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.

抽象的 T细胞急性淋巴细胞白血病（T-ALL）是胸腺细胞的侵略性恶性肿瘤，影响了数千 每年在美国的儿童和成人。尽管原发性T-患者的结局改善了 所有这些，升高的治疗率在很大程度上归因于剧毒化疗，并且短期和长期都 术语不利影响。此外，化学疗法通常无效地反对t-all的复发，这是一个令人沮丧的 儿童的5年生存率为30％，成人<10％。因此，识别新的可操作的药物靶标 在T-All中是一项重大研究和临床命令。这项工作的总体目的是确定 蛋白酪氨酸磷酸酶Prl-3，在T-ALL生长和自我更新中。 PRL3在基因组上通过 MYC吞噬蛋白在12％的人类T-All中，在45％的主要T-ALL中高度表达。中央 假设是，致癌PRL3通过增加复发性白血病的自我更新来驱动T-ALL生长 传播细胞（LPC）并抑制细胞凋亡，其阻断杀死了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 靶向这种磷酸酶或其直接下游靶标可以用于治疗T-all。 AIM 1将确定PRL3调节T-ALL生长，维护和自我更新的细胞功能。 对于这些研究，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启动，异质性，自我更新和凋亡中的作用。这项工作将扩展 对于人类患者衍生的异种移植模型，将PRL3确立为人类T-All中的真正药物靶标。这 目的1的工作假设是PRL3增强了LPC自我更新并抑制凋亡。这是 还期望PRL3在体内持续的白血病持续增长需要。 AIM 2会发现 PRL3调节人类T-ALL的生长的分子机制。我们将使用小说 磷酸蛋白质组学方法，CRISPR/CAS9筛选和磷酸酶底物陷阱测定法 调节诱导凋亡的过程的候选底物。详细的分子分析将确定 PRL3底物改变人类T-ALL的生存力和生长的确切机制。工作 AIM 2的假设是PRL3的直接底物抑制人类T-的下游凋亡途径 全部。这项工作的成功完成将1）确定PRL3下游的可操作的药物靶标 人类T-All的途径，以及2）发现PRL3的下游基板，可能提供新的生物标志物 用于评估对T-all的药物影响和其他药物靶标的用于治疗T-all。我们的工作是 意义重大，可能会产生积极的翻译影响，因为它提供了新的机械见解 PRL3如何在T-ALL中起作用并确定该磷酸酶是T-ALL中的真正的治疗靶标。这 PRL3的致癌基因在广泛的癌症中表明我们的研究将具有积极的翻译 对prl3癌基因表达的T-ALL肿瘤以外的其他肿瘤的影响。

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