Exploring microRNA degradation in T-cell acute lymphoblastic leukemia

探索 T 细胞急性淋巴细胞白血病中的 microRNA 降解

• 批准号: 10717486
• 负责人: Jonathan D. Licht
• 金额: $ 50.38万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717486
• 关键词: Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Adenosine; Affect; Apoptosis; Apoptotic; B-Cell Acute Lymphoblastic Leukemia; Base Pairing; Binding; Biochemical; Biology; CRISPR screen; CRISPR/Cas technology; Cancer Intervention; Cell Death; Cell Line; Cell Membrane Permeability; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collecting Cell; DNA; Data Set; Degradation Pathway; Development; Dexamethasone; Elements; Enzymes; Event; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glucocorticoid-induced apoptosis; Glucocorticoids; Hematopoietic Neoplasms; Hybrids; Induction of Apoptosis; Leukemia Acute Lymphoblastic Chemotherapy; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Mediating; Messenger RNA; MicroRNAs; Mixed B- and T-Cell Leukemia; Molecular; Mus; Mutate; Mutation; Mutation Analysis; Names; Nucleotides; Oncogene Activation; Oncogenic; Pathologic; Pathway Analysis; Pathway interactions; Patients; Persons; Physiological; Process; Proteins; Protocols documentation; RNA; Regulation; Regulator Genes; Repression; Resistance; Role; Sampling; Sequence Analysis; Small RNA; Steroids; System; Tail; Therapeutic Intervention; Transcript; Translating; Translations; Tumor Suppressor Proteins; Untranslated RNA; Untranslated Regions; Uridine; Validation; Xenograft Model; acute T-cell lymphoblastic leukemia cell; aged; bioinformatics pipeline; cancer cell; cancer diagnosis; cancer therapy; chemotherapy; combat; crosslink; differential expression; gene discovery; gene regulatory network; genetic information; genome-wide; improved; innovation; leukemia; mitochondrial membrane; mutant; novel; novel therapeutics; patient derived xenograft model; prevent; pro-apoptotic protein; resistance mechanism; response; standard care; therapeutic RNA; transcriptome sequencing; ubiquitin ligase

PROJECT SUMMARY Gene expression, the flow of genetic information from DNA to messenger RNA (mRNA) to protein, involves delicate regulation by a group of small RNAs named microRNAs. MicroRNAs can inhibit gene expression by binding to mRNAs and prevent them from being translated into proteins. MicroRNA levels in cancer cells are usually different from the microRNA levels in healthy cells, leading to differential expression of certain cancer-related genes. Controlling microRNA levels therefore offers a promising target for cancer treatment. Recently, we found that when T-cell acute lymphoblastic leukemia (T-ALL) cells are treated with dexamethasone, a glucocorticoid steroid commonly used in leukemia chemotherapy, two highly related and pro-cancer microRNAs (miR-221/222) are degraded by their target mRNA (BIM). This is surprising because microRNAs usually control the levels of their targets, but not the other way around. This is also exciting because it represents an emerging gene regulation mode carried out by the mRNAs and opens up strategies for cancer intervention. In this proposal, we first aim to understand how BIM mRNA triggers miR-221/222 degradation. Our second aim is to explore how miR-221/222 degradation enhances killing of T-ALL cells during chemotherapy. In the final aim, we will develop an innovative biochemical and computational protocol to globally identify sequences in different target mRNAs that can induce miRNA degradation in T-ALL patient samples. Collectively, our efforts will examine a new mechanism of gene regulation in T-ALL, in which mRNAs counteract microRNAs. Because resistance to glucocorticoid is a serious limitation for T-ALL chemotherapy, elucidating the underlying mechanism of resistance may provide the basis for improving current therapeutic interventions. Given that we have discovered a potentially widespread occurrence of the mRNA-induced microRNA degradation pathway in cancer, identifying the mRNAs that can degrade miRNAs and the proteins involved in this process would help develop new therapies to combat T-ALL.

项目概要 基因表达，遗传信息从 DNA 到信使 RNA (mRNA) 再到蛋白质的流动， 涉及一组称为 microRNA 的小 RNA 的精细调节。 MicroRNAs可以抑制基因 通过与 mRNA 结合来表达并阻止它们被翻译成蛋白质。微小RNA 癌细胞中的 microRNA 水平通常与健康细胞中的 microRNA 水平不同，从而导致 某些癌症相关基因的差异表达。因此，控制 microRNA 水平可以提供 癌症治疗的有希望的目标。 最近，我们发现，当 T 细胞急性淋巴细胞白血病 (T-ALL) 细胞接受 地塞米松是一种常用于白血病化疗的糖皮质激素类固醇，两者高度相关 和促癌 microRNA (miR-221/222) 被其靶 mRNA (BIM) 降解。这令人惊讶 因为 microRNA 通常控制其靶标的水平，但反之则不然。这也是 令人兴奋的是，它代表了一种由 mRNA 执行的新兴基因调控模式，并开启了 制定癌症干预策略。 在本提案中，我们首先旨在了解 BIM mRNA 如何触发 miR-221/222 降解。我们的 第二个目标是探索 miR-221/222 降解如何增强 T-ALL 细胞的杀伤作用 化疗。在最终目标中，我们将开发一种创新的生化和计算协议 全局识别不同靶标 mRNA 中可诱导 T-ALL 中 miRNA 降解的序列 患者样本。 总的来说，我们的努力将研究 T-ALL 基因调控的新机制，其中 mRNA 抵消 microRNA。因为对糖皮质激素的耐药性是 T-ALL 的严重限制 阐明化疗耐药的潜在机制可能为改善化疗提供依据 目前的治疗干预措施。鉴于我们发现了一种可能广泛存在的现象 研究癌症中 mRNA 诱导的 microRNA 降解途径，鉴定出能够 降解 miRNA 和参与这一过程的蛋白质将有助于开发新的疗法来对抗 高的。