Oncogenic pathways and therapeutic targets in T cell acute lymphoblastic leukemia

T细胞急性淋巴细胞白血病的致癌途径和治疗靶点

基本信息

批准号：
10225314
负责人：
David Michael Langenau
金额：
$ 39.12万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225314
关键词：
Acute Myelocytic Leukemia Acute T Cell Leukemia Address Adult Adverse effects Affect Apoptosis Apoptotic Automobile Driving Biological Assay Biological Markers Blood Cells CRISPR screen Cell Cycle Cell Death Cell Fraction Cell physiology Cells Child Clinic Clinical Complement Data Development Disease Drug Synergism Drug Targeting Frequencies Future Genes Goals Growth Heterogeneity Human Investigation Learning Letters Longevity Maintenance Malignant Neoplasms Modeling Molecular Molecular Analysis Mus Neoplasm Metastasis Oncogenes Oncogenic Oncoproteins Outcome Pathogenesis Pathway interactions Patient-Focused Outcomes Pharmaceutical Preparations Phosphoric Monoester Hydrolases Process Protein Dephosphorylation Protein Tyrosine Phosphatase Relapse Reporting Research Role Signal Induction Solid Neoplasm Survival Rate T-Cell Receptor Testing Therapeutic Toxic effect Transgenic Model Translating United States VAV1 gene Work Xenograft procedure Zebrafish acute T-cell lymphoblastic leukemia cell cell type chemotherapy human disease improved improved outcome in vivo innovation insight leukemia malignant breast neoplasm new therapeutic target novel novel marker novel therapeutics patient derived xenograft model phosphoproteomics self-renewal small molecule small molecule inhibitor targeted treatment therapeutic target thymocyte translational impact treatment strategy tumor

项目摘要

ABSTRACT T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes that affects thousands of children and adults annually in the United States. Despite improved outcomes for patients with primary T- ALL, the elevated cure rates are largely attributable to highly toxic chemotherapy with both short- and long- term adverse effects. Moreover, chemotherapy is often ineffective against relapsed T-ALL, which has a dismal 5-year survival rate of 30% in children and <10% in adults. Thus, identification of new actionable drug targets in T-ALL is a major research and clinical imperative. The overall objective of this work is to define the role of a protein tyrosine phosphatase, PRL-3, in T-ALL growth and self-renewal. PRL3 is genomically amplified with the MYC oncoprotein in 12% of human T-ALL and is highly expressed in 45% of primary T-ALL. The central hypothesis is that oncogenic PRL3 drives T-ALL growth by increasing self-renewal of relapse-driving leukemia propagating cells (LPCs) and suppressing apoptosis, and that its blockade kills T-ALL cells. The rationale for the proposed research is that by understanding how PRL3 promotes T-ALL growth and progression, drugs targeting this phosphatase or its immediate downstream targets could be developed for the treatment of T-ALL. Aim 1 will identify the cellular function by which PRL3 modulates T-ALL growth, maintenance and self-renewal. For these studies, an innovative zebrafish transgenic model of MYC-induced T-ALL will be used to assess a role for PRL3 in altering T-ALL initiation, heterogeneity, self-renewal and apoptosis. This work will be extended to human patient-derived xenograft models, establishing PRL3 as a bona fide drug target in human T-ALL. The working hypothesis underlying Aim 1 is that PRL3 enhances LPC self-renewal and suppresses apoptosis. It is also expected that PRL3 will be required for continued leukemia growth in vivo. Aim 2 will uncover the molecular mechanism(s) by which PRL3 regulates the growth of human T-ALL. We will use a novel phosphoproteomic approach, a CRISPR/Cas9 screen and phosphatase substrate trap assay to identify candidate substrates that regulate processes that induce apoptosis. Detailed molecular analysis will identify the precise mechanism by which PRL3 substrates alter the viability and growth of human T-ALL. The working hypothesis for Aim 2 is that direct substrates of PRL3 suppress downstream apoptotic pathways in human T- ALL. Successful completion of this work will 1) identify actionable drug targets downstream of the PRL3 pathway in human T-ALL, and 2) discover the downstream substrates of PRL3, likely providing new biomarkers for assessing drug effects on T-ALL and additional drug targets for the treatment of T-ALL. Our work is significant and will likely have a positive translational impact because it provides novel mechanistic insights into how PRL3 functions in T-ALL and establishes this phosphatase as a bona fide therapeutic target in T-ALL. The oncogene status of PRL3 in a wide range of cancers suggests that our studies will have a positive translational impact on tumors other than T-ALL that are addicted to PRL3 oncogene expression.

