Transcriptional network in B cells: IRFS in the development of B cells and lymphomagenesis

Yurchenko M., Shlapatska L.M., Kovalevska L.M., Sidorenko S.P.

M. Yurchenko, L.M. Shlapatska, L.M. Kovalevska, S.P. Sidorenko

R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology NAS of Ukraine, Kyiv, Ukraine

The family of interferon regulatory factors (IRF) is comprised of 9 members: IRF1, IRF2, IRF3, IRF4/PIP/LSIRF/ICSAT/MUM1, IRF5, IRF6, IRF7, IRF8/ICSBP and IRF9/ISGF3γ. All members of this family of transcription factors contain the homological DNA-binding domain, which is responsible for interaction with DNA binding motifs ICS, ISRE, IRFE, EICE. IRF4 and IRF8 proteins share the most homology among other IRFs, and their expression is narrowed to the cells of immune system. For transcriptional regulation of target genes IRF4 and IRF8 form complexes with each other or with other transcription factors and adaptor proteins (Ets family — PU.1, SpiB, TEL; E47, NFAT, FOXP3, STAT proteins, MyD88, IBP, TRAF6). IRF1, IRF2, IRF4 and IRF8 play the central role in the regulation of immune cells differentiation and maturation. IRF4 and IRF8 are key regulators of multiple steps of B cell differentiation, starting from stage of pre-B cells. IRFs 4 and 8 together with other transcription factors (BCL6, BLIMP1, XBP1, Pax5) control GC formation, CSR, memory versus plasma cell differentiation. IRF4 and IRF8 were shown to be deregulated in B cell malignancies. IRF8 was mainly shown to function as tumor suppressor protein, but IRF4 was found to be overexpressed in some tumors (multiple myeloma, Hodgkin’s lymphoma, some diffuse large B cell lymphoma cases, etc), and at the same time could have tumor suppressor functions in B-acute lymphoblastic leukemia.

Still there is not so much data on regulation of IRFs expression by different signals and signaling pathways in normal and malignant B cells. B cell receptor and CD40 are the most potent up-regulators of IRF4 expression. However, nothing is known about receptor-mediated downregulation of this transcription factor. We have shown that CD150 receptor expression decreased the levels of IRF4 mRNA and protein in DT40 CD150+ transfectants — the stage of pre-B cells. Prolonged stimulation of activated human tonsillar B cells via CD150 resulted in upregulation of IRF4 mRNA. Signals via CD150 and BCR induced the upregulation of IRF4 mRNA expression by Burkitt’s lymphoma cells BJAB. Overall, CD150 and BCR had different impact on IRF4 expression by malignant and normal human B cells. The identification of surface receptors and signaling pathways involved in the regulation of IRFs expression could help to develop new strategies for tumor cells elimination.

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