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.

项目摘要 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的精细调控。microRNA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。microRNA 癌细胞中的microRNA水平通常与健康细胞中的microRNA水平不同， 某些癌症相关基因的差异表达。因此，控制microRNA水平提供了 有希望的癌症治疗靶点。 最近，我们发现，当T细胞急性淋巴细胞白血病（T-ALL）细胞用 地塞米松是白血病化疗中常用的一种糖皮质激素类固醇， 而促癌microRNA（miR-221/222）被其靶mRNA（BIM）降解。这是令人惊讶 因为microRNA通常控制它们的目标水平，而不是相反。这也是 令人兴奋，因为它代表了一种新兴的基因调控模式，由mRNA进行，并打开了 制定癌症干预策略。 在这项提案中，我们首先旨在了解BIM mRNA如何触发miR-221/222降解。我们 第二个目的是探索miR-221/222降解如何增强T-ALL细胞的杀伤， 化疗在最终目标中，我们将开发一种创新的生物化学和计算协议， 在T-ALL中全面鉴定不同靶mRNA中可诱导miRNA降解的序列 患者样本。 总的来说，我们的努力将研究T-ALL中基因调控的新机制，其中mRNA 抵消microRNA。因为对糖皮质激素的抵抗是T-ALL的严重限制， 阐明耐药的潜在机制可能为改善化疗提供基础。 目前的治疗措施。鉴于我们已经发现了一种潜在的广泛发生 在癌症中mRNA诱导的microRNA降解途径，确定可以 降解miRNAs和参与这一过程的蛋白质将有助于开发新的治疗方法， T-ALL。