HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis
Satoshi Takahashi,Akinori Kanai,Hiroshi Okuda,Ryo Miyamoto,Takeshi Kawamura,Hirotaka Matsui,Toshiya Inaba,Akifumi Takaori-Kondo,Akihiko Yokoyama +8 more
TL;DR: In this article, the authors showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their TRX2 domain.
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Abstract: Leukemic oncoproteins cause uncontrolled self-renewal of hematopoietic progenitors by aberrant gene activation, eventually causing leukemia. However, the molecular mechanism of aberrant gene activation remains elusive. Here, we showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their TRX2 domain. Among many MLL fusions, MLL-ELL particularly depended on its association with the HBO1 complex for leukemic transformation. The C-terminal portion of ELL provided a binding platform for multiple factors including AF4, EAF1 and p53. MLL-ELL activated gene expression by loading an AF4 /ENL/P-TEFb complex (AEP) onto the target promoters. The HBO1 complex promoted the use of AEP over EAF1 and p53. Moreover, the NUP98-HBO1 fusion protein exerted its oncogenic properties via interaction with MLL but not its intrinsic HAT activity. Thus, the interaction between HBO1 and MLL is an important nexus in leukemic transformation, which may serve as a therapeutic target for drug development.
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References
Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression.
Zhanxin Wang,Jikui Song,Thomas A. Milne,Gang Greg Wang,Haitao Li,C. David Allis,Dinshaw J. Patel +6 more
TL;DR: The results highlight the role of PHD3-Bromo cassette as a regulatory platform, orchestrating MLL1 binding of H3K4me3/2 marks and cyclophilin-mediated repression through HDAC recruitment.
KAT7 is a genetic vulnerability of acute myeloid leukemias driven by MLL rearrangements.
Yan Zi Au,Yan Zi Au,Muxin Gu,Etienne De Braekeleer,Malgorzata Gozdecka,Malgorzata Gozdecka,Demetrios Aspris,Yusuke Tarumoto,Jonathan L. Cooper,Jason S. L. Yu,Jason S. L. Yu,Swee Hoe Ong,Xi Chen,Konstantinos Tzelepis,Konstantinos Tzelepis,Brian J. P. Huntly,George S. Vassiliou,George S. Vassiliou,Kosuke Yusa,Kosuke Yusa +19 more
TL;DR: The findings reveal that KAT7 is a plausible therapeutic target for this poor prognosis AML subtype and propose that acetylated histones provide a platform for the recruitment of MLL-fusion-associated adaptor proteins such as BRD4 and AF4 to gene promoters.
Human Mediator Subunit Med26 Functions As A Docking Site For Transcription Elongation Factors
Hidehisa Takahashi,Tari Parmely,Shigeo Sato,Chieri Tomomori-Sato,Charles A.S. Banks,Stephanie E. Kong,Henrietta Szutorisz,Selene K. Swanson,Skylar Martin-Brown,Michael P. Washburn,Michael P. Washburn,Laurence Florens,Chris Seidel,Chengqi Lin,Edwin R. Smith,Ali Shilatifard,Ronald C. Conaway,Ronald C. Conaway,Joan W. Conaway,Joan W. Conaway +19 more
TL;DR: Evidence is presented consistent with the model that MED26 can function as a molecular switch that interacts first with TFIID in the Pol II initiation complex and then exchanges TFIIDs for complexes containing ELL/EAF and P-TEFb to facilitate transition of Pol II into the elongation stage of transcription.
TBP loading by AF4 through SL1 is the major rate-limiting step in MLL fusion-dependent transcription.
TL;DR: It is proposed that TBP loading by AF4 through SL1 is the major rate-limiting step in MLL fusion-dependent transcription, which is the key activity responsible for the oncogenic property of MLL-AEP fusion proteins.
MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters
Hiroshi Okuda,Marie Kawaguchi,Akinori Kanai,Hirotaka Matsui,Takeshi Kawamura,Toshiya Inaba,Issay Kitabayashi,Akihiko Yokoyama +7 more
TL;DR: The results indicate that chromatin context-dependent gene activation is the fundamental mechanism by which MLL fusion proteins maintain the expression of the cellular memory/hematopoietic stem cell program genes.