Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene regulation following MIF stimulation.

ABSTRACT: Lasting B-cell persistence depends on survival signals that are transduced by cell surface receptors. Here, we describe a novel biological mechanism essential for survival and homeostasis of normal peripheral mature B cells and chronic lymphocytic leukemia (CLL) cells, regulated by the heparin-binding cytokine, midkine (MK), and its proteoglycan receptor, the receptor-type tyrosine phosphatase zeta (RPTPζ). We demonstrate that MK initiates a signaling cascade leading to B cell survival, by binding to RPTPζ. In mice lacking PTPRZ, the proportion and number of the mature B cell population is reduced. Our results emphasize a unique and critical function for MK signaling in the previously described MIF/CD74 induced survival pathway. Stimulation of CD74 with MIF leads to c-Met activation, resulting in elevation of MK expression in both normal mouse splenic B and CLL cells. Our results indicate that MK and RPTPζ are important regulators of the B cell repertoire. These findings could pave the way towards understanding the mechanisms shaping B cell survival, and suggest novel therapeutic strategies based on the blockade of the midkine/RPTPζ-dependent survival pathway. 2 samples were incubated with or without MIF.

ORGANISM(S): Mus musculus

SUBMITTER: Idit Shachar

PROVIDER: E-GEOD-33352 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:CD74 is a cell-surface receptor for the cytokine macrophage migration inhibitory factor (MIF). MIF binding to CD74 induces a signaling cascade resulting in the release of its cytosolic intracellular domain (CD74-ICD), which regulates transcription in naive B and chronic lymphocytic leukemia (CLL) cells. In the current study, we investigated the role of CD74 in the regulation of the immunosuppressive tumor microenvironment (TME) in triple-negative breast cancer (TNBC). TNBC is the most aggressive breast cancer subtype, in which there is a massive infiltration of immune cells to the tumor microenvironment, making this tumor a good candidate for immunotherapy. The tumor and immune cells in TNBC express high levels of CD74, however, the function of this receptor in this environment was not fully characterized. Regulatory B cells (Bregs) and tolerogenic dendritic cells )tol-DCs( were previously shown to attenuate the antitumor immune response in TNBC. Here, we demonstrate that CD74 enhances tumor growth by inducing the expansion of tumor-infiltrating tol-DCs and Bregs. Utilizing CD74-KO mice, conditionally CD74 -/- Cre-flox mice lacking CD74 in CD23+ mature B cells and mice lacking CD74 in the CD11c+ population and a CD74 inhibitor (DRQ), revealed that MIF secreted from the tumor cells activate CD74 expressed on DCs. This activation induces the binding of CD74-ICD to the SP1 promotor, resulting in the upregulation of SP1 expression. SP1 binds the IL-1β promotor, leading to the downregulation of its transcription. The reduced levels of IL-1β lead to decreased anti-tumor activity by allowing expansion of the tol-DC, which induce the expansion of the Breg population, suggesting the cross-talk between these two populations. Taken together, these results suggest that CD74+ CD11c+ DCs are the dominant cell type involved in the regulation of the TNBC progression. These findings indicate that CD74 might serve as a novel therapeutic target in triple-negative breast cancer.