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.