Nucleic Acid-Based, mRNA-Targeted Therapeutics for Hematologic Malignancies
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
To target the malignant B-cell lymphomas, we are investigating the utility of targeting Bcl6 mRNA. Bcl6 is a zinc finger protein, which acts as a sequence-specific transcriptional repressor (111). Although Bcl6 mRNA is ubiquitous, its expression is highest in germinal center B-cells where it is thought to repress the expression of genes involved in B-cell activation, cell cycle progression, and terminal differentiation. In non-Hodgkin’s lymphomas, Bcl6 is the most frequently deregulated gene, and abnormal expression is found in approximately 30% to 40% of DLCL, and approximately 14% of follicular lymphomas (FL). We found that cells transfected with an appropriately targeted ASODN exhibited an approximately 50% drop in viability within 24 hours. Coincident with the drop in viability, we found a sevenfold decrease in Bcl6 mRNA expression in cells transfected with 1310, and little change in cells transfected with control oligonucleotides (Fig. 2).
The Non-Hodgkin’s Lymphomas and Plasma Cell Dyscrasias
Harold R. Schumacher, William A. Rock, Sanford A. Stass in Handbook of Hematologic Pathology, 2019
Diffuse large B-cell lymphomas have clonal rearrangements of the Ig heavy and light chain genes. The TCR genes are usually in the germline configuration. A subset of cases have the t(14;18) by conventional cytogenetics or rearrangement of the bcl-2 oncogene by molecular diagnostic techniques. These lymphomas may represent histologic transformation of FCL. Patients with de-novo DLBCL with bcl-2 rearrangement have an increased tendency to relapse compared to histologically similar tumors without bcl-2 rearrangement, similar to the behavior of FCL. Another subset of DLBCL have translocations or other abnormalities that involve chromosome 3q27. This locus is the site of the bcl-6 gene, a zinc finger transcription factor and putative oncogene. The bcl-6 gene is rearranged in approximately one-third of these neoplasms, more often in those that arise in extranodal sites.
Mucosal B cells and their function
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
In germinal center responses in peripheral lymphoid organs and, likely in GALT, newly activated B cells can be recruited into existing germinal centers that contain dividing B cells with other specificities, providing that the cognate T-cell help has developed prior to their colonization to sustain specific germinal center B-cell growth. Germinal center B cells (centroblasts) undergo proliferation (expressing Ki67) in the germinal center “dark zone” (Figure 10.4). Here, activation-induced cytidine deaminase (AID) supports somatic hypermutation of their surface antibody's antigen-binding variable (IgV) regions and class-switch (e.g., IgM to IgA) of the effector constant region. These cells then relocate within the germinal center to compete as centrocytes for antigen with B cells bearing surface antibodies of related specificities but with different mutations in the germinal center “light zone.” The cells bearing the antibody with the highest avidity compete successfully for antigens presented on the follicular dendritic cells (FDCs) that extend throughout the germinal center light zone. Thus, under the influence of local T-follicular-helper (TFH) cells, germinal center B cells are selected for sustained expansion, further mutation and differentiation into memory cells, and antibody-secreting cells that exit the germinal center and potentially undergo further differentiation in the lamina propria. In this setting, BCL6 is a germinal center-targeted transcription factor that directs T cells to become TFH cells and protects DNA in B cells from excessive damage but allows somatic hypermutation and class-switch recombination.
Therapeutic melanoma vaccine with cancer stem cell phenotype represses exhaustion and maintains antigen-specific T cell stemness by up-regulating BCL6
Published in OncoImmunology, 2020
Patrycja Czerwinska, Marcin Rucinski, Nikola Wlodarczyk, Anna Jaworska, Iga Grzadzielewska, Katarzyna Gryska, Lukasz Galus, Jacek Mackiewicz, Andrzej Mackiewicz
Among others, BCL6 aroused our interest due to its role as a transcriptional regulator (gene repressor) as well as its involvement in T cell differentiation and exhaustion.11-16 We analyzed the expression of Bcl6 target genes and several exhaustion markers using normalized microarray data and found that GPR183, CD69, and PRDM1 (encoding for Blimp-1) target genes14 were down-regulated and, thus, inversely correlated with BCL6 expression level (Figure 3c). RT-qPCR analyses further confirmed this finding (Figure 3d). The expression of several exhaustion markers (CTLA4, KLRG1, PTGER2, IKZF2, TIGIT) was also down-regulated in the peripheral T cells of AGI-101H-immunized patients compared to healthy subjects and untreated patients (Figure 3e). This observation was further confirmed using RT-qPCR analysis. We observed analogous patterns in the relative gene expression levels for tested exhaustion markers (Figure 3a, f). However, only CTLA4 and IKZF2 were significantly down-regulated in peripheral T cells of AGI-101H-vaccinated patients (AV) when compared to untreated patients (C).
BCL6 as a therapeutic target for lymphoma
Published in Expert Opinion on Therapeutic Targets, 2018
Rebecca J Leeman-Neill, Govind Bhagat
BCL6 represses the expression of numerous target genes through binding, in complex with co-repressors (most potently in a ternary complex with BCOR and SMRT) at gene promoters [16,17]. Some of the key cellular functions affected by the activity of BCL6 at gene promoters are illustrated in Figure 1 and they include (1) signaling through the B cell receptor and CD40-CD40 ligand pathways, which in turn activate downstream NF-κB and the MAPK signaling pathways [18] (2) interactions between B and T cells through regulation of CD80 and PDL1 (CD274) [4,19] (3) inhibition of post-GC B cell differentiation through repression of PRDM1 and IRF4 [16,20–23], (4) regulation of B cell responses to chemokines and cytokines [4,16], (5) cell cycle control, either directly, by repressing target genes that regulate the cell cycle or indirectly, interacting with Miz1 to represses transcription of CDKN1 [20,24] and (6) modulation of the DNA damage response via inhibition of p53 [25], which can result in accrual of detrimental and potentially oncogenic mutations in B cells.
Novel approaches to targeted protein degradation technologies in drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Yu Xue, Andrew A. Bolinger, Jia Zhou
MGs with novel mechanisms for targeting various neosubstrates have also been reported. Koegl’s group developed BI-3802 (28) in 2017, an interaction blocker that induces degradation of oncogenic transcription factor (TF) B cell lymphoma 6 (BCL6) [42]. 28 bound to the Broad-complex, Tramtrack, and Bric-à-brac (BTB) domain of BCL6 to strongly induce BCL6-repressed genes expression. In-depth research by Ebert’s group proved that 28 promoted dimerization between two BCL6 monomers, with a mechanism different from the direct MG-induced E3-neosubstrate coupling [43]. The E3 ligase SIAH1 responded to this dimerization and triggered further degradation. Furthermore, despite the intrinsic but weak binding of SIAH1 to BCL6, the presence of 28 significantly enhanced the interactions, suggesting that 28 was an MG.
Related Knowledge Centers
- B Cell
- Corepressor
- Germinal Center
- Lymph Node
- Protein
- Somatic Hypermutation
- Gene
- Follicular B Helper T Cells
- B-Cell Lymphoma
- BCL-2