HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis

白血病を引き起こすタンパク質間相互作用の発見. 京都大学プレスリリース. 2021-08-31.Leukemic oncoproteins cause uncontrolled self-renewal of hematopoietic progenitors by aberrant gene activation, eventually causing leukemia. However, the molecular mechanism underlying aberrant gene activation remains elusive. Here, we showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their trithorax homology domain 2 (THD2) in various human cell lines. MLL proteins associated with the HBO1 complex through multiple contacts mediated mainly by the ING4/5 and PHF16 subunits in a chromatin-bound context where histone H3 lysine 4 tri-methylation marks were present. Of the many MLL fusions, MLL-ELL particularly depended on the THD2-mediated 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 in murine hematopoietic progenitors by loading an AF4/ENL/P-TEFb (AEP) complex onto the target promoters wherein the HBO1 complex promoted the association with AEP complex 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 the HBO1 complex and MLL is an important nexus in leukemic transformation, which may serve as a therapeutic target for drug development

MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins

Altered transcriptional machinery promotes aberrant self-renewal of non-stem hematopoietic progenitors. Here the authors show that AF10 fusion proteins cause aberrant self-renewal via ENL, which promotes leukemic transformation by binding to MOZ/MORF lysine acetyltransferase

SGO1 is involved in the DNA damage response in MYCN-amplified neuroblastoma cells

Shugoshin 1 (SGO1) is required for accurate chromosome segregation during mitosis and meiosis; however, its other functions, especially at interphase, are not clearly understood. Here, we found that downregulation of SGO1 caused a synergistic phenotype in cells overexpressing MYCN. Downregulation of SGO1 impaired proliferation and induced DNA damage followed by a senescence-like phenotype only in MYCN-overexpressing neuroblastoma cells. In these cells, SGO1 knockdown induced DNA damage, even during interphase, and this effect was independent of cohesin. Furthermore, MYCN-promoted SGO1 transcription and SGO1 expression tended to be higher in MYCN- or MYC-overexpressing cancers. Together, these findings indicate that SGO1 plays a role in the DNA damage response in interphase. Therefore, we propose that SGO1 represents a potential molecular target for treatment of MYCN-amplified neuroblastom

Linear IFMIF Prototype Accelerator (LIPAc): Installation activities for Phase-B beam commissioning in Rokkasho

The construction of the Linear IFMIF Prototype Accelerator (LIPAc) is in progress in order to demonstrate the feasibility of the low energy section of an IFMIF deuteron accelerator up to 9 MeV with a beam current of 125 mA in CW. The next milestone of the project is the so-called Phase-B beam commissioning, and one of the missions is to demonstrate the acceleration of the proton beam up to 2.5 MeV or the deuteron beam up to 5.0 MeV in pulsed mode with a low duty cycle of 0.1% through RFQ. Most of the components and subsystems necessary for Phase-B were delivered by 2016 under the responsibility of Fusion for Energy (F4E) as in-kind contributions of several European institutes, namely CEA (France), CIEMAT (Spain), INFN (Italy), and SCK-CEN (Belgium), and QST is in charge of the installation of the delivered equipment. The installation and check-out of the RFQ subsystem and the RF power system was completed by July 2017, and the RF conditioning of the RFQ cavity started. Also, the installation and the check-out of the important sub-systems for Phase-B, namely MEBT and beam diagnostics, have been completed. Keywords: IFMIF, LIPAc, RFQ, Accelerator, Deuteron, Neutron sourc