Juszczynski Przemyslaw, Kutok Jeffery L, Li Cheng, Mitra Joydeep, Aguiar Ricardo C T, Shipp Margaret A
Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA.
Mol Cell Biol. 2006 Jul;26(14):5348-59. doi: 10.1128/MCB.02351-05.
BAL1 is a transcription modulator that is overexpressed in chemoresistant, diffuse large B-cell lymphomas (DLBCLs). BAL1 complexes with a recently described DELTEX family member termed BBAP. Herein, we characterized BAL1 and BBAP expression in primary DLBCL subtypes defined by their comprehensive transcriptional profiles. BAL1 and BBAP were most abundant in lymphomas with a brisk host inflammatory response, designated host response (HR) tumors. Although these DLBCLs include significant numbers of tumor-infiltrating lymphocytes and interdigitating dendritic cells, BAL1 and BBAP were expressed primarily by malignant B cells, prompting speculation that the genes might be induced by host-derived inflammatory mediators such as gamma interferon (IFN-gamma). In fact, IFN-gamma induced BAL1 and BBAP expression in DLBCL cell lines; doxycycline-induced BAL1 also increased the expression of multiple IFN-stimulated genes, directly implicating BAL1 in an IFN signaling pathway. We show that BAL1 and BBAP are located on chromosome 3q21 in a head-to-head orientation and are regulated by a IFN-gamma-responsive bidirectional promoter. BBAP regulates the subcellular localization of BAL1 by a dynamic shuttling mechanism, highlighting the functional requirement for coordinated BBAP and BAL1 expression. IFN-gamma-induced BAL1/BBAP expression contributes to the molecular signature of HR DLBCLs and highlights the interplay between the inflammatory infiltrate and malignant B cells in these tumors.
BAL1是一种转录调节因子，在化疗耐药的弥漫性大B细胞淋巴瘤（DLBCL）中过表达。BAL1与最近描述的DELTEX家族成员BBAP形成复合物。在此，我们根据原发性DLBCL亚型的综合转录谱对BAL1和BBAP的表达进行了表征。BAL1和BBAP在具有活跃宿主炎症反应的淋巴瘤中最为丰富，这类淋巴瘤被称为宿主反应（HR）肿瘤。尽管这些DLBCL包含大量肿瘤浸润淋巴细胞和指状突细胞，但BAL1和BBAP主要由恶性B细胞表达，这促使人们推测这些基因可能由宿主来源的炎症介质如γ干扰素（IFN-γ）诱导。事实上，IFN-γ可诱导DLBCL细胞系中BAL1和BBAP的表达；强力霉素诱导的BAL1也增加了多个IFN刺激基因的表达，直接表明BAL1参与了IFN信号通路。我们发现BAL1和BBAP以头对头的方向位于3号染色体的q21区域，并受一个IFN-γ应答性双向启动子调控。BBAP通过一种动态穿梭机制调节BAL1的亚细胞定位，突出了协调BBAP和BAL1表达的功能需求。IFN-γ诱导的BAL1/BBAP表达有助于HR DLBCL的分子特征形成，并突出了这些肿瘤中炎症浸润与恶性B细胞之间的相互作用。
