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.

慢性克隆血液疾病，例如骨髓增生性肿瘤（MPN）和慢性期（CP）慢性 随着时间的流逝，脊髓性白血病（CML）可能分别转化为次级急性髓样白血病 （AML）和爆炸危机（BC）CML，对当前可用疗法的反应不佳，包括 同种异体干细胞移植。那就是，新颖和更有效的治疗的可用性是真正的未经 这些患者的需求。 MicroRNA（miRNA）是针对Messenger RNA并调节相应的小型非编码RNA 蛋白质水平。编码miR-142的miR142是一种高度保守的“基因”，在高水平中表示 造血细胞，参与髓样，淋巴样和巨核细胞的发育和功能 红细胞祖细胞。 MIR142已被发现在淋巴瘤和AML中突变和/或下调。 此外，miR-142敲除（KO）导致斑马鱼和小鼠造血受损，并扩张 造血干和祖细胞（HSPC）和改善造血输出。 我们最近证明了具有克隆骨髓增生性疾病的小鼠模型中的miR-142 KO（MPDS； 即，FLT3-ITD+ MPN或CP CML）提示转化为AML样疾病，并明显地承认 这些动物的生存更短。我们的数据支持miR-142防御在放松管制的作用中的作用 克隆造血干细胞（HSC），通过转向更高水平的氧化磷酸化（Oxphos）通过 脂肪酸氧化增加（FAO）；这些变化可能在克隆HSC的转换中起关键作用 进入白血病干细胞（LSC）。我们证明了用新颖的mir-142模仿的mir-142防御拯救mir-142防御 化合物（CPG-M-MIR-142）降低了LSC的Oxphos水平和活力，LSC燃烧和活性降低 并长时间的BC CML小鼠生存。那就是这一提议的核心假设是 了解miR-142下调的细胞和分子基础及其对其对 克隆MPD转化为侵略性AML样疾病将使我们能够设计和优化新颖 治疗以补偿miR-142赤字，预防和治愈MPD转化。我们建议 以下特定目的（SAS）：SA＃1：定义miR-142防御在SAML/BC CML转换中的作用。 SA＃2：剖析miR-142定义有助于SAML/BC CML的分子机制 转型。 SA＃3：研究药代动力学（PK），药效学（PD）和治疗效果 合成的CPG-M-MIR-142，该合成将在SAML/BC CML中挽救miR-142防御。