[PubMed] [Google Scholar] 2. B-cells through the actions of follicular T-helper and follicular dendritic cells. BCL6 also represses genes involved in terminal differentiation such as IRF4 and PRDM1 [1,4], and so must be downregulated for exit from the GC reaction to occur. Hence BCL6 not only enables but also maintains the GC B-cell phenotype. The checkpoint suppression properties of BCL6 are inherently pro-oncogenic and accordingly BCL6 is almost universally expressed in DLBCLs. DLBCLs can be subclassified according to gene expression profiles into various disease subtypes. Among these the ABC (activated B-cell)-DLBCLs are OSU-03012 generally considered to be derived from late GC B-cells in which BCL6 downregulation would normally occur [6]. Accordingly ABC-DLBCLs feature more frequent translocation of the BCL6 locus to heterologous promoters allowing for its constitutive expression. Although ABC-DLBCLs are often thought of as being BCL6-unfavorable, this is likely a due to the relatively low sensitivity of standard immunohistochemistry methods and indeed BCL6 protein can be detected in ABC-DLBCL cells when evaluated by more sensitive methods such as immunoblotting. The more prevalent GCB-type DLBCLs tend to express higher BCL6 protein levels even in the absence of translocations, reflecting their origin from GC B-cells [6]. Altogether, a majority of ABC and GCB type DLBCLs require and are hence addicted to BCL6 to maintain their proliferation and survival, reflecting its function in normal GC B-cells and supporting the notion that BCL6 is usually a broadly relevant therapeutic target for DLBCLs [7C9]. Biochemical and functional studies have provided the basis and rational for development of OSU-03012 highly specific and non-toxic BCL6 inhibitors. From the biochemical standpoint BCL6 contains a BTB-POZ domain name at its N-terminus, which has autonomous transcriptional repressor activity [10]. The BTB/POZ domain name represses transcription by recruiting three corepressor proteins: SMRT, NCoR and BCoR to a specific groove motif that is formed by BCL6 BTB domain name homodimers [10]. Notably the BCL6 BTB domain name surface residues that interface with these corepressors are unique to BCL6. Point mutations of key surface residues abrogate corepressor binding and hence repressor activity of the BTB domain name. The reciprocal 18 aminoacid regions of SMRT, NCoR and BCoR that binds to BCL6 are also unique and do not associate with other BTB domains [10]. Thus the physical contacts between the BCL6 BTB domain name and its cofactors appear to be unique to BCL6, providing a pharmacological basis for rational design of specific BCL6 BTB domain name inhibitors unlikely to affect other BTB proteins. BCL6 knockout OSU-03012 mice are unable to form germinal centers, but of more concern from the therapeutic standpoint display a lethal phenotype manifesting as a rapidly OSU-03012 fatal inflammatory syndrome due to hyperactivity of T-cells and macrophages [1]. BCL6 deficient macrophages are also linked to the development of accelerated atherosclerosis in mice [11]. These serious consequences of BCL6 deficiency could temper enthusiasm for development of BCL6 inhibitors due to concerns for potential toxicity. However more recent studies suggest that these concerns may be unwarranted, since in fact BCL6 may function through distinct biochemical mechanisms in different cell types. Remarkably, mice engineered to express BCL6 with point mutations that disrupt the BTB domain-corepressor complex live normal healthy lives without inflammation, but still exhibit failure to form GC B-cells [12]. Closer examination of lymphoid follicles in BCL6-BTB mutant animals revealed failure of activated B-cells to proliferate and survive after antigen stimulation. In contrast, functions of BCL6 in macrophages and T-cells, which are responsible for the inflammatory phenotype, were perfectly intact [12]. Instead the inflammatory macrophage function appeared to be more dependent on BCL6 competition with STAT proteins for binding to DNA, since both factors share comparable DNA binding sequences [12]. Targeting the BCL6 BTB domain name corepressor interface could thus specifically Rabbit Polyclonal to TGF beta Receptor II (phospho-Ser225/250) suppress B-cell survival without inducing acute or chronic inflammatory effects that instead would be expected to occur with the complete loss of BCL6. Along these lines OSU-03012 proof of theory studies using recombinant.