Gene Expression Profiling Identifies IRF4-Associated Molecular Signatures in Hematological Malignancies

The lymphocyte-specific transcription factor Interferon (IFN) Regulatory Factor 4 (IRF4) is implicated in certain types of lymphoid and myeloid malignancies. However, the molecular mechanisms underlying its interactions with these malignancies are largely unknown. In this study, we have first profiled molecular signatures associated with IRF4 expression in associated cancers, by analyzing existing gene expression profiling datasets. Our results show that IRF4 is overexpressed in melanoma, in addition to previously reported contexts including leukemia, myeloma, and lymphoma, and that IRF4 is associated with a unique gene expression pattern in each context. A pool of important genes involved in B-cell development, oncogenesis, cell cycle regulation, and cell death including BATF, LIMD1, CFLAR, PIM2, and CCND2 are common signatures associated with IRF4 in non-Hodgkin B cell lymphomas. We confirmed the correlation of IRF4 with LIMD1 and CFLAR in a panel of cell lines derived from lymphomas. Moreover, we profiled the IRF4 transcriptome in the context of EBV latent infection, and confirmed several genes including IFI27, IFI44, GBP1, and ARHGAP18, as well as CFLAR as novel targets for IRF4. These results provide valuable information for understanding the IRF4 regulatory network, and improve our knowledge of the unique roles of IRF4 in different hematological malignancies.

淋巴细胞特异性转录因子干扰素调节因子4（IRF4）与某些类型的淋巴和髓系恶性肿瘤有关。然而，其与这些恶性肿瘤相互作用的分子机制尚属未知。在本研究中，我们首先通过对现有基因表达谱数据集进行分析，描绘了与IRF4表达相关的分子特征。研究结果显示，IRF4在黑色素瘤中过度表达，除先前报道的包括白血病、骨髓瘤和淋巴瘤在内的情境外，且在每种情境下，IRF4均与独特的基因表达模式相关。在非霍奇金B细胞淋巴瘤中，与B细胞发育、肿瘤发生、细胞周期调控和细胞死亡相关的关键基因，如BATF、LIMD1、CFLAR、PIM2和CCND2，是IRF4的常见分子特征。我们在来自淋巴瘤的细胞系面板中证实了IRF4与LIMD1和CFLAR的相关性。此外，我们在EBV潜伏感染背景下分析了IRF4转录组，并证实了包括IFI27、IFI44、GBP1和ARHGAP18在内的几个基因以及CFLAR作为IRF4的新靶点。这些结果为理解IRF4调控网络提供了宝贵信息，并加深了我们对于IRF4在不同血液恶性肿瘤中独特作用的理解。