TY  - 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 . .