mRNA stability and its impact on hematopoiesis and acute leukemia

mRNA稳定性及其对造血和急性白血病的影响

• 批准号: 10339742
• 负责人: Iannis Aifantis
• 金额: $ 54.01万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339742
• 关键词: 3' Untranslated Regions; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Acute leukemia; Address; Adult; Affect; Apoptosis; Binding; Binding Proteins; Blood; CRISPR screen; CRISPR/Cas technology; Cell Differentiation process; Cell physiology; Cells; Child; Data; Differentiation Therapy; Differentiation and Growth; Elements; Enhancers; Epigenetic Process; Family; Family Study; Gene Expression Alteration; Genetic Diseases; Genetic Transcription; Genetic Translation; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Human; Human Genetics; In Vitro; Intervention; Laboratories; Lead; Length; Leukemic Cell; Maintenance; Malignant - descriptor; Malignant Neoplasms; Maps; Messenger RNA; Modification; Mus; Myelogenous; Myeloid Leukemia; Patients; Pattern; Pharmaceutical Preparations; Poly(A) Tail; Post-Transcriptional Regulation; Proteins; RNA; RNA Recognition Motif; RNA Splicing; RNA-Binding Proteins; Regulator Genes; Regulon; Role; Shapes; Spliceosomes; Surface Antigens; Survival Rate; Testing; Transcript; Undifferentiated; Yin-Yang; ZFP36L2 gene; Zinc Fingers; acute myeloid leukemia cell; epigenomics; gain of function; genome-wide; in vivo; leukemia; leukemic stem cell; leukemic transformation; mRNA Stability; mRNA Transcript Degradation; member; monocyte; neoplastic cell; novel; overexpression; paralogous gene; progenitor; screening; self-renewal; stem; stem cell differentiation; stem cells; stemness; targeted treatment; tumor initiation; tumor progression; 3' Untranslated Regions; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Acute leukemia; Address; Adult; Affect; Apoptosis; Binding; Binding Proteins; Blood; CRISPR screen; CRISPR/Cas technology; Cell Differentiation process; Cell physiology; Cells; Child; Data; Differentiation Therapy; Differentiation and Growth; Elements; Enhancers; Epigenetic Process; Family; Family Study; Gene Expression Alteration; Genetic Diseases; Genetic Transcription; Genetic Translation; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Human; Human Genetics; In Vitro; Intervention; Laboratories; Lead; Length; Leukemic Cell; Maintenance; Malignant - descriptor; Malignant Neoplasms; Maps; Messenger RNA; Modification; Mus; Myelogenous; Myeloid Leukemia; Patients; Pattern; Pharmaceutical Preparations; Poly(A) Tail; Post-Transcriptional Regulation; Proteins; RNA; RNA Recognition Motif; RNA Splicing; RNA-Binding Proteins; Regulator Genes; Regulon; Role; Shapes; Spliceosomes; Surface Antigens; Survival Rate; Testing; Transcript; Undifferentiated; Yin-Yang; ZFP36L2 gene; Zinc Fingers; acute myeloid leukemia cell; epigenomics; gain of function; genome-wide; in vivo; leukemia; leukemic stem cell; leukemic transformation; mRNA Stability; mRNA Transcript Degradation; member; monocyte; neoplastic cell; novel; overexpression; paralogous gene; progenitor; screening; self-renewal; stem; stem cell differentiation; stem cells; stemness; targeted treatment; tumor initiation; tumor progression

