Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Gene Regulation in Bob1-/- and miR-146a-/- Murine Pre-B Cells

ABSTRACT: 5d IL-7-supported bone marrow cultures from C57BL/6 mice deficient for either the transcription factor Bob1 or microRNA-146a Micro-RNAs (miRNAs) are required for many processes during hematopoietic development and activation, including B-cell differentiation. The lymphocyte-specific transcription factor Bob1 is critical for the proper development and function of B cells. Bob1-/- mice are immunodeficient and lack germinal centers. Microarray expression analysis of Bob1-deficient B cells shows numerous up-regulated genes, suggesting that Bob1 may affect targets indirectly via the control of miRNAs. Using a gain-of-function/loss-of-function approach in WEHI-231 and primary pro-B and pre-B cells, we identified miR-146a as a direct target of Bob1. Ttranscriptome-wide analysis of miR-146a-/- B cells shows a number of misregulated genes involved in immune regulation, while analysis of Bob1-/- cells shows increased expression of cell cycle-related genes. These results support previous evidence that Bob1 suppresses proliferation, a previously underappreciated role for Bob1 that is in line with the cancer-prone phenotype of mir-146a-/- mice. 8 samples in total; 2 biological duplicates each of Bob1wt, Bob1KO, wild-type C57BL/6Ncrl, and mir-146aKO

ORGANISM(S): Mus musculus

SUBMITTER: John Lindner

PROVIDER: E-GEOD-44986 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Pathologic activation of the Toll-like receptor (TLR) pathway underlies various human disorders such as autoimmune diseases, chronic inflammatory diseases and lymphoid malignancies. Current therapy of these diseases relies on immunosuppressive or chemotherapeutic agents, but more effective therapeutics tailored to disease-causing mechanisms are needed. Pivotal to TLR signaling is the IL-1 receptor-associated kinase 4 (IRAK4), which is recruited to TLRs by the adaptor protein MyD88. Recruitment of IRAK kinases to MyD88, triggers the formation of a signaling competent myddosome complex, which underlies the pathogenesis of many immuno-inflammatory disorders, suggesting that IRAK4 inhibitors might be useful in the treatment of these diseases. Gain-of-function MYD88 mutations activate IRAK4 in several mature B cell malignancies, including activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). Development of selective IRAK4 inhibitors has been confounded by the challenging structure of the IRAK4 catalytic domain. Using structure-based drug design methodologies, we identified potent and selective IRAK4 inhibitors. These small molecules suppress LPS-induced TNFalpha production in vitro and in vivo, and are efficacious in mouse models of collagen-induced arthritis and MyD88-dependent inflammatory gout. Human ABC DLBCL cell lines that harbor the activating, oncogenic MyD88 L265P mutation are killed by IRAK4 inhibitors, both in vitro and in mouse xenograft models. IRAK4 inhibitors synergize with the BTK inhibitor ibrutinib, with the Syk inhibitor PRT062607, and with the Bcl-2 inhibitor ABT-199 in killing ABC DLBCL cells, suggesting new therapeutic strategies for this refractory cancer. Four ABC DLBCL cell lines (OCI-Ly10, TMD8, HBL1 and OCI-Ly3), were treated with either ND-2158 or the structurally related negative control compound ND-1659 for 6, 12, 24 or 36 h in culture. Gene expression profiling was performed using two-color human Agilent 4x44K gene expression arrays comparing signal from control compound-treated (ND-1659) control cells (Cy3), toÂ cells treated with ND-2158 for the indicated times (Cy5).

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Gene Regulation in Bob1-/- and miR-146a-/- Murine Pre-B Cells

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