Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma
Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma
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DOI：
10.1038/sj.onc.1205629
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发表时间：
2002-07-25
期刊：
影响因子：
8
通讯作者：
Junker, S
中科院分区：
文献类型：
--
作者：
Hertel, CB;Zhou, XG;Junker, S
在经典霍奇金淋巴瘤中，恶性霍奇金/里德-斯滕伯格（HRS）细胞特征性地仅构成肿瘤负荷的一小部分。它们的起源已经争论了几十年，但基于免疫球蛋白（IG）基因的重排和体细胞超突变，HRS细胞现在被归因于B细胞谱系。然而，HRS细胞在表型上已丧失其B细胞特性：它们通常缺乏常见的B细胞特异性表面标记物，如CD 19和CD 79 a以及IG基因转录物。在这里，我们证明了IG启动子以及内含子和3'增强子序列在HRS细胞系中是转录失活的。这种失活与其表达所需的几种B细胞特异性转录因子Oct-2、OBF-1、PU. 1、E47/E12、PAX-5和EBF的水平降低或甚至完全缺乏相关。此外，我们证明了PU.1和PAX-5在原发性肿瘤组织的病理标本中的HRS细胞中显著下调。然而，这些转录因子的强制表达可以激活沉默的B细胞标记基因的调节序列，并且在一种情况下还激活来自沉默的内源基因座的转录。因此，HRS细胞是去分化的B细胞，具有B细胞特异性基因的全面下调。
In classical Hodgkin lymphoma the malignant Hodgkin/Reed-Sternberg (HRS) cells characteristically constitute only a small minority of the tumour load. Their origin has been debated for decades, but on the basis of rearrangement and somatic hypermutations of their immunoglubulin (Ig) genes, HRS cells are now ascribed to the B-cell lineage. Nevertheless, phenotypically HRS cells have lost their B cell identity: they usually lack common B cell-specific surface markers such as CD19 and CD79a as well as Ig gene transcripts. Here we demonstrate that Ig promoters as well as both intronic and 3' enhancer sequences are transcriptionally inactive in HRS cell lines. This inactivity correlates with either reduced levels or even a complete lack of several B cell-specific transcription factors required for their expression: Oct-2, OBF-1, PU.1, E47/E12, PAX-5 and EBF. Moreover, we demonstrate that PU.1 and PAX-5 are significantly down-regulated in HRS cells in pathological specimens from primary tumour tissues. However, forced expression of these transcription factors can activate regulatory sequences of silenced B cell marker genes, and in one instance also transcription from a silenced endogenous locus. Thus, HRS cells are dedifferentiated B cells with global down-regulation of B cell-specific genes.