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: 10367856
• 负责人: GUIDO MARCUCCI
• 金额: $ 54.29万
• 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/10367856
• 关键词: Acute Myelocytic Leukemia; Address; Allogenic; Animals; B-Lymphocytes; Behavior; Blast Phase; Blood Vessels; Bone Marrow; Bone marrow failure; Cell Compartmentation; 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; Data; Development; Disease; Dose; Down-Regulation; Drug Kinetics; Dysmyelopoietic Syndromes; Endothelial Cells; Ensure; Erythroid; Experimental Designs; FLT3 gene; Gene Expression; Genes; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Hemorrhagic Thrombocythemia; Homeostasis; Human; Impairment; In Vitro; Institution; Knock-out; Lead; 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; 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; Therapeutic; Time; Untranslated RNA; Zebrafish; acute myeloid leukemia cell; arteriole; base; chronic myeloid leukemia cell; density; design; drug testing; effective therapy; fatty acid oxidation; in vivo; knock-down; leukemia; leukemic stem cell; leukemic transformation; 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.

慢性克隆性血液病，如骨髓增生性肿瘤（MPN）和慢性期（CP）慢性 骨髓性白血病（CML）可能随着时间的推移分别转化为继发性急性骨髓性白血病 (AML)和急变期（BC）CML，这些疾病对目前可用的治疗反应不良，包括 异基因干细胞移植因此，新的和更有效的治疗方法的可用性是一个真正的未满足 需要这些患者。 microRNAs（miRNAs）是一类以信使RNA为靶点的非编码小分子RNA， 蛋白质水平MIR142编码miR-142，是一种高度保守的"基因"，在大肠杆菌中高水平表达。 造血细胞，并参与骨髓，淋巴和巨核细胞的发育和功能， 红系祖细胞已经发现MIR142在淋巴瘤和AML中突变和/或下调。 此外，miR-142敲除（KO）导致斑马鱼和小鼠的造血功能受损， 造血干细胞和祖细胞（HSPC）和减少的造血输出。 我们最近证明，miR-142 KO在克隆性骨髓增生性疾病（MPD; 也就是说，FLT3-ITD + MPN或CP CML）促使转化为AML样疾病，并赋予显著的免疫应答。 这些动物的生存时间更短。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），通过氧化磷酸化（OxPhos）转换到更高水平， 增加脂肪酸氧化（FAO）;这些变化可能在克隆HSC的转化中起关键作用 白血病干细胞（LSC）。我们证明了用一种新的miR-142模拟物拯救miR-142缺陷， 化合物（CpG-M-miR-142）降低LSC的OxPhos水平和活力，降低LSC负荷和活性， 并且延长了治疗的BC CML小鼠的存活。因此，这一建议的核心假设是， 了解miR-142下调的细胞和分子基础及其对 克隆MPD转化为侵袭性AML样疾病将使我们能够设计和优化新的 治疗以补偿miR-142缺陷并预防和治愈MPD转化。我们建议 SA#1：确定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 转型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将拯救sAML/BC CML中的miR-142缺陷。