Pan-HDAC Inhibitors Restore PRDM1 Response to IL21 in CREBBP-Mutated Follicular Lymphoma
Pan-HDAC Inhibitors Restore PRDM1 Response to IL21 in CREBBP-Mutated Follicular Lymphoma
复制标题
DOI：
10.1158/1078-0432.ccr-18-1153
复制
发表时间：
2019-01-15
影响因子：
11.5
通讯作者：
Fest, Thierry
中科院分区：
文献类型：
--
作者：
Desmots, Fabienne;Roussel, Mikael;Fest, Thierry
目的：滤泡性淋巴瘤起源于生发中心B细胞的增殖，与肿瘤微环境，尤其是滤泡辅助T细胞(TFH)的双向相互作用。我们探讨了滤泡性淋巴瘤细胞的分化停滞与CREBBP乙酰转移酶功能丧失之间的关系。实验设计：研究使用的原代细胞来自以体细胞突变为特征的滤泡性淋巴瘤肿瘤，或来自正常生发中心B细胞的炎性扁桃体。转录组和功能分析被用来解释B细胞和T细胞的串扰。结果：与正常B细胞相反，滤泡性淋巴瘤细胞不能上调浆细胞分化所需的转录抑制因子PRDM1。尽管滤泡性淋巴瘤微环境富含由Tfhs高度产生的PRDM1和IL21的有效诱导剂，但这种缺陷仍会发生。在携带CREBBP功能缺失突变的滤泡性淋巴瘤中，我们发现缺乏IL21介导的PRDM1反应，与PRDM1基因中BCL6蛋白抑制物异常增加有关。此外，在这些滤泡性淋巴瘤细胞中，PAN-HDAC抑制剂voinostat通过降低与PRDM1结合的BCL6来恢复它们对IL21的PRDM1反应。我们对滤泡性淋巴瘤患者使用另一种PAN-HDAC抑制剂进行治疗的探索加强了这一发现。患者表现出浆细胞识别基因的增加，主要是PRDM1和XBP1，这突显了滤泡性淋巴瘤B细胞在分化过程中的进展。结论：我们的数据揭示了一种新的机制，即PAN-HDAC抑制剂可能通过诱导浆细胞基因的表达来积极治疗滤泡性淋巴瘤患者。
Purpose: Follicular lymphoma arises from a germinal center B-cell proliferation supported by a bidirectional crosstalk with tumor microenvironment, in particular with follicular helper T cells (Tfh). We explored the relation that exists between the differentiation arrest of follicular lymphoma cells and loss-of-function of CREBBP acetyltransferase.Experimental Design: The study used human primary cells obtained from either follicular lymphoma tumors characterized for somatic mutations, or inflamed tonsils for normal germinal center B cells. Transcriptome and functional analyses were done to decipher the B- and T-cell crosstalk. Responses were assessed by flow cytometry and molecular biology including ChIP-qPCR approaches.Results: Conversely to normal B cells, follicular lymphoma cells are unable to upregulate the transcription repressor, PRDM1, required for plasma cell differentiation. This defect occurs although the follicular lymphoma microenvironment is enriched in the potent inducer of PRDM1 and IL21, highly produced by Tfhs. In follicular lymphoma carrying CREBBP loss-of-function mutations, we found a lack of IL21-mediated PRDM1 response associated with an abnormal increased enrichment of the BCL6 protein repressor in PRDM1 gene. Moreover, in these follicular lymphoma cells, pan-HDAC inhibitor, vorinostat, restored their PRDM1 response to IL21 by lowering BCL6 bound to PRDM1. This finding was reinforced by our exploration of patients with follicular lymphoma treated with another pan-HDAC inhibitor. Patients showed an increase of plasma cell identity genes, mainly PRDM1 and XBP1, which underline the progression of follicular lymphoma B cells in the differentiation process.Conclusions: Our data uncover a new mechanism by which pan-HDAC inhibitors may act positively to treat patients with follicular lymphoma through the induction of the expression of plasma cell genes.