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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

基本信息

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
项目类别：
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

项目摘要

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，如骨髓增生性肿瘤（MPN）和慢性慢性期（CP）