Butrym Aleksandra, Łacina Piotr, Rybka Justyna, Chaszczewska-Markowska Monika, Mazur Grzegorz, Bogunia-Kubik Katarzyna
Department of Physiology, Wroclaw Medical University, Wroclaw, Poland.
Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
Arch Immunol Ther Exp (Warsz). 2016 Dec;64(Suppl 1):151-156. doi: 10.1007/s00005-016-0442-6. Epub 2017 Jan 12.
Multiple myeloma (MM) is a plasma-cell malignancy derived from an early precursor of the B-cell lineage characterised by bone-marrow infiltration, lytic bone lesions, and the presence of a monoclonal protein in serum and/or urine. Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B-cell development and function that is required during immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells. Immunomodulatory drugs, derivatives of thalidomide, are commonly used in therapy against MM. They are known to target a protein called cereblon (CRBN); however, the exact mechanism remains unknown. The present study aimed to assess the association of two (rs12203592 and rs872071) polymorphisms within the IRF4 gene and two (rs711613 and rs1045433) in the CRBN gene with MM susceptibility, progression, and response to treatment. For this purpose, 144 MM patients and 126 healthy individuals were genotyped for the IRF4 and CRBN alleles. The presence of the IRF4 (rs872071) G allele was more frequently detected in patients than healthy individuals (OR 1.78; P = 0.034), and this relationship was especially pronounced in women (OR 2.83; P = 0.012). The CRBN (rs711613) A allele-carriers were better responders to the treatment (P = 0.012), in particular to thalidomide including therapy (P = 0.023). These results underline the prognostic significance of the IRF4 and CRBN polymorphisms in patients with MM.
多发性骨髓瘤（MM）是一种起源于B细胞谱系早期前体的浆细胞恶性肿瘤，其特征为骨髓浸润、溶骨性骨病变以及血清和/或尿液中存在单克隆蛋白。干扰素调节因子4（IRF4）是B细胞发育和功能中的关键转录调节因子，在免疫反应期间，淋巴细胞激活和分泌免疫球蛋白的浆细胞生成均需要该因子。免疫调节药物，即沙利度胺的衍生物，常用于MM的治疗。已知它们靶向一种名为cereblon（CRBN）的蛋白质；然而，确切机制尚不清楚。本研究旨在评估IRF4基因内的两个多态性（rs12203592和rs872071）以及CRBN基因内的两个多态性（rs711613和rs1045433）与MM易感性、疾病进展和治疗反应之间的关联。为此，对144例MM患者和126名健康个体的IRF4和CRBN等位基因进行了基因分型。与健康个体相比，患者中更频繁地检测到IRF4（rs872071）G等位基因（比值比1.78；P = 0.034），这种关系在女性中尤为明显（比值比2.83；P = 0.012）。CRBN（rs711613）A等位基因携带者对治疗的反应更好（P = 0.012），尤其是对包括沙利度胺在内的治疗（P = 0.023）。这些结果强调了IRF4和CRBN多态性在MM患者中的预后意义。
