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

慢性克隆性血液疾病，如骨髓增生性肿瘤(MPN)和慢性期(CP) 随着时间的推移，髓系白血病可分别转化为继发性(S)急性髓系白血病 急性髓细胞白血病(AML)和急性髓细胞白血病(BC)，对目前可用的治疗反应较差，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得到满足的问题 对这些病人的需求。 MicroRNAs(MiRNAs)是一种小的非编码RNA，以信使RNA为靶标，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，参与髓系、淋巴系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/或表达下调。 此外，miR-142基因敲除(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)减少，造血量减少。 我们最近证明miR-142 KO在克隆性骨髓增殖性疾病(MPDS； 即Flt3-ITD+MPN或CP CML)促使转化为AML样疾病，并显著 这些动物的生存时间更短。我们的数据支持miR-142缺陷在解除对 克隆性造血干细胞(HSCs)，通过基因转换为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性HSCs的转化中起关键作用 转化为白血病干细胞(LSC)。我们证明了用一种新的miR-142模拟物来挽救miR-142缺陷 化合物(CpG-M-miR-142)降低LSCOXPhos水平和存活率，降低LSC负荷和活性 延长经治疗的BC慢性粒细胞白血病小鼠的存活时间。因此，这一提议的中心假设是 了解miR-142下调的细胞和分子基础及其对细胞的影响 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的 弥补miR-142缺陷和防治MPD转化的治疗。我们建议 以下特定目标(SA)：SA#1：定义miR-142缺陷在SAML/BC CML转换中的作用。 SA#2：剖析miR-142缺陷导致SAML/BC CML的分子机制 转型。SA#3：研究其药代动力学(PK)、药效学(PD)和疗效 一种合成的CpG-M-miR-142将挽救SAML/BC CML中miR-142的缺陷。

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.