Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia
2017
Преузимање 🢃
Аутори
Okuda, HiroshiStanojević, Boban
Kanai, Akinori
Kawamura, Takeshi
Takahashi, Satoshi
Matsui, Hirotaka
Takaori-Kondo, Akifumi
Yokoyama, Akihiko
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
The eleven-nineteen leukemia (ENL) protein family, composed of ENL and AF9, is a common component of 3 transcriptional modulators: AF4-ENL-P-TEFb complex (AEP), DOT1L-AF10-ENL complex (referred to as the DOT1L complex) and polycomb-repressive complex 1 (PRC1). Each complex associates with chromatin via distinct mechanisms, conferring different transcriptional properties including activation, maintenance, and repression. The mixed-lineage leukemia (MLL) gene often fuses with ENL and AF10 family genes in leukemia. However, the functional interrelationship among those 3 complexes in leukemic transformation remains largely elusive. Here, we have shown that MLL-ENL and MLL-AF10 constitutively activate transcription by aberrantly inducing both AEP-dependent transcriptional activation and DOT1L-dependent transcriptional maintenance, mostly in the absence of PRC1, to fully transform hematopoietic progenitors. These results reveal a cooperative transcriptional activation mechanism of AEP and DO...T1L and suggest a molecular rationale for the simultaneous inhibition of the MLL fusion-AF4 complex and DOT1L for more effective treatment of MLL-rearranged leukemia.
Извор:
Journal of Clinical Investigation, 2017, 127, 5, 1918-1931Финансирање / пројекти:
- Japan Society for the Promotion of Science (JSPS) KAKENHI [16H05337]
- Dainippon Sumitomo Pharma Co. Ltd.
DOI: 10.1172/JCI91406
ISSN: 0021-9738; 1558-8238
PubMed: 28394257
WoS: 000400381000030
Scopus: 2-s2.0-85018955347
Колекције
Институција/група
VinčaTY - JOUR AU - Okuda, Hiroshi AU - Stanojević, Boban AU - Kanai, Akinori AU - Kawamura, Takeshi AU - Takahashi, Satoshi AU - Matsui, Hirotaka AU - Takaori-Kondo, Akifumi AU - Yokoyama, Akihiko PY - 2017 UR - https://vinar.vin.bg.ac.rs/handle/123456789/1538 AB - The eleven-nineteen leukemia (ENL) protein family, composed of ENL and AF9, is a common component of 3 transcriptional modulators: AF4-ENL-P-TEFb complex (AEP), DOT1L-AF10-ENL complex (referred to as the DOT1L complex) and polycomb-repressive complex 1 (PRC1). Each complex associates with chromatin via distinct mechanisms, conferring different transcriptional properties including activation, maintenance, and repression. The mixed-lineage leukemia (MLL) gene often fuses with ENL and AF10 family genes in leukemia. However, the functional interrelationship among those 3 complexes in leukemic transformation remains largely elusive. Here, we have shown that MLL-ENL and MLL-AF10 constitutively activate transcription by aberrantly inducing both AEP-dependent transcriptional activation and DOT1L-dependent transcriptional maintenance, mostly in the absence of PRC1, to fully transform hematopoietic progenitors. These results reveal a cooperative transcriptional activation mechanism of AEP and DOT1L and suggest a molecular rationale for the simultaneous inhibition of the MLL fusion-AF4 complex and DOT1L for more effective treatment of MLL-rearranged leukemia. T2 - Journal of Clinical Investigation T1 - Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia VL - 127 IS - 5 SP - 1918 EP - 1931 DO - 10.1172/JCI91406 ER -
@article{ author = "Okuda, Hiroshi and Stanojević, Boban and Kanai, Akinori and Kawamura, Takeshi and Takahashi, Satoshi and Matsui, Hirotaka and Takaori-Kondo, Akifumi and Yokoyama, Akihiko", year = "2017", abstract = "The eleven-nineteen leukemia (ENL) protein family, composed of ENL and AF9, is a common component of 3 transcriptional modulators: AF4-ENL-P-TEFb complex (AEP), DOT1L-AF10-ENL complex (referred to as the DOT1L complex) and polycomb-repressive complex 1 (PRC1). Each complex associates with chromatin via distinct mechanisms, conferring different transcriptional properties including activation, maintenance, and repression. The mixed-lineage leukemia (MLL) gene often fuses with ENL and AF10 family genes in leukemia. However, the functional interrelationship among those 3 complexes in leukemic transformation remains largely elusive. Here, we have shown that MLL-ENL and MLL-AF10 constitutively activate transcription by aberrantly inducing both AEP-dependent transcriptional activation and DOT1L-dependent transcriptional maintenance, mostly in the absence of PRC1, to fully transform hematopoietic progenitors. These results reveal a cooperative transcriptional activation mechanism of AEP and DOT1L and suggest a molecular rationale for the simultaneous inhibition of the MLL fusion-AF4 complex and DOT1L for more effective treatment of MLL-rearranged leukemia.", journal = "Journal of Clinical Investigation", title = "Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia", volume = "127", number = "5", pages = "1918-1931", doi = "10.1172/JCI91406" }
Okuda, H., Stanojević, B., Kanai, A., Kawamura, T., Takahashi, S., Matsui, H., Takaori-Kondo, A.,& Yokoyama, A.. (2017). Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia. in Journal of Clinical Investigation, 127(5), 1918-1931. https://doi.org/10.1172/JCI91406
Okuda H, Stanojević B, Kanai A, Kawamura T, Takahashi S, Matsui H, Takaori-Kondo A, Yokoyama A. Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia. in Journal of Clinical Investigation. 2017;127(5):1918-1931. doi:10.1172/JCI91406 .
Okuda, Hiroshi, Stanojević, Boban, Kanai, Akinori, Kawamura, Takeshi, Takahashi, Satoshi, Matsui, Hirotaka, Takaori-Kondo, Akifumi, Yokoyama, Akihiko, "Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia" in Journal of Clinical Investigation, 127, no. 5 (2017):1918-1931, https://doi.org/10.1172/JCI91406 . .