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: 10543125
• 负责人: Iannis Aifantis
• 金额: $ 52.93万
• 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/10543125
• 关键词: 3' Untranslated Regions; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Acute leukemia; Adult; Affect; Apoptosis; Binding; Binding Proteins; CRISPR screen; CRISPR/Cas technology; Cell Differentiation process; Cell physiology; Cells; Child; Data; Differentiation Therapy; Elements; Enhancers; Epigenetic Process; Family; Gene Expression; Genetic Diseases; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Human; Human Genetics; In Vitro; Intervention; Laboratories; 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; ZFP36L2 gene; Zinc Fingers; acute myeloid leukemia cell; cell growth; epigenomic profiling; gain of function; genome-wide; in vivo; leukemia; leukemic stem cell; leukemic transformation; mRNA Stability; mRNA Transcript Degradation; mRNA Translation; member; monocyte; neoplastic cell; novel; overexpression; paralogous gene; posttranscriptional; 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.

摘要 这项应用主要针对急性髓系白血病(AML)，这是一种以低分化性为特征的血癌 存活率和可用的靶向治疗很少。急性髓系白血病的五年总体存活率低于 成人为30%，儿童为65%左右。有趣的是，一种干预类型一直是 对一种亚型AML(急性早幼粒细胞白血病，APL)的成功治疗是一种“分化”疗法， 药物可以诱导肿瘤细胞分化和凋亡。在这里我们呈现表面抗原- 在AML中进行引导、CRISPR/Cas9鉴别筛查，并研究其中最突出的命中之一 筛选得到RNA结合蛋白(RBP)Zfp3612。限制性商业惯例可以在多个层面上修改RNA，包括 拼接、加工、改性和降解。考虑到限制性商业惯例是基因的关键调控因子 表达，这些蛋白质的改变也与几种人类遗传病有关， 包括癌症。我们实验室最近提出了CRISPR/CAS9对限制性商业惯例的筛查 人类白血病的类型，并确定了血癌剪接体机制的新调节器。 我们的CRISPR筛查发现了Zfp36l2，它是TIS11/TTP锌指家族的成员 限制性商业惯例，这也包括ZFP 36和ZFP 36L1对虾。我们能够证明Zfp36l2结合 早期控制的许多mRNA3‘非翻译区(UTRs)上的富Au元素 造血系和髓系分化。这种相互作用促进了靶基因的降解和 保持无差别的状态。这些研究表明Zfp36l2可以结合和降解 TIS11/TTP家族的另外两个成员，ZFP 36和ZFP 36L1，创造了潜在的额外 分化的转录后调控水平。抑制Zfp36l2恢复mRNA稳定性 并触发白血病细胞经历髓系分化并最终 细胞凋亡。一些原发AML患者的表观基因组图谱显示增强子模块 附近的Zfp36l2与不同的AML细胞状态相关，建立了协调的表观遗传学 以及形成白血病分化的转录后机制。在此应用程序中，我们最初 (目的1)重点研究Zfp36l2在AML中的体内作用，并确定mRNAs，这是可以控制的直接靶点 AML细胞的分化和生长。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髓系白血病中的作用。