The Role of miR-142 in the Transformation of Clonal Hematopoietic Disorders into AML

miR-142 在克隆性造血障碍转化为 AML 中的作用

• 批准号: 10544734
• 负责人: GUIDO MARCUCCI
• 金额: $ 53.2万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 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 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544734
• 关键词: Acute Myelocytic Leukemia; Address; Allogenic; Animals; B-Lymphocytes; Behavior; Blast Phase; Blood Vessels; Bone Marrow; Bone marrow failure; Cell Differentiation process; Cell Respiration; Cell Survival; Cells; Chromosome abnormality; Chronic; Chronic Myeloid Leukemia; Chronic Phase; Chronic-Phase Myeloid Leukemia; Clinical; Clinical Trials; Clonal Evolution; Clonal Hematopoietic Stem Cell; Compensation; Data; Development; Disease; Dose; Down-Regulation; Drug Kinetics; Dysmyelopoietic Syndromes; Endothelial Cells; Ensure; Erythroid; Exclusion; Experimental Designs; FLT3 gene; Gene Expression; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Hemorrhagic Thrombocythemia; Homeostasis; Human; Impairment; In Vitro; Institution; Knock-out; Lymphoid; Lymphoma; Malignant Neoplasms; Megakaryocytes; Messenger RNA; Metabolism; MicroRNAs; Mitochondria; Molecular; Molecular Abnormality; Mononuclear; Mus; Mutate; Mutation; Myelodysplastic/Myeloproliferative Disease; Myelofibrosis; Myelogenous; Myeloproliferative disease; Names; Output; Oxidative Phosphorylation; PECAM1 gene; Pathogenesis; Patient-Focused Outcomes; Patients; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Play; Polycythemia Vera; Prognosis; Proteins; Reactive Oxygen Species; Reporting; Risk; Role; Safety; Sampling; Schedule; Secondary acute myeloid leukemia; Secondary to; Splenomegaly; Stem cell transplant; T-Lymphocyte; Testing; Therapeutic; Time; Untranslated RNA; Zebrafish; acute myeloid leukemia cell; arteriole; chronic myeloid leukemia cell; density; design; effective therapy; fatty acid oxidation; gene conservation; in vivo; knock-down; leukemia; leukemic stem cell; leukemic transformation; manufacture; molecular targeted therapies; mouse model; novel; novel therapeutics; precursor cell; prevent; progenitor; prognostic; programs; risk stratification; self-renewal; stem cells; stemness; therapeutically effective

Chronic clonal blood disorders such as myeloproliferative neoplasms (MPN) and chronic phase (CP) chronic myelogenous leukemia (CML) may over time transform, respectively, into secondary (s) acute myeloid leukemia (AML) and blast crisis (BC) CML, which are poorly responsive to currently available therapies, including allogeneic stem cell transplantation. Thus, the availability of novel and more effective treatments is a true unmet need for these patients. MicroRNAs (miRNAs) are small non-coding RNAs that target messenger RNAs and regulate the corresponding protein levels. MIR142, encoding miR-142, is a highly conserved “gene”, expressed at high levels in hematopoietic cells and is involved in the development and function of myeloid, lymphoid and megakaryocyte- erythroid progenitors. MIR142 has been found mutated and/or downregulated both in lymphoma and AML. Furthermore, miR-142 knock-out (KO) causes impaired hematopoiesis in zebra fish and mice, with expansion of hematopoietic stem and progenitor cells (HSPCs) and decreased hematopoietic output. We recently demonstrated that miR-142 KO in mouse models with clonal myeloproliferative disorders (MPDs; i.e., FLT3-ITD+ MPN or CP CML) prompts transformation into an AML-like disease and confers a significantly shorter survival to these animals. Our data support a role of miR-142 deficit in deregulation of the metabolism of clonal hematopoietic stem cells (HSCs), with a switch to higher levels of oxidative phosphorylation (OxPhos) via increased fatty acid oxidation (FAO); these changes likely play a key role in the transformation of clonal HSCs into leukemic stem cells (LSCs). We demonstrated that rescue of miR-142 deficit with a novel miR-142 mimic compound (CpG-M-miR-142) reduced OxPhos levels and viability of LSCs, decreased LSC burden and activity and prolonged survival of treated BC CML mice. Thus, the central hypothesis of this proposal is that the understanding of the cellular and molecular basis of miR-142 downregulation and its impact on the transformation of clonal MPD into aggressive AML-like disease will allow us to design and optimize novel treatments to compensate for the miR-142 deficit and prevent and cure MPD transformation. We propose the following Specific Aims (SAs): SA#1: To define the role of miR-142 deficit in the sAML/BC CML transformation. SA#2: To dissect the molecular mechanisms through which miR-142 deficit contributes to sAML/BC CML transformation. SA#3: To investigate the pharmacokinetic (PK), pharmacodynamic (PD) and therapeutic impact of a synthetic CpG-M-miR-142 that will rescue miR-142 deficit in sAML/BC CML.

慢性克隆性血液疾病，例如骨髓增生性肿瘤 (MPN) 和慢性期 (CP) 随着时间的推移，粒细胞白血病 (CML) 可能分别转变为继发性急性粒细胞白血病 (AML) 和急变期 (BC) CML，对目前可用的疗法反应不佳，包括 同种异体干细胞移植。因此，寻找新的、更有效的治疗方法是一个真正的未满足的问题 这些患者的需要。 MicroRNA (miRNA) 是一种小型非编码 RNA，其靶向信使 RNA 并调节相应的 蛋白质水平。 MIR142 编码 miR-142，是一个高度保守的“基因”，在 造血细胞，参与骨髓细胞、淋巴细胞和巨核细胞的发育和功能 红系祖细胞。已发现 MIR142 在淋巴瘤和 AML 中发生突变和/或下调。 此外，miR-142 敲除 (KO) 会导致斑马鱼和小鼠的造血功能受损，从而导致 造血干细胞和祖细胞（HSPC）和造血输出减少。 我们最近在患有克隆性骨髓增殖性疾病（MPD； 即 FLT3-ITD+ MPN 或 CP CML）促使转化为 AML 样疾病，并赋予显着的 这些动物的生存期较短。我们的数据支持 miR-142 缺陷在代谢失调中的作用 克隆造血干细胞 (HSC)，通过切换至更高水平的氧化磷酸化 (OxPhos) 增加脂肪酸氧化（FAO）；这些变化可能在克隆 HSC 的转化中发挥关键作用 转化为白血病干细胞（LSC）。我们证明了用新型 miR-142 模拟物可以挽救 miR-142 缺陷 化合物 (CpG-M-miR-142) 降低了 LSC 的 OxPhos 水平和活力，降低了 LSC 的负担和活性 并延长接受治疗的 BC CML 小鼠的生存期。因此，该提案的中心假设是 了解 miR-142 下调的细胞和分子基础及其对 将克隆性 MPD 转化为侵袭性 AML 样疾病将使我们能够设计和优化新型 补偿 miR-142 缺陷并预防和治愈 MPD 转化的治疗方法。我们建议 具体目标 (SA) 如下： SA#1：定义 miR-142 缺陷在 sAML/BC CML 转化中的作用。 SA#2：剖析 miR-142 缺陷导致 sAML/BC CML 的分子机制 转变。 SA#3：研究药代动力学 (PK)、药效学 (PD) 和治疗影响 合成的 CpG-M-miR-142 将挽救 sAML/BC CML 中的 miR-142 缺陷。