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Ref Type Journal Article
PMID (26766589)
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.
Journal Cancer cell
Vol 29
Issue 1
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.


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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