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Related Concept Videos

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Abnormal Proliferation

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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
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The nucleolus is the most prominent substructure of the nucleus. When it was first discovered, it was considered to be an isolated organelle that forms fibrils and granules. In 1931, the relationship between the nucleolus and chromosomes was first described by Heitz. He observed that the appearance and size of nucleolus varies depending on the stage of the cell cycle. He also noticed constricted regions on different chromosomes clustered together at definite cell cycle stages. These regions,...
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Biosynthesis of Nucleic Acids01:28

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Nucleic acid biosynthesis is a fundamental biochemical process that produces the purine and pyrimidine nucleotides essential for DNA and RNA synthesis. This pathway maintains a balanced nucleotide pool, preventing imbalances that could jeopardize genetic integrity and cellular function. Given the crucial role of nucleotides, their synthesis is tightly regulated to ensure proper cellular homeostasis.Purine BiosynthesisThe biosynthesis of purine nucleotides begins with ribose-5-phosphate, a...
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The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
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Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
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DNMT3A mutation promotes leukemia development through NAM-NAD metabolic reprogramming.

Xuejiao Yang1, Xiao Wang1, Ying Yang1

  • 1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Journal of Translational Medicine
|July 18, 2023
PubMed
Summary

Mutations in DNMT3A drive acute myeloid leukemia (AML) by upregulating NAMPT, disrupting NAD metabolism and accelerating cell cycles. Targeting NAMPT offers a potential metabolic therapy for AML with DNMT3A mutations.

Keywords:
AMLDNMT3A mutationMetabolic reprogrammingNAM-NAD metabolismNAMPT

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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Reprogramming

Background:

  • DNA methyltransferase 3A (DNMT3A) mutations, particularly Arg882His (R882H), are common in acute myeloid leukemia (AML).
  • DNMT3A mutations are implicated in leukemogenesis via hypomethylation of genes controlling cell growth and differentiation.
  • This study investigates the role of DNMT3A R882H in AML progression through metabolic reprogramming.

Purpose of the Study:

  • To elucidate the function of DNMT3A R882H in AML malignant progression.
  • To investigate the link between DNMT3A mutation and metabolic reprogramming in AML.
  • To explore NAMPT as a potential therapeutic target in AML with DNMT3A mutations.

Main Methods:

  • Utilized UHPLC-HRMS/MS for serum metabolite analysis in mice with Dnmt3a mutations.
  • Employed MeDIP-seq and RNA-seq for DNA methylation and gene expression profiling in mouse bone marrow cells.
  • Analyzed human TCGA and GO databases, performed co-immunoprecipitation, immunoblotting, and flow cytometry.
  • Evaluated NAMPT inhibition efficacy in vivo using a mouse model of AML.

Main Results:

  • DNMT3A mutation led to increased NAMPT expression via DNA hypomethylation, altering NAM-NAD metabolism and accelerating cell cycle progression.
  • Inhibition of NAMPT reduced Cyclin-CDK binding, enhanced CDK inhibitor interactions, and demonstrated higher sensitivity in NAMPT-overexpressing cells.
  • Targeting NAMPT significantly improved survival and reduced tumor cell infiltration in vivo.

Conclusions:

  • DNMT3A mutations promote NAMPT overexpression, reprogramming NAM-NAD metabolism and driving abnormal proliferation in AML.
  • This metabolic reprogramming presents a potential therapeutic strategy for AML patients with DNMT3A mutations.
  • Targeting NAMPT offers a promising metabolic approach for AML treatment.