Epigenetic Gene Regulation by JAK1 Kinase in Diffuse Large B-Cell Lymphoma

JAK1 激酶在弥漫性大 B 细胞淋巴瘤中的表观遗传基因调控

• 批准号: 8836849
• 负责人: Lixin Rui
• 金额: $ 35万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836849
• 关键词: Agammaglobulinaemia tyrosine kinase; Autocrine Communication; B-Lymphocytes; Biological; Cancer Center; Cell Proliferation; Cell Survival; Cells; ChIP-seq; Chromatin; Collaborations; Combined Modality Therapy; Cytokine Signaling; Data; Development; Disease; Disease remission; Down-Regulation; Drug resistance; Epigenetic Process; Exhibits; Feedback; Funding; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genome Mappings; Goals; Growth; Histone H3; Histones; IL6 gene; IRF4 gene; Individual; Interleukin-10; Interruption; JAK1 gene; Lead; Leukocytes; Lymphocyte; Lymphoma; Malignant Neoplasms; Maps; Mediating; Modification; Molecular; Molecular Target; NF-kappa B; NFKB Signaling Pathway; Non-Hodgkin' s Lymphoma; Nuclear; Oncogenes; Oncogenic; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Phosphotransferases; Protein Tyrosine Kinase; Publishing; RNA Interference; Regulator Genes; Research; Resistance; Role; STAT3 gene; Sampling; Signal Pathway; Signal Transduction; Technology; Testing; Therapeutic Intervention; Time; Toxic effect; Transcriptional Activation; Transcriptional Regulation; Treatment Protocols; Tyrosine; Tyrosine Kinase Inhibitor; United States; Universities; Wisconsin; Xenograft procedure; autocrine; base; cancer cell; cell growth; cell killing; cytokine; gain of function mutation; genetic information; genome-wide; improved; inhibitor/antagonist; insight; killings; large cell Diffuse non-Hodgkin' s lymphoma; loss of function; mortality; mouse model; neoplastic cell; next generation sequencing; novel; novel therapeutics; protein H(3); public health relevance; synergism; targeted treatment; working group

DESCRIPTION (provided by applicant): Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, and the most aggressive subtype, activated B-cell-like (ABC), kills 60% of patients within three years. One important feature of ABC DLBCL is autocrine signaling by the cytokines IL6 and IL10, which is essential for cancer growth. The molecular mechanisms underlying the cytokine signaling pathway remain undefined and will be a focus of this study. In preliminary results, we identified the constitutively activated kinase downstream of the cytokine pathway as JAK1. Cancer cells require JAK1 activity for survival; JAK1 inhibition by RNA interference or the pharmaceutical inhibitor AZD1480 is lethal to cultured ABC DLBCL cells. As a tyrosine kinase, JAK1 regulates gene expression through phosphorylating STAT3 as well as through a surprising non- canonical mechanism, directly targeting the histone protein H3 for tyrosine 41 phosphorylation (H3Y41p). Genome-wide mapping of this modification identified 2,582 JAK1 target genes. Some of these genes that are induced for expression through H3Y41p are independent of STAT3, including the oncogene MYC and important NF-kB genes MYD88 and IRF4. Given that NF-kB activation is a hallmark of ABC DLBCL and causes auto-secretion of the cytokines IL6 or IL10, JAK1 and NF-kB signaling pathways form a positive feedback loop to promote the survival and proliferation of cancer cells. These findings support the hypothesis that JAK1 regulates gene expression via two complementary pathways to promote cancer cell survival and proliferation, and JAK1 downstream target genes are potential candidates for therapeutic intervention in ABC DLBCL. In fact, the Bruton tyrosine kinase (BTK, upstream of IRF4) inhibitor, Ibrutinib, has been effective in ABC DLBCL. Due to drug resistance, however, Ibrutinib only achieves a temporary remission. The proposed research will test the hypothesis that overcoming acquired resistance to Ibrutinib by combined targeted therapies helps further improve outcomes of ABC DLBCL. Specifically, dual interruption of NF-kB and JAK1 by their inhibitors will be conducted in ABC DLBCL xenograft mouse models as well as in primary patient samples. The goals of the proposed research are to establish a conceptual framework for understanding how JAK1 mediates transcription activation through these two distinct (STAT3-mediated or chromatin targeting) mechanisms, to identify novel molecular targets of JAK1, and to develop a new therapeutic strategy for the disease.

描述（由申请人提供）：弥漫性大b细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤，最具侵袭性的亚型，活化b细胞样（ABC），在三年内杀死60%的患者。ABC型DLBCL的一个重要特征是细胞因子IL6和IL10的自分泌信号，这是肿瘤生长所必需的。细胞因子信号通路的分子机制仍不明确，这将是本研究的重点。在初步结果中，我们确定了细胞因子通路下游的组成型活化激酶为JAK1。癌细胞需要JAK1活性才能存活；通过RNA干扰或药物抑制剂AZD1480抑制JAK1对培养的ABC DLBCL细胞是致命的。作为一种酪氨酸激酶，JAK1通过磷酸化STAT3调控基因表达，也通过令人惊讶的非规范机制，直接靶向组蛋白H3进行酪氨酸41磷酸化（H3Y41p）。该修饰的全基因组图谱鉴定出2582个JAK1靶基因。其中一些通过H3Y41p诱导表达的基因不依赖于STAT3，包括癌基因MYC和重要的NF-kB基因MYD88和IRF4。鉴于NF-kB激活是ABC型DLBCL的标志，并引起细胞因子IL6或IL10的自分泌，JAK1和NF-kB信号通路形成正反馈回路，促进癌细胞的存活和增殖。这些发现支持了JAK1通过两条互补途径调控基因表达促进癌细胞存活和增殖的假设，并且JAK1下游靶基因是ABC型DLBCL治疗干预的潜在候选基因。事实上，IRF4上游的布鲁顿酪氨酸激酶（BTK）抑制剂伊鲁替尼对ABC型DLBCL有效。然而，由于耐药，伊鲁替尼只能达到暂时的缓解。拟议的研究将验证联合靶向治疗克服伊鲁替尼获得性耐药有助于进一步改善ABC型DLBCL预后的假设。具体来说，将在ABC DLBCL异种移植小鼠模型和原发性患者样本中进行NF-kB和JAK1抑制剂的双重中断。该研究的目标是建立一个概念框架，以了解JAK1如何通过这两种不同的机制（stat3介导或染色质靶向）介导转录激活，确定JAK1的新分子靶点，并开发一种新的治疗策略。