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

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 该应用重点关注急性髓系白血病 (AML)，这是一种血癌，其特点是低 生存率和可用的靶向治疗很少。 AML 的五年总生存率如下 成人为 30%，儿童为 65% 左右。有趣的是，一种干预措施 成功治疗 AML 亚型（急性早幼粒细胞白血病，APL）的是一种“分化”疗法， 其中药物可以诱导肿瘤细胞分化和凋亡。在这里我们介绍表面抗原- CRISPR/CAS9 引导下的 AML 分化筛选，并研究了这些领域最突出的成果之一 筛选 RNA 结合蛋白 (RBP) ZFP36L2。 RBP 可以在多个水平上修饰 RNA，包括 剪接、加工、修饰和降解。考虑到 RBP 是基因的关键调节因子 这些蛋白质的表达和改变也与多种人类遗传疾病有关， 包括癌症。我们的实验室最近在多个领域展示了 CRISPR/CAS9 筛选 RBP 人类白血病的类型并确定了血癌中剪接体机制的新型调节因子。 我们的 CRISPR 筛选鉴定出 ZFP36L2，它是包含 TIS11/TTP 锌指家族的成员 RBP，还包括 ZFP36 和 ZFP36L1 旁系同源物。我们能够证明 ZFP36L2 结合 许多控制早期的 mRNA 的 3' 非翻译区 (UTR) 上富含 AU 元件 造血和骨髓分化。这种相互作用促进靶标 mRNA 降解， 维持未分化状态。这些研究表明 ZFP36L2 可以结合并降解 TIS11/TTP 系列的另外两个成员 ZFP36 和 ZFP36L1，创造了一个潜在的额外 分化的转录后调节水平。抑制 ZFP36L2 可恢复 mRNA 稳定性 靶向转录本并触发白血病细胞进行骨髓分化并最终 细胞凋亡。许多原发性 AML 患者的表观基因组分析揭示了增强子模块 附近的 ZFP36L2 与不同的 AML 细胞状态相关，建立协调的表观遗传 以及塑造白血病分化的转录后机制。在这个应用程序中，我们最初 （目标 1）关注 ZFP36L2 在 AML 中的体内作用并识别 mRNA，即可以控制的直接靶标 AML 细胞分化和生长。在目标 2 中，我们研究了 ZFP36/TIS11 家族的所有三个成员 并详细研究它们在造血和粒细胞白血病中的作用。