The Biology of Mutant STAT6 in Follicular Lymphoma

滤泡性淋巴瘤中突变 STAT6 的生物学

• 批准号: 10368629
• 负责人: Sami Nimer Malek
• 金额: $ 35.69万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10368629
• 关键词: ARID1A gene; ATAC-seq; ATP6AP1 gene; Amino Acids; Autophagocytosis; B-Cell Lymphomas; B-Cell Neoplasm; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Binding; Binding Sites; Biological; Biology; CCL17 gene; Cell Line; Cell Survival; Cells; Cellular biology; Characteristics; Chronic Lymphocytic Leukemia; DNA Binding; DNA Binding Domain; Data; Dependence; Disease; Disease remission; Ecosystem; Enhancers; FRAP1 gene; Follicular Lymphoma; Follow-Up Studies; Frequencies; Future; Gene Expression; Gene Mutation; Gene-Modified; Genes; Genetic Transcription; Histones; Hodgkin Disease; Human; Immuno-Chemotherapy; Immunotherapy; In Vitro; Incidence; Intercistronic Region; Interleukin-4; Introns; Link; Lymphoma; Lymphoma cell; Mantle Cell Lymphoma; Maps; Mediastinal; Molecular; Mutate; Mutation; Non-Hodgkin' s Lymphoma; Non-Malignant; Pathway interactions; Patients; Pharmaceutical Preparations; Property; Proteins; Publishing; Recombinants; Recurrence; Relapse; Role; STAT protein; Structure of germinal center of lymph node; Survival Rate; T-Lymphocyte Subsets; Work; base; experimental study; gain of function; genome-wide; improved; in vivo; inhibitor; innovation; large cell Diffuse non-Hodgkin' s lymphoma; lymph nodes; mutant; new therapeutic target; novel; novel therapeutics; preference; programs; promoter; side effect; standard of care; targeted treatment; therapeutic target; therapy development; transcription factor; transcriptome

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.

滤泡性淋巴瘤(FL)是美国第二常见的非霍奇金淋巴瘤(NHL)，超过 10万名患有这种疾病的患者。虽然10年存活率有所提高，但几乎所有患有 FL在其一生中接受多次化疗或免疫治疗，大多数最终复发和进展。 目前还没有对FL进行高效的靶向治疗，FL患者的护理标准仍然很高 以化学免疫疗法为基础。新药如BTK抑制剂伊布鲁替尼和PIK3CD/PI3Kδ抑制剂 Idealisib已经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，这些药物对FL的疗效较差，或者与严重的副作用有关。 在过去的八年里，我们为发现和初步描述细胞的功能做出了贡献 FL中的反复突变，包括SWI/SNF组件ARID1A，连接子组蛋白(HIST1H1 B-E)，IRF8， MTOR调节子RRAGC、自噬的各种成分和mTOR调节子vATPase(ATP6V1B2， VMA21)和STAT6。从我们的努力中出现的一个重要基因是信号转化器和 转录激活子(STAT6)，在11-23%的FL和转化FL(TfL)中发生突变。频密 在原发性纵隔B细胞淋巴瘤(PMBCL)、霍奇金淋巴瘤中也发现了STAT6基因突变 淋巴瘤(HL)和弥漫性大B细胞淋巴瘤(DLBCL)。STAT6是IL-4/JAK/STAT6生存轴的一部分 B细胞，它也被FL LNS中升高的IL-4水平激活。与FL相关的基因突变 STAT6靶向氨基酸热点，位于STAT6 DNA结合区。我们已经证明了 突变的STAT6蛋白导致已知的STAT6靶基因表达的过度激活(例如， FCER2、CISH、CCL17、NFIL3)。这些函数增益属性的识别改变了流行的 淋巴瘤相关的STAT6突变的视图，以前被认为是亚型。 然而，与分子性质和功能有关的重要问题仍然悬而未决 突变(Mut)STAT6在淋巴瘤中的后果是本提案的重点。其中包括 B细胞中MUT与WT STAT6全基因组结合位点的比较 MUT STAT6转录调控基因的特征。此外，这些属性 以及转录程序在FL B中被STAT6激活或抑制的生物学后果 细胞或正常生发中心B细胞很大程度上是未知的。未来还有未开发的潜力。 IL-4/JAK/STAT6轴在FL中的靶向和我们拟议的研究旨在为以下方面提供理论基础 这样的研究。最后，我们将探讨STAT6mut FL B细胞与FL淋巴结间的相互作用 居住微环境，特别是关于T细胞亚群。