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|Ref Type||Journal Article|
|Authors||Cheung N, Fung TK, Zeisig BB, Holmes K, Rane JK, Mowen KA, Finn MG, Lenhard B, Chan LC, So CW|
|Title||Targeting Aberrant Epigenetic Networks Mediated by PRMT1 and KDM4C in Acute Myeloid Leukemia.|
|Date||2016 Jan 11|
|Abstract Text||Transcriptional deregulation plays a major role in acute myeloid leukemia, and therefore identification of epigenetic modifying enzymes essential for the maintenance of oncogenic transcription programs holds the key to better understanding of the biology and designing effective therapeutic strategies for the disease. Here we provide experimental evidence for the functional involvement and therapeutic potential of targeting PRMT1, an H4R3 methyltransferase, in various MLL and non-MLL leukemias. PRMT1 is necessary but not sufficient for leukemic transformation, which requires co-recruitment of KDM4C, an H3K9 demethylase, by chimeric transcription factors to mediate epigenetic reprogramming. Pharmacological inhibition of KDM4C/PRMT1 suppresses transcription and transformation ability of MLL fusions and MOZ-TIF2, revealing a tractable aberrant epigenetic circuitry mediated by KDM4C and PRMT1 in acute leukemia.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|AMI-408||AMI-408 inhibits PRMT1, potentially resulting in decreased tumor cell growth (PMID: 26766589).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|KMT2A GAS7||KMT2A - GAS7||fusion||gain of function||KMT2A-GAS7 results from the fusion of KMT2A and GAS7, and leads to activation of downstream targets and transformation of cells in culture, and induces leukemia in mouse models (PMID: 26766589, PMID: 12620410). KMT2A-GAS7 has been identified in acute myeloid leukemia (PMID: 10706619) and B-cell acute lymphoblastic leukemia (PMID: 16956839).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|KMT2A - GAS7||leukemia||sensitive||AMI-408||Preclinical - Cell line xenograft||Actionable||In a preclinical study, treatment with AMI-408 decreased growth of leukemia cells expressing KMT2A-GAS7 (MLL-GAS7) in culture, and increased survival in xenograft models (PMID: 26766589).||26766589|