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

• 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
• 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

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.

摘要 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， 每年在美国的儿童和成人。尽管原发性T细胞癌患者的预后有所改善， ALL，治愈率的提高在很大程度上归因于短期和长期的高毒性化疗。 长期不良影响。此外，化疗通常对复发的T-ALL无效，其具有令人沮丧的 5-儿童年生存率为30%，成人年生存率<10%。因此，确定新的可操作的药物靶点 在T-ALL中是一项重要的研究和临床需要。这项工作的总体目标是确定一个 蛋白酪氨酸磷酸酶PRL-3在T-ALL生长和自我更新中的作用。PRL 3基因组扩增， MYC癌蛋白在12%的人T-ALL中表达，在45%的原发性T-ALL中高度表达。中央 一种假说是致癌的PRL 3通过增加复发驱动白血病的自我更新来驱动T-ALL生长 增殖细胞（LPC）和抑制凋亡，并且其阻断杀死T-ALL细胞。的理由 拟议的研究是，通过了解PRL 3如何促进T-ALL生长和进展， 靶向该磷酸酶或其直接下游靶点的药物可用于治疗T-ALL。 目的1将确定PRL 3调节T-ALL生长、维持和自我更新的细胞功能。 对于这些研究，将使用MYC诱导的T-ALL的创新性斑马鱼转基因模型来评估MYC诱导的T-ALL。 PRL 3在改变T-ALL起始、异质性、自我更新和凋亡中的作用。这项工作将延长 人类患者来源的异种移植模型，建立PRL 3作为人类T-ALL中真正的药物靶点。的 作为目标1基础的工作假设是PRL 3增强LPC自我更新并抑制细胞凋亡。是 还预期PRL 3将是白血病在体内持续生长所必需的。目标2将揭示 PRL 3调节人T-ALL生长的分子机制。我们会用一本小说 磷酸蛋白质组学方法、CRISPR/Cas9筛选和磷酸酶底物陷阱测定来鉴定 调节诱导凋亡的过程的候选底物。详细的分子分析将确定 PRL 3底物改变人T-ALL的活力和生长的精确机制。工作 目标2假设是PRL 3的直接底物抑制人T细胞中的下游凋亡途径， 所有.这项工作的成功完成将1）确定PRL下游的可操作药物靶标3 人T-ALL中的通路，以及2）发现PRL 3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的作用以及用于治疗T-ALL的其他药物靶点。我们的工作是 重要的，并可能有积极的翻译影响，因为它提供了新的机械见解， PRL 3在T-ALL中的功能，并将这种磷酸酶确定为T-ALL中真正的治疗靶点。的 在广泛的癌症中，PRL 3的癌基因状态表明，我们的研究将对PRL 3的翻译产生积极的影响。 对除T-ALL以外的依赖于PRL 3癌基因表达的肿瘤的影响。

项目成果

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