New mechanisms for modulating the MALT1 oncoprotein

调节 MALT1 癌蛋白的新机制

• 批准号: 9445635
• 负责人: PETER C LUCAS
• 金额: $ 53.69万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-13 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9445635
• 关键词: Affect; Antigen Receptors; Antigens; B-Cell Lymphomas; B-Lymphocytes; Binding; Biochemical; Biology; Cells; Cleaved cell; Clinical; Complex; Coupled; Cytoplasmic Protein; Development; Diagnosis; Evaluation; Event; G protein coupled receptor kinase; G-substrate; GTP-Binding Protein Regulators; Goals; Growth; Human; Immunologic Deficiency Syndromes; In Vitro; Intervention; Investigation; Knowledge; Laboratories; Lead; Lymphocyte; Lymphocyte Activation; Lymphoma; Lymphomagenesis; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Mantle Cell Lymphoma; Mediating; Molecular; Movement; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mus; Mutation; N-terminal; Oncoproteins; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peptide Hydrolases; Pharmacologic Substance; Phenotype; Phosphotransferases; Plant Roots; Play; Protein Region; Proteins; Receptors, Antigen, B-Cell; Recurrence; Regulation; Role; Series; Signal Pathway; Signal Transduction; Signaling Protein; Specimen; Study models; Therapeutic; Tumor Suppressor Proteins; United States; Xenograft Model; actionable mutation; adaptive immune response; antitumor effect; cell type; clinical application; curative treatments; design; gain of function; gain of function mutation; genetic analysis; immune health; improved; in vivo; inhibitor/antagonist; innovation; insight; large cell Diffuse non-Hodgkin' s lymphoma; mimetics; mucosa-associated lymphoid tissue; mucosa-associated lymphoid tissue lymphoma; mutant; novel; novel strategies; novel therapeutic intervention; prognostic; protein protein interaction; receptor; recruit; scaffold; small molecule; therapeutic protein; transcription factor; treatment strategy; tumor

PROJECT SUMMARY: Lymphoma is the sixth most common form of cancer in the United States, affecting an estimated 23 per 100,000 people. While there have been significant advances in our understanding of lymphoma biology and our ability to provide curative therapy, many patients with lymphoma continue to suffer poor outcomes with approximately 20,000 people dying from lymphoma in the US each year. Novel approaches to the diagnosis and treatment of lymphoma are urgently needed. This application is focused on elucidating the molecular mechanisms that regulate MALT1, a central oncoprotein in B-cell lymphoma. MALT1 is a cytoplasmic protein that serves to mediate antigen receptor- dependent lymphocyte activation, proliferation and survival, via stimulation of the canonical pro-survival NF-κB transcription factor. In B-lymphocytes, the antigen receptor is known as the B-cell receptor (BCR). In these cells, BCR-induced, MALT1-dependent NF-κB activation is a required event during the normal adaptive immune response, but dysregulated activation of this pathway can lead to lymphoma. Indeed, genetic analysis has revealed that in specific subtypes of B-cell lymphoma, malignant B cells highjack BCR signaling pathways in order to promote their own growth and survival. BCR stimulation results in assembly of the CARMA1-Bcl10-MALT1 (CBM) protein signaling complex, where MALT1 serves as the effector by carrying out two important functions. First, MALT1 acts as a scaffold to recruit and activate downstream signaling proteins, and second, MALT1 acts as a protease to cleave specific substrate signaling proteins and alter their activities. The critical importance of achieving appropriate regulation of MALT1 activity is demonstrated by the fact that gain-of-function mutations in BCR subunits or in CARMA1, resulting in exaggerated MALT1 activity, are recurrently detected in human B-cell lymphoma. Thus, MALT1 is the subject of intense investigation as a key regulator of B-lymphomagenesis and a promising new target for pharmaceutical inhibition. This proposal investigates the innovative hypothesis that specific proteins are capable of controlling MALT1 function, such that their loss in some subtypes of B-cell lymphoma may contribute to aberrant MALT1 activity. The presence of gain-of-function BCR or CARMA1 mutants may synergize with loss of such proteins in promoting lymphomagenesis; conversely, loss alone may be pathogenic. Our goals for this proposal are to elucidate the molecular underpinnings by which specific protein-protein interactions can abrogate MALT1 activity, to determine how this interaction influences lymphocyte growth and survival, and to utilize this information to inform the design of novel therapeutic approaches to MALT1-dependent lymphoma.

项目概要： 淋巴瘤是美国第六大常见癌症，估计23%的人患有淋巴瘤。 十万人。虽然我们对淋巴瘤生物学的理解有了重大进展， 尽管我们有能力提供治愈性治疗，但许多淋巴瘤患者的预后仍然很差， 在美国，每年大约有20，000人死于淋巴瘤。新的诊断方法 和淋巴瘤的治疗是迫切需要的。 本申请集中于阐明调节MALT 1的分子机制，MALT 1是一种中枢神经系统。 B细胞淋巴瘤中的癌蛋白。MALT 1是一种细胞质蛋白，其用于介导抗原受体- 依赖性淋巴细胞活化、增殖和存活，通过刺激典型的促存活NF-κB 转录因子在B淋巴细胞中，抗原受体被称为B细胞受体（BCR）。在这些 BCR诱导的MALT 1依赖性NF-κB活化是正常适应性细胞中必需的事件。 免疫反应，但这一途径的失调激活可导致淋巴瘤。事实上，基因分析 揭示了在B细胞淋巴瘤的特定亚型中，恶性B细胞劫持BCR信号通路， 以促进自身的成长和生存。 BCR刺激导致CARMA 1-Bcl 10-MALT 1（CBM）蛋白信号传导复合物的组装， 其中MALT 1通过执行两个重要功能而充当效应子。首先，MALT 1充当支架 招募和激活下游信号蛋白，其次，MALT 1作为蛋白酶切割 特异性底物信号蛋白并改变其活性。至关重要的是， MALT 1活性的调节通过BCR亚基或BCR亚基中的功能获得性突变的事实来证明。 CARMA 1导致MALT 1活性增强，在人B细胞淋巴瘤中反复检测到。因此，在本发明中， MALT 1作为B淋巴瘤发生的关键调节因子和一个有前途的新的研究对象， 药物抑制靶点。 这项提案调查了创新的假设，即特定蛋白质能够控制 MALT 1功能，因此它们在某些B细胞淋巴瘤亚型中的缺失可能导致MALT 1异常 活动功能获得性BCR或CARMA 1突变体的存在可能与这些蛋白质的丧失协同作用 在促进淋巴瘤发生;相反，损失单独可能是致病性的。我们提出这项建议的目的是 阐明特定蛋白质-蛋白质相互作用可以消除MALT 1的分子基础 活性，以确定这种相互作用如何影响淋巴细胞的生长和存活，并利用这种 这些信息为MALT 1依赖性淋巴瘤的新型治疗方法的设计提供了信息。