TET2-mediated epitranscriptomic regulation in leukemia microenvironment

TET2介导的白血病微环境中的表观转录组调控

• 批准号: 10801348
• 负责人: Jianjun Chen
• 金额: $ 68.42万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10801348
• 关键词: Acute Myelocytic Leukemia; Apical; Basic Science; Binding; Biological; Biological Assay; Biological Process; Biology; Bone Marrow; Bone Marrow Transplantation; CXCR4 gene; Cells; Chemicals; Chemoresistance; Clonal Expansion; Coupled; Cytosine; DNA; DNA binding protein B; DNMT3a; Data; Development; Dioxygenases; Drug resistance; Enzymes; FLT3 gene; Genetic Transcription; Hematopoietic Neoplasms; Homing; In Vitro; Investigation; Knock-in Mouse; Knockout Mice; Knowledge; Ligands; MLL-AF9; MLL-rearranged leukemia; Maintenance; Mass Spectrum Analysis; Mediating; Medical; Messenger RNA; Methylation; Modeling; Modification; Molecular; Mus; Mutate; Mutation; NPM1 gene; Nucleotides; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Prognosis; RNA; RNA Stability; RNA-Binding Proteins; RUNX1 gene; Regimen; Regulation; Relapse; Reporting; Resolution; Role; Signal Transduction; Stromal Cell-Derived Factor 1; Survival Rate; Testing; Therapeutic; Transcript; Transfer RNA; Transgenic Organisms; Treatment Efficacy; Validation; adverse outcome; bisulfite sequencing; chemokine receptor; clinical prognosis; conventional therapy; crosslinking and immunoprecipitation sequencing; demethylation; epitranscriptomics; gain of function; hematopoietic stem cell self-renewal; high risk; improved; in vivo; infancy; inhibitor; leukemia; leukemogenesis; loss of function; migration; mouse model; mutant; new therapeutic target; novel; overexpression; oxidation; patient derived xenograft model; pharmacologic; programs; self-renewal; stem; transcriptome; transcriptome sequencing; translational medicine; tumor microenvironment

PROJECT SUMMARY: Background: Acute myeloid leukemia (AML) is one of the most aggressive types of hematopoietic malignancies with various genetic alterations. Ten-Eleven Translocation 2 (TET2), an enzyme involved in DNA demethylation, is deleted or mutated in 15-20% of AML patients. Those patients with TET2 deficiency are poorly responsive to currently available therapeutic regimens, leading to more adverse outcomes than patients with other AML subtypes. Thus, it is urgent to identify new therapeutic target(s) and develop novel effective approaches to treat TET2-deficient AMLs. Tet2 loss in mice facilitates the self-renewal of hematopoietic stem cells (HSCs) and leukemic stem/initiating cells (LSCs/LICs). The LSCs/LICs reside in a specialized microenvironment called “niche” in the bone marrow (BM) to support their survival and self-renewal. There are several critical gaps in our current knowledge of the molecular mechanism underlying LSC/LIC homing and of the role of TET2 deficiency in the BM microenvironment. Meanwhile, evidence is emerging to support a novel function for TET2-mediated oxidation of methyl-5-cytosine (m5C) in RNAs, including messenger RNA (mRNA). However, it is unknown whether and (if so) how TET2-mediated RNA m5C demethylation contributes to leukemogenesis. Our preliminary study showed that Tet2 deficiency stimulates the Tetraspanin 13 (Tspan13)/C-X-C motif chemokine receptor 4 (Cxcr4) axis to facilitate AML homing/migration into the BM microenvironment, giving rise to increased LSC/LIC self-renewal and fast leukemogenesis in vivo. Tet2 deficiency-mediated increase of mRNA m5C modification in Tspan13 is recognized by Y-box binding protein 1 (YBX1), which in turn stabilizes Tspan13 transcript and increases its expression, thereby activating the Cxcr4 signaling. Pharmacological inhibition of CXCR4 suppresses LSC/LIC homing into the BM microenvironment and shows a synergistic effect with hypomethylating agents in killing TET2-deficient AMLs. These results lead to our central hypothesis that TET2-mediated mRNA m5C demethylation is involved in reprogramming BM microenvironment. Guided by strong preliminary data, we propose three Specific Aims to test our hypothesis: (1) Determine the definitive role of TET2 in the homing of LSCs/LICs into BM microenvironment; (2) Characterize the mRNA m5C-dependent and functionally essential targets of TET2 and decipher the molecular mechanisms underlying the role of TET2 in LSC/LIC homing and self-renewal; and (3) Assess the therapeutic potential of targeting the TET2/CXCR4 axis in high-risk TET2-deficient AMLs. Overall, our proposed studies will substantially advance our understanding of the fundamental biology of TET2-mediated epitranscriptomic changes in BM microenvironment and may result in the development of novel effective approaches to treat AMLs with TET2 deficiency. Thus, our project is of high novelty and significance in both basic research and translational medicine.

项目摘要：背景：急性髓系白血病 (AML) 是最具侵袭性的类型之一 具有各种基因改变的造血系统恶性肿瘤 10-11 易位 2 (TET2)，一种酶。 参与 DNA 去甲基化的 TET2 基因在 15-20% 的 AML 患者中被删除或突变。 缺乏症对目前可用的治疗方案反应不佳，导致更多不良后果 因此，迫切需要确定新的治疗靶点并开发新的治疗靶点。 治疗小鼠 TET2 缺陷的 AML 的有效方法 干细胞（HSC）和白血病干/起始细胞（LSC/LIC）。 骨髓（BM）中有一个称为“生态位”的微环境来支持它们的生存和自我更新。 我们目前对 LSC/LIC 归巢分子机制的了解存在几个关键差距 同时，越来越多的证据支持 TET2 缺乏在 BM 微环境中的作用。 TET2介导的RNA（包括信使RNA）中甲基5-胞嘧啶（m5C）氧化的新功能 然而，TET2 介导的 RNA m5C 去甲基化是否以及（如果是的话）如何发挥作用尚不清楚。 我们的初步研究表明 Tet2 缺乏会刺激 Tetraspanin 13。 (Tspan13)/C-X-C 基序趋化因子受体 4 (Cxcr4) 轴促进 AML 归巢/迁移到 BM 微环境，导致 LSC/LIC 自我更新增加和体内 Tet2 快速生成。 Y-box 结合蛋白 1 识别 Tspan13 中缺陷介导的 mRNA m5C 修饰增加 (YBX1)，进而稳定 Tspan13 转录物，从而增加其表达，激活 Cxcr4 CXCR4 的药理学抑制可抑制 LSC/LIC 归巢至 BM 微环境并 显示出与低甲基化药物在杀死 TET2 缺陷的 AML 方面具有协同作用。 核心假设是 TET2 介导的 mRNA m5C 去甲基化参与了 BM 重编程 在强有力的初步数据的指导下，我们提出了三个具体目标来检验我们的假设：(1) 确定 TET2 在 LSC/LIC 归巢至 BM 微环境中的决定性作用 (2) 表征； TET2 的 mRNA m5C 依赖性和功能必需靶标并破译分子机制 TET2 在 LSC/LIC 归巢和自我更新中的作用；(3) 评估 TET2 的治疗潜力； 总体而言，我们提出的研究将在高风险 TET2 缺陷的 AML 中靶向 TET2/CXCR4 轴。 我们对 TET2 介导的 BM 表观转录组变化的基本生物学进展的理解 微环境，可能会导致开发出用 TET2 治疗 AML 的新有效方法 因此，我们的项目在基础研究和转化医学方面都具有很高的新颖性和意义。