Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 152, Issue 2, Pages 182-190Publisher
WILEY-BLACKWELL PUBLISHING, INC
DOI: 10.1111/j.1365-2141.2010.08497.x
Keywords
Hodgkin lymphoma; IRF4; MUM1; CD40; microenvironment; chemokines
Categories
Funding
- Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.), Milan, Italy
- Ministero della Salute, Ricerca Finalizzata FSN, I.R.C.C.S., Rome, Italy
- Ministero della Salute, Rome
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P>Interferon regulatory factor 4 (IRF4) expression is detected in many lymphoid and myeloid malignancies, and may be a promising therapeutic target. IRF4 is strongly expressed in classical Hodgkin lymphoma (cHL) and its expression is up-regulated by CD40L and down-regulated by both anti-proliferative and pro-apoptotic stimuli. This study analysed the effects of IRF4 silencing in a panel of HL-derived cell lines. We demonstrated that IRF4 down-modulation determined a remarkable decrease of both cell number and clonogenic growth in L-1236, L-428, KM-H2 and HDLM-2 cells, but not in IRF4-negative L-540 cells. IRF4 silencing induced apoptosis, as evaluated by caspase-3 activation and Annexin-V staining and up-regulation of the pro-apoptotic molecule Bax. CD40 engagement by both soluble and membrane bound-CD40L almost totally reduced IRF4 down-modulation and growth inhibition by IRF4 silencing in both L-1236 and L-428 cells. Finally, IRF4 silencing decreased CCL5 secretion in all HL cell lines tested and CCL17 in KM-H2 cells. Taken together, our results demonstrated that IRF4 down-modulation by IRF4 silencing was reversed by CD40 engagement, inhibited HL cells proliferation, induced apoptosis and decreased CCL5 secretion, thus suggesting that IRF4 may be involved in HL pathobiology.
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