukemogenesis, but milder intestinal effects than pan-Notch inhibitors. Mechanistically, genome-wide chromatin profiling studies demonstrate that Ets1 inactivation impairs recruitment of multiple Notch-associated factors and Notch-dependent activation of transcriptional elements controlling major Notch-driven oncogenic effector pathways. These results uncover previously unrecognized hierarchical heterogeneity of Notch-controlled genes and points to Ets1-mediated enucleation of Notch-Rbpj transcriptional complexes as a target for developing specific anti-Notch therapies in T-ALL that circumvent the barriers of pan-Notch inhibition. |
