The transcription factor c-MYC in lymphocyte expansion and restriction of stemness

转录因子c-MYC在淋巴细胞扩增和干性限制中的作用

• 批准号: 10750609
• 负责人: Takeshi Egawa
• 金额: $ 56.58万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750609
• 关键词: Activated Lymphocyte; Address; Adoptive Cell Transfers; Affinity; Antibodies; Antigen Receptors; Antigens; B cell differentiation; B-Lymphocytes; Binding; CD8-Positive T-Lymphocytes; Cell Proliferation; Cells; Chronic; Clonal Expansion; Coupled; Data; Development; Dissection; Dissociation; Effector Cell; Generations; Genes; Genetic; Goals; Hematopoietic stem cells; Human; Immunity; Immunotherapy; Infection; Infection Control; Interferon Type II; Invaded; Link; Longevity; Lymphocyte; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mature Lymphocyte; Mechanics; Mediating; Memory; Memory B-Lymphocyte; Memory Loss; Molecular; Mus; Mutation; Oncogenic; Plasma Cells; Plasmablast; Process; Proliferating; Property; Risk Reduction; Structure of germinal center of lymph node; T cell response; T-Lymphocyte; Testing; Transcription Initiation; Transcriptional Silencer Elements; Translating; Tumor Suppression; Tumor Suppressor Proteins; Virus Diseases; c-myc Genes; cancer therapy; cell injury; cell type; chimeric antigen receptor T cells; cytotoxic; efficacious treatment; exhaustion; experimental study; factor C; gene regulatory network; in vivo; insight; lymphocyte proliferation; pathogen; postnatal; prevent; progenitor; programs; response; self-renewal; stem; stem-like cell; stemness; transcription factor; tumor; tumorigenesis

Abstract Lymphocytes are capable of robust expansion upon antigen receptor stimulation and are one of the most rapidly dividing cells postnatally. Their proliferation capacity is critical for establishing broad antigen receptor repertoires during development and also for rapidly amplifying antigen-specific immunity upon pathogen invasion. In addition, T cells can also be expanded ex vivo for experiments or adoptive cell therapies and the generation of CAR-T cells, which have been translated into anti-cancer therapies. While such robust expansion of T cells generates many effector cells, they are short-lived and unsustainable for efficacious control of infection and cancers. The goal of the proposed study is to dissect the mechanisms by which robust proliferation is coupled to such differentiation at the molecular level. We will elucidate the gene regulatory network initiated by the transcription factor c-MYC, which is oncogenic but also critical for rapid proliferation of lymphocytes at many checkpoints, in developing lymphocytes and mature lymphocytes, and define key MYC downstream genes specifically associated with the differentiation processes. Insights from these studies and selective inhibition of the differentiation processes will disclose unappreciated tumor suppressor programs and facilitate expansion of antigen-specific lymphocytes with memory/stem-like properties for long-lasting protection against infection and cancers.

摘要 淋巴细胞能够在抗原受体刺激后稳健扩增，并且是免疫调节剂中的一种。 最快速分裂的细胞。它们的增殖能力是建立广泛抗原的关键 在发育过程中的受体库，也用于快速扩增抗原特异性免疫， 病原体入侵此外，T细胞也可以离体扩增用于实验或过继细胞疗法 以及CAR-T细胞的产生，这些细胞已被转化为抗癌疗法。虽然如此强大， T细胞的扩增产生许多效应细胞，它们对于有效的免疫应答是短暂的和不可持续的。 控制感染和癌症。拟议研究的目标是剖析机制， 增殖在分子水平上与这种分化相关。我们将阐明基因调控 由转录因子c-MYC启动的网络，c-MYC是致癌的，但也是快速增殖的关键。 在许多检查点，在发展中的淋巴细胞和成熟的淋巴细胞，并确定关键MYC 与分化过程相关的下游基因。从这些研究中得出的见解， 对分化过程的选择性抑制将揭示不受重视的肿瘤抑制程序， 促进具有记忆/干细胞样特性的抗原特异性淋巴细胞的扩增， 防止感染和癌症。

项目成果

PD-1 Signaling Promotes Control of Chronic Viral Infection by Restricting Type-I-Interferon-Mediated Tissue Damage.

PD-1 信号传导通过限制 I 型干扰素介导的组织损伤来促进慢性病毒感染的控制。

• DOI: 10.1016/j.celrep.2019.10.092
• 发表时间: 2019
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Raju,Saravanan;Verbaro,DanielJ;Egawa,Takeshi
• 通讯作者: Egawa,Takeshi

Cutting Edge: The Histone Methyltransferase G9a Is Required for Silencing of Helper T Lineage-Associated Genes in Proliferating CD8 T Cells.

• DOI: 10.4049/jimmunol.1701700
• 发表时间: 2018-06-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Verbaro DJ;Sakurai N;Kim B;Shinkai Y;Egawa T
• 通讯作者: Egawa T

Lrp1 is essential for lethal Rift Valley fever hepatic disease in mice.

• DOI: 10.1126/sciadv.adh2264
• 发表时间: 2023-07-14
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Schwarz, Madeline M.;Ganaie, Safder S.;Feng, Annie;Brown, Griffin;Yangdon, Tenzin;White, J. Michael;Hoehl, Ryan M.;McMillen, Cynthia M.;Rush, Rachael E.;Connors, Kaleigh A.;Cui, Xiaoxia;Leung, Daisy W.;Egawa, Takeshi;Amarasinghe, Gaya K.;Hartman, Amy L.
• 通讯作者: Hartman, Amy L.