The Biology of Mutant STAT6 in Follicular Lymphoma

滤泡性淋巴瘤（FL）是美国第二常见的非霍奇金淋巴瘤（NHL）， 10万名患者患有这种疾病。虽然10年生存率有所提高，但几乎所有患有 FL在其一生中接受多次化疗或免疫治疗，最后复发和进展。 目前还没有高效的靶向治疗FL，FL患者的护理标准在很大程度上仍然是 基于化学免疫疗法。BTK抑制剂伊布替尼和PIK 3CD/PI 3 K δ抑制剂等新药 idealisib改善了慢性淋巴细胞白血病（CLL）和套细胞淋巴瘤（MCL）的治疗。 然而，这些药物在FL中效果较差，或者与严重的副作用有关。 在过去的八年里，我们为发现和初步的功能表征做出了贡献。 FL中的复发性突变，包括SWI/SNF组分ARID 1A、接头组蛋白（HIST 1H 1 B-E）、IRF 8， mTOR调节剂RRAGC，自噬和mTOR调节剂vATPase（ATP 6V 1B 2， VMA 21）和STAT 6。在我们的努力中出现的一个重要基因是信号转导子， 转录激活因子（STAT 6），在所有FL和转化FL（tFL）的11-23%中突变。频繁 在原发性纵隔B细胞淋巴瘤（PMBCL）、霍奇金淋巴瘤（Hodgkin's Lymphoma）、淋巴瘤（NHL）和淋巴瘤（NHL）中也描述了STAT 6的突变。 淋巴瘤（HL）和弥漫性大B细胞淋巴瘤（DLBCL）。STAT 6是IL-4/JAK/STAT 6生存轴的一部分 的B细胞，这也是激活的IL-4水平升高存在于FL淋巴结。FL相关突变在 STAT 6靶向氨基酸热点，其位于STAT 6 DNA结合结构域中。我们已经证明 突变的STAT 6蛋白导致已知的STAT 6靶基因（例如， FCER2、CISH、CCL17、NFIL3）。这些功能增益特性的识别改变了流行的 淋巴瘤相关的STAT 6突变的观点，以前被认为是亚型。 然而，仍然存在与分子性质和功能有关的重要未回答的问题。 突变（MUT）STAT 6在淋巴瘤中的后果是本提案的重点。其中包括 在B细胞中与WT STAT 6相比，MUT的全基因组结合位点的描绘和完整的 图10示出了由MUT STAT 6转录调控的基因的表征。此外，属性 以及FL B中由STAT 6激活或抑制的转录程序的生物学后果 细胞或正常的生发中心B细胞在很大程度上是未知的。未来还有未开发的潜力 IL-4/JAK/STAT 6轴在FL中的靶向作用，我们提出的研究旨在提供基本原理， 这样的研究。最后，我们将探讨STAT 6 MUT FL B细胞和FL淋巴结之间的相互作用 居住的微环境，特别是关于T细胞亚群。

Follicular lymphoma (FL) is the second most common non-Hodgkin's lymphoma (NHL) in the US, with over 100,000 patients living with the disease. While survival rates at 10 years have improved, almost all patients with FL receive multiple chemo- or immunotherapies over their lifetime and most eventually relapse and progress. There exists no highly effective targeted therapy for FL and the standard of care for FL patients remains largely based on chemoimmunotherapy. New drugs like the BTK inhibitor ibrutinib and the PIK3CD/PI3Kδ inhibitor idealisib have improved the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). However, these drugs are less effective in FL or are linked to serious side effects. Over the last eight years we have contributed to the discovery and initial functional characterization of recurrent mutations in FL, including in the SWI/SNF component ARID1A, linker histones (HIST1H1 B-E), IRF8, the mTOR regulator RRAGC, various components of the autophagy and mTOR regulator vATPase (ATP6V1B2, VMA21) and STAT6. One of the important genes that emerged from our efforts is Signal Transducer and Activator of Transcription (STAT6), which is mutated in 11-23% of all FL and transformed FL (tFL). Frequent mutations in STAT6 have also been described in primary mediastinal B cell lymphoma (PMBCL), Hodgkin's lymphoma (HL) and diffuse large B cell lymphoma (DLBCL). STAT6 is part of the IL-4/JAK/STAT6 survival axis of B cells, which is also activated by elevated IL-4 levels present in FL LNs. The FL-associated mutations in STAT6 target amino acid hotspots, which are located in the STAT6 DNA binding domain. We have demonstrated that mutated STAT6 proteins result in the hyper activation of the expression of known STAT6 target genes (e.g. FCER2, CISH, CCL17, NFIL3). The identification of these gain-of-function properties changed the prevailing view of lymphoma-associated STAT6 mutations, which previously were believed to be hypomorphs. There remain however important unanswered questions pertaining to the molecular properties and functional consequences of mutated (MUT) STAT6 in lymphoma that are the focus of this proposal. These include the delineation of genome-wide binding sites of MUT as compared with WT STAT6 in B cells and the complete characterization of the genes that are transcriptionally regulated by MUT STAT6. Furthermore, the properties and biological consequences of the transcriptional programs that are activated or repressed by STAT6 in FL B cells or normal germinal center B cells are largely unknown. There is also untapped potential for the future targeting of the IL-4/JAK/STAT6 axis in FL and our proposed studies aim at providing the rationale to inform such studies. Finally, we will explore the interactions between STAT6 MUT FL B cells and the FL lymphnode resident microenvironment, especially with regards to T cell subsets.