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Principal Investigator: GUIDO MARCUCCI
Organization: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
Fiscal Year: 2024
Award: $515,745
Funding agency: National Cancer Institute
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.
Terms: <AML - Acute Myeloid Leukemia><Aberrant Chromosome><Active Oxygen><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Address><Allogenic><Animals><Autoregulation><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Behavior><Blast Crisis><Blast Phase><Blast Phase CML><Blast Phase Chronic Granulocytic Leukemia><Blast Phase Chronic Myelocytic Leukemia><Blast Phase Chronic Myelogenous Leukemia><Blast Phase Chronic Myeloid Leukemia><Blastic Phase CML><Blastic Phase Chronic Granulocytic Leukemia><Blastic Phase Chronic Myelocytic Leukemia><Blastic Phase Chronic Myelogenous Leukemia><Blastic Phase Chronic Myeloid Leukemia><Blood Diseases><Blood Precursor Cell><Blood Vessels><Blood megakaryocyte><Bone Marrow><Bone Marrow Fibrosis><Bone Marrow Reticuloendothelial System><Bone marrow failure><Brachydanio rerio><CD31><Cancers><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Respiration><Cell Survival><Cell Viability><Cells><Cellular Respiration><Chromosomal Aberrations><Chromosomal Abnormalities><Chromosomal Alterations><Chromosomal, Gene, or Protein Abnormality><Chromosome Aberrations><Chromosome Alterations><Chromosome Anomalies><Chromosome abnormality><Chronic><Chronic Granulocytic Leukemia><Chronic Myelocytic Leukemia><Chronic Myelogenous Leukemia><Chronic Myeloid Leukemia><Chronic Phase><Chronic Phase CML><Chronic Phase Chronic Granulocytic Leukemia><Chronic Phase Chronic Myelocytic Leukemia><Chronic-Phase Myelogenous Leukemia><Chronic-Phase Myeloid Leukemia><Clinical><Clinical Trials><Clonal Evolution><Clonal Hematopoietic Stem Cell><Compensation><Cytogenetic Aberrations><Cytogenetic Abnormalities><Cytogenetic or Molecular Genetic Abnormality><Danio rerio><Data><Development><Disease><Disorder><Dose><Down-Regulation><Drug Kinetics><Drugs><Dysmyelopoietic Syndromes><Endothelial Cells><Enlarged Spleen><Ensure><Erythremia><Erythroid><Essential Thrombocytemia><Essential Thrombocythemia><Essential Thrombocytosis><Exclusion><Experimental Designs><FLK2><FLT3><FLT3 gene><FMS-like tyrosine kinase 3><Fms-Related Tyrosine Kinase 3><Functional RNA><Gene Expression><Genetic Abnormality><Genetic Alteration><Genetic Change><Genetic defect><Germinoblastic Sarcoma><Germinoblastoma><Goals><Granulocytic Leukemia, Chronic, Stable-Phase><Hematologic Diseases><Hematological Disease><Hematological Disorder><Hematopoiesis><Hematopoietic><Hematopoietic Cell Tumor><Hematopoietic Cellular Control Mechanisms><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Progenitor Cells><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Hematopoietic stem cells><Hemorrhagic Thrombocythemia><Homeostasis><Human><Idiopathic Thrombocythemia><Impairment><In Vitro><Institution><Intermediary Metabolism><Knock-out><Knockout><Leukemia, Granulocytic, Chronic-Phase><Leukemic progenitor and stem cell><Lymphoid><Lymphoma><Malignant Hematopoietic Neoplasm><Malignant Lymphoma><Malignant Neoplasms><Malignant Tumor><Medication><Megakaryocytes><Megalokaryocyte><Messenger RNA><Metabolic Processes><Metabolism><Mice><Mice Mammals><Micro RNA><MicroRNAs><Mitochondria><Modern Man><Molecular><Molecular Abnormality><Mononuclear><Murine><Mus><Mutate><Mutation><Myelodysplastic Disease><Myelodysplastic Syndromes><Myelodysplastic/Myeloproliferative Disease><Myelodysplastic/myeloproliferative neoplasm><Myelofibrosis><Myelogenous><Myelogenous Leukemia, Chronic, Chronic-Phase><Myeloid><Myeloid Disease><Myeloid Leukemia, Chronic, Chronic-Phase><Myeloid Leukemia, Chronic, Stable-Phase><Myeloid Malignancy><Myeloid Neoplasm><Myeloid Tumor><Myeloproliferative Disorders><Myeloproliferative Tumors><Myeloproliferative disease><Myeloproliferative/Myelodysplastic Disorders><Myeloproliferative/Myelodysplastic Syndromes><Myelosclerosis><Names><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Osler-Vaquez Disease><Output><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxygen Radicals><PECAM1><PECAM1 gene><Pathogenesis><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peripheral><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Physiological Homeostasis><Play><Polycythemia Rubra Vera><Polycythemia Vera><Primary Thrombocythemia><Primary Thrombocytosis><Pro-Oxidants><Progenitor Cell Transplantation><Progenitor Cells><Prognosis><Proteins><Reactive Oxygen Species><Refractory Anemia with an Excess of Blasts><Refractory anaemia with excess blasts><Reporting><Reticulolymphosarcoma><Risk><Role><STK-1 kinase><STK1><Safety><Sampling><Schedule><Secondary acute myeloid leukemia><Secondary to><Smoldering Leukemia><Splenomegaly><Stable-Phase Myeloid Leukemia><Stem Cell Transplantation><Stem Cell Tyrosine Kinase 1><Stem Cell like><Stem cell transplant><T-Cells><T-Lymphocyte><Testing><Therapeutic><Time><Untranslated RNA><Zebra Danio><Zebra Fish><Zebrafish><acute granulocytic leukemia><acute granulocytic leukemia cell><acute myeloblastic leukemia cell><acute myelocytic leukemia cell><acute myelogenous leukemia cell><acute myeloid leukemia><acute myeloid leukemia cell><acute nonlymphocytic leukemia cell><aerobic metabolism><aerobic respiration><arteriole><blood cancer><blood cell formation><blood cell progenitor><blood disorder><blood progenitor><blood stem cell><blood-forming stem cell><cancer of blood><cancer of the blood><cellular differentiation><chromosomal defect><chromosome defect><chronic myelogenous leukemia cell><chronic myeloid leukemia cell><clone hematopoietic stem cell><density><design><designing><developmental><drug/agent><effective therapy><effective treatment><fatty acid oxidation><fetal liver kinase-2><fetal liver kinase-3><gene conservation><genome mutation><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><in vivo><knock-down><knockdown><leukemia><leukemic progenitor><leukemic stem cell><leukemic transformation><mRNA><malignancy><manufacture><miRNA><miRNAs><mitochondrial><molecular aberrations><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mouse model><murine model><myelodysplasia><myeloproliferative neoplasm><name><named><naming><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><noncoding><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oxidative metabolism><patient oriented outcomes><precursor cell><prevent><preventing><progenitor><progenitor transplantation><prognostic><programs><risk stratification><sAML><secondary AML><self-renew><self-renewal><social role><stem and progenitor cell transplantations><stem cell characteristics><stem cells><stemness><stratify risk><therapeutically effective><thymus derived lymphocyte><vascular>