Fusion of OTT to BSAC results in aberrant up-regulation of transcriptional activity.
OTT/RBM15-BSAC/MAL/MKL1/MRTF-A was identified as a fusion transcript generated by t(1;22)(p13;q13) in acute megakaryoblastic leukemia. Previous studies have shown that BSAC (basic, SAP, and coiled-coil domain) activates the promoters containing CArG boxes via interaction with serum response factor, and OTT (one twenty-two) negatively regulates the development of megakaryocytes and myeloid cells. However, the mechanism by which OTT-BSAC promotes leukemia is largely unknown. Here we show that OTT-BSAC, but not BSAC or OTT strongly activates several promoters containing a transcription factor Yin Yang 1-binding sequence. In addition, although BSAC predominantly localizes in the cytoplasm and its nuclear translocation is considered to be regulated by the Rho-actin signaling pathway, OTT-BSAC exclusively localizes in the nucleus. Moreover, OTT interacts with histone deacetylase 3, but this interaction is abolished in OTT-BSAC. Collectively, these functional and spatial changes of OTT and BSAC caused by the fusion might perturb their functions, culminating in the development of acute megakaryoblastic leukemia.
Sawada
Taisuke
T
Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Nishiyama
Chiharu
C
Kishi
Takuma
T
Sasazuki
Tomonari
T
Komazawa-Sakon
Sachiko
S
Xue
Xin
X
Piao
Jiang-Hu
JH
Ogata
Hideko
H
Nakayama
Jun-ichi
J
Taki
Tomohiko
T
Hayashi
Yasuhide
Y
Watanabe
Mamoru
M
Yagita
Hideo
H
Okumura
Ko
K
Nakano
Hiroyasu
H
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics / Q000378:metabolism*; D008533:Megakaryocytes / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000099186:Histone Deacetylase 3
D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D015514:Oncogene Proteins, Fusion; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D050986:YY1 Transcription Factor; D000099186:Histone Deacetylase 3; C431575:MRTFA protein, human; C431574:RBM15 protein, human; C494698:YY1 protein, human