Abstract This application focuses on acute myeloid leukemia (AML), a blood cancer that is characterized by low survival rates and few available targeted therapies. The five-year overall survival rate for AML is below 30 percent in adults and around 65% in children. Interestingly, one type of intervention that has been successful for a subtype of AML (acute promyelocytic leukemia, APL) is a “differentiation” therapy, where drugs can induce tumor cell differentiation and apoptosis. Here we present surface antigen- guided, CRISPR/CAS9 differentiation screens in AML and study one of the most prominent hits in these screens, the RNA binding protein (RBP) ZFP36L2. RBPs can modify RNA at multiple levels, including splicing, processing, modification and degradation. Considering that RBPs are key regulators of gene expression, alterations of these proteins are also implicated in several human genetic diseases, including cancer. Our laboratory has recently presented CRISPR/CAS9 screening of RBPs in several types of human leukemia and identified novel regulators of the spliceosome machinery in blood cancers. Our CRISPR screens identified ZFP36L2, a member of the TIS11/TTP zinc-finger containing family of RBPs, that also includes the ZFP36 and ZFP36L1 paralogs. We were able to show that ZFP36L2 binds AU-rich elements on 3’ untranslated regions (UTRs) of a number of mRNAs that that control early hematopoietic and myeloid differentiation. This interaction promotes target mRNA degradation and the maintenance of an undifferentiated state. These studies showed that ZFP36L2 can bind and degrade the two other members of the TIS11/TTP family, ZFP36 and ZFP36L1, creating a potential additional level of post-transcriptional regulation of differentiation. Inhibition of ZFP36L2 restores mRNA stability of targeted transcripts and triggers leukemia cells to undergo myeloid differentiation and eventual apoptosis. Epigenomic profiling of a number of primary AML patients revealed enhancer modules nearby ZFP36L2 that associated with distinct AML cell states, establishing a coordinated epigenetic and post-transcriptional mechanism that shapes leukemic differentiation. In this application we initially (Aim 1) focus on the in vivo role of ZFP36L2 in AML and identify mRNAs, direct targets that can control AML cell differentiation and growth. In Aim 2, we study all three members of the ZFP36/TIS11 family and study in detail their roles in hematopoiesis and myeloid leukemia.

抽象的 该应用的重点是急性髓细胞性白血病（AML），该血液癌的特征是低 存活率和几乎没有可用的靶向疗法。 AML的五年总生存率低于 成人30％，儿童约为65％。有趣的是，一种干预 成功的AML亚型（急性寄宿细胞白血病，APL）是一种“分化”疗法， 药物可以诱导肿瘤细胞分化和凋亡。在这里，我们提出表面抗原 AML中的指导性CRISPR/CAS9分化屏幕，研究其中最突出的热门歌曲之一 屏幕，RNA结合蛋白（RBP）ZFP36L2。 RBP可以在多个级别上修改RNA，包括 剪接，处理，修改和降解。考虑到RBP是基因的关键调节因子 表达，这些蛋白质的改变也在几种人类遗传疾病中实施， 包括癌症。我们的实验室最近介绍了RBP的CRISPR/CAS9筛选。 人类白血病的类型并确定了血液中剪接体机械的新型调节剂。 我们的CRISPR屏幕确定了ZFP36L2，Tis11/ttp锌指的成员，其中包含的家族 RBP，还包括ZFP36和ZFP36L1旁系同源物。我们能够证明ZFP36L2绑定 在3'未翻译区域（UTRS）上的许多mRNA的元素富含元素 造血和髓样分化。这种相互作用促进了目标mRNA降解和 维持未分化状态。这些研究表明ZFP36L2可以结合并降解 TIS11/TTP家族的其他两个成员ZFP36和ZFP36L1，创造了潜在的额外 转录后分化的调节水平。抑制ZFP36L2恢复mRNA稳定性 有针对性的转录本和触发白血病细胞以经历髓样分化和最终 凋亡。许多主要AML患者的表观基因组分析显示增强子模块 与不同的AML细胞状态相关的附近ZFP36L2，建立了协调的表观遗传 以及塑造白血病分化的转录后机制。在此应用程序中，我们最初 （目标1）专注于ZFP36L2在AML中的体内作用并识别mRNA，可以控制的直接靶标 AML细胞分化和生长。在AIM 2中，我们研究ZFP36/TIS11家族的所有三个成员 并详细研究它们在造血和髓样白血病中的作用。