抽象的 T 细胞急性淋巴细胞白血病 (T-ALL) 是一种侵袭性胸腺细胞恶性肿瘤，影响数千人每年在美国的儿童和成人。尽管原发性 T- 患者的预后有所改善 ALL 治愈率的提高很大程度上归因于短期和长期的高毒性化疗术语不利影响。此外，化疗通常对复发性 T-ALL 无效，复发性 T-ALL 的治疗效果令人沮丧。儿童5年生存率为30%，成人<10%。因此，识别新的可操作药物靶点 T-ALL 的治疗是一项重大的研究和临床任务。这项工作的总体目标是定义蛋白酪氨酸磷酸酶 (PRL-3) 在 T-ALL 生长和自我更新中的作用。 PRL3 通过基因组扩增 MYC 癌蛋白在 12% 的人类 T-ALL 中表达，并在 45% 的原发性 T-ALL 中高表达。中央假设致癌性 PRL3 通过增加复发性白血病的自我更新来驱动 T-ALL 生长增殖细胞 (LPC) 并抑制细胞凋亡，并且其阻断可杀死 T-ALL 细胞。理由拟议的研究是通过了解 PRL3 如何促进 T-ALL 生长和进展，药物可以开发针对这种磷酸酶或其直接下游靶标的药物来治疗 T-ALL。目标 1 将确定 PRL3 调节 T-ALL 生长、维持和自我更新的细胞功能。在这些研究中，MYC 诱导的 T-ALL 的创新斑马鱼转基因模型将用于评估 PRL3 在改变 T-ALL 起始、异质性、自我更新和细胞凋亡中的作用。这项工作将延长到人类患者来源的异种移植模型，将 PRL3 确立为人类 T-ALL 的真正药物靶点。这目标 1 的工作假设是 PRL3 增强 LPC 自我更新并抑制细胞凋亡。这是还预计 PRL3 是白血病在体内持续生长所必需的。目标 2 将揭开 PRL3 调节人 T-ALL 生长的分子机制。我们将用小说磷酸蛋白质组学方法、CRISPR/Cas9 筛选和磷酸酶底物捕获分析来鉴定调节诱导细胞凋亡过程的候选底物。详细的分子分析将确定 PRL3 底物改变人类 T-ALL 活力和生长的精确机制。工作中目标 2 的假设是 PRL3 的直接底物抑制人 T-细胞中的下游凋亡途径全部。成功完成这项工作将 1) 确定 PRL3 下游可操作的药物靶点人类 T-ALL 中的途径，2) 发现 PRL3 的下游底物，可能提供新的生物标志物用于评估药物对 T-ALL 的作用以及治疗 T-ALL 的其他药物靶点。我们的工作是意义重大，并且可能会产生积极的转化影响，因为它提供了新颖的机制见解 PRL3 如何在 T-ALL 中发挥作用，并将这种磷酸酶确立为 T-ALL 的真正治疗靶点。这 PRL3 在多种癌症中的癌基因状态表明我们的研究将具有积极的转化作用对 T-ALL 以外的依赖 PRL3 癌基因表达的肿瘤的影响。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mutant IL7R collaborates with MYC to induce T-cell acute lymphoblastic leukemia.

DOI：
10.1038/s41375-022-01590-5
发表时间：
2022-06
期刊：
Leukemia
影响因子：
11.4
作者：
Oliveira ML;Veloso A;Garcia EG;Iyer S;Pereira C;Barreto VM;Langenau DM;Barata JT
通讯作者：
Barata JT