Prevent IgM MGUS Progression by Targeting the Driver Mutation

通过针对驱动突变来预防 IgM MGUS 进展

基本信息

批准号：
10745013
负责人：
XINFANG YU
金额：
$ 48.28万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745013
关键词：
Adaptor Signaling Protein Affect Agammaglobulinaemia tyrosine kinase Amino Acid Substitution Amyloidosis Antibodies Artificial Intelligence Attenuated B-Cell Activation B-Lymphocytes Binding Binding Sites Biochemical Reaction Cells Chemicals Chronic Lymphocytic Leukemia Collaborations DNA DNA Vaccines Extranodal Genes Growth Human Cell Line Immune Immunity Immunoglobulin M Immunologics In complete remission Inflammation Interleukin-1 Receptors Knock-out Leucine Light Link Lymphoma Lymphoma cell Lysine Malignant Neoplasms Mediating Missense Mutation Modification Monoclonal gammopathy of uncertain significance Mus Mutation Myelogenous Names Non-Hodgkin&apos s Lymphoma Nuclear Oncogenic Oncoproteins Pathogenesis Pathway interactions Patients Phosphotransferases Physiological Polyubiquitin Polyubiquitination Positioning Attribute Post-Translational Protein Processing Prevention Primary Neoplasm Proline Proteins Ring Finger Domain Risk Signal Pathway Signal Transduction T cell response TLR3 gene TNFRSF5 gene Technology Testing Testis Toll-like receptors Toxic effect Transgenic Organisms Ubiquitination Vaccination Waldenstrom Macroglobulinemia Work Xenograft procedure cancer prevention causal variant deep learning driver mutation drug discovery efficacy validation humanized mouse large cell Diffuse non-Hodgkin&apos s lymphoma morphogens neoplastic cell neural network p65 plasmid DNA premalignant prevent protein degradation response screening small molecule tumorigenesis ubiquitin-protein ligase vaccine candidate virtual

项目摘要

Prevent IgM MGUS Progression by Targeting the Driver Mutation Project Summary Patients with monoclonal gammopathy of undetermined significance of the IgM class (IgM MGUS) are at increased risk for Waldenstrom macroglobulinemia (WM), non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or primary light-chain (AL) amyloidosis. Myeloid differentiation factor 88 (MYD88) was discovered in the 1990s as a primary differentiation response gene in myeloid precursors. A missense mutation (L265P) changing leucine at position 265 to proline in MYD88 is found in ~90% of WM. This driver mutation also occurs in >50% of primary extranodal lymphomas and ~29% of activated B-cell diffuse large B- cell lymphomas (ABC-DLBCL), as well as in ~52% of IgM MGUS. No precancer-cancer pairs other than IgM MGUS-WM have a single amino acid substitution like MYD88 L265P occurring in most precancer and ~90% of cancer, making MYD88 L265P paradigmatic for the study of a single causative mutation in cancer prevention and interception. We found that the RING finger protein 138 (RNF138) attaches lysine 63 (K63)-linked polyubiquitin chains to MYD88 L265P, yet strikingly, it has little activity on WT MYD88. This posttranslational modification on MYD88 L265P is essential to its oncogenic action. We have used a deep learning artificial intelligence (AI) technology based on a neural network to virtually screen about ten million compounds. We identified scores of primary hit compounds targeting a binding site near L265P in MYD88. We validated primary hits from AI screening and evaluated their inhibition of MYD88 L265P ubiquitination and xenograft tumorigenesis. One compound attenuated lymphoma growth from NHL cells with MYD88 L265P but not that with WT MYD88. The E3 ligase RNF138 is primarily expressed in the testis and in immune cells, and its whole- body knockout in mice does not affect physiological functions other than that in the testis. RNF138 deletion attenuates tumorigenesis from WM and DLBCL cells with MYD88 L265P but not from cells with WT MYD88. We hypothesize that targeting the MYD88 L265P-RNF138 interaction prevents IgM MGUS progression. In this application, we propose two specific aims to identify and validate chemo- and immune-prevention agents to target MYD88 L265P-RNF138 and prevent IgM MGUS progression into WM and NHL. In Aim 1, we will use the AI-developed MYD88 L265P-targeting compound to prevent IgM MGUS progression. In Aim 2, we will use DNA vaccines against RNF138 to prevent IgM MGUS progression. We expect to generate effective chemical and immunological agents without overt toxicities for cancer prevention and interception against IgM MGUS progression.

通过靶向驱动器突变来防止IgM MGU进展项目摘要 IgM类（IgM MGU）具有不确定意义的单克隆性腔症患者（IGM MGU） waldenstrom巨型球蛋白血症（WM），非霍奇金淋巴瘤（NHL），慢性淋巴细胞的风险增加白血病（CLL）或原发性轻链（AL）淀粉样变性。髓样分化因子88（MyD88）是在1990年代被发现是髓样前体中的主要分化反应基因。错过在Myd88中，在左右的左右，在左右的proline位置将亮氨酸更换为脯氨酸的突变（L265p）在WM的〜90％中发现。这个驱动程序突变也发生在> 50％的原发性外淋巴瘤中，约有29％的活化的B细胞弥漫性大B- 细胞淋巴瘤（ABC-DLBCL）以及〜52％的IgM MGU。除IGM以外，没有其他癌症对 MGUS-WM具有单个氨基酸的替代，例如大多数前锋发生的MyD88 L265P，〜90％癌症，使MYD88 L265p范式用于研究癌症预防中的单个病因突变和拦截。我们发现环手指蛋白138（RNF138）连接赖氨酸63（K63）连接多泛素链至MyD88 L265p，但令人惊讶的是，它在WT MyD88上几乎没有活动。这种翻译后 MyD88 L265p的修改对于其致癌作用至关重要。我们使用了一个深度学习的人造基于神经网络的智能（AI）技术实际上筛选了大约一千万化合物。我们确定了针对MyD88 L265p附近结合位点的主要命中化合物的得分。我们验证了 AI筛查中的主要命中率，并评估了其对MyD88 L265p泛素化和异种移植的抑制作用肿瘤发生。一种复合使NHL细胞中MyD88 L265p的淋巴瘤衰减，但没有与wt myd88。 E3连接酶RNF138主要在睾丸和免疫细胞中表达，其整个小鼠的身体敲除不影响睾丸以外的生理功能。 RNF138删除用MyD88 L265p从WM和DLBCL细胞中减弱肿瘤发生，而不是WT MyD88的细胞。我们假设针对MYD88 L265P-RNF138相互作用可阻止IgM MGUS进展。在这个应用，我们提出了两个具体目的，以识别和验证预先预防剂和免疫预防剂靶向MYD88 L265P-RNF138，并防止IgM MGUS进展为WM和NHL。在AIM 1中，我们将使用 AI开发的MyD88 L265p靶向化合物，以防止IgM MGUS进展。在AIM 2中，我们将使用针对RNF138的DNA疫苗可防止IgM MGUS进展。我们希望产生有效的化学物质没有明显毒性预防癌症和对IGM MGU的毒性的免疫学药物进展。