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

基本信息

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
项目类别：
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&apos 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&apos 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

项目摘要

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) 是非霍奇金淋巴瘤最常见的形式，也是最具侵袭性的亚型，即活化 B 细胞样 (ABC)，可在 3 年内杀死 60% 的患者年。 ABC DLBCL 的一个重要特征是细胞因子 IL6 和 IL10 的自分泌信号传导，这对于癌症生长至关重要。细胞因子信号通路的分子机制仍不清楚，这将是本研究的重点。在初步结果中，我们将细胞因子途径下游的组成型激活激酶鉴定为 JAK1。癌细胞需要 JAK1 活性才能生存； RNA 干扰或药物抑制剂 AZD1480 抑制 JAK1 对于培养的 ABC DLBCL 细胞是致命的。作为一种酪氨酸激酶，JAK1 通过磷酸化 STAT3 以及通过令人惊讶的非经典机制直接靶向组蛋白 H3 进行酪氨酸 41 磷酸化 (H3Y41p) 来调节基因表达。该修饰的全基因组图谱确定了 2,582 个 JAK1 靶基因。其中一些通过 H3Y41p 诱导表达的基因独立于 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 DLBCL 的标志，并导致细胞因子 IL6 或 IL10 的自动分泌，JAK1 和 NF-kB 信号通路形成正反馈环，促进癌细胞的存活和增殖。这些发现支持这样的假设：JAK1 通过两条互补途径调节基因表达以促进癌细胞存活和增殖，并且 JAK1 下游靶基因是 ABC DLBCL 治疗干预的潜在候选基因。事实上，布鲁顿酪氨酸激酶（BTK，IRF4 上游）抑制剂伊布替尼（Ibrutinib）对 ABC DLBCL 有效。然而，由于耐药性，依鲁替尼只能实现暂时缓解。拟议的研究将检验以下假设：通过联合靶向治疗克服依鲁替尼获得性耐药有助于进一步改善 ABC DLBCL 的预后。具体来说，将在 ABC DLBCL 异种移植小鼠模型以及原发患者样本中进行 NF-kB 和 JAK1 抑制剂对 NF-kB 和 JAK1 的双重阻断。拟议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（STAT3 介导的或染色质靶向）机制介导转录激活，识别 JAK1 的新分子靶标，并开发一种新的治疗策略疾病。