title: Targeting Aberrant Epigenetic Networks Mediated by PRMT1 and KDM4C in Acute Myeloid Leukemia.
abstract: 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.
authors.affiliation: Leukemia and Stem Cell Biology Group, Division of Cancer Studies, Department of Haematological Medicine, King's College London, Denmark Hill Campus, London SE5 9NU, UK.
authors.forename: Ngai
authors.initials: N
authors.lastname: Cheung
authors.affiliation: Leukemia and Stem Cell Biology Group, Division of Cancer Studies, Department of Haematological Medicine, King's College London, Denmark Hill Campus, London SE5 9NU, UK.
authors.forename: Tsz Kan
authors.initials: TK
authors.lastname: Fung
authors.affiliation: Leukemia and Stem Cell Biology Group, Division of Cancer Studies, Department of Haematological Medicine, King's College London, Denmark Hill Campus, London SE5 9NU, UK.
authors.forename: Bernd B
authors.initials: BB
authors.lastname: Zeisig
authors.affiliation: Leukemia and Stem Cell Biology Group, Division of Cancer Studies, Department of Haematological Medicine, King's College London, Denmark Hill Campus, London SE5 9NU, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Holmes
authors.affiliation: Leukemia and Stem Cell Biology Group, Division of Cancer Studies, Department of Haematological Medicine, King's College London, Denmark Hill Campus, London SE5 9NU, UK.
authors.forename: Jayant K
authors.initials: JK
authors.lastname: Rane
authors.affiliation: Department of Chemical Physiology and Immunology & Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Kerri A
authors.initials: KA
authors.lastname: Mowen
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Finn
authors.affiliation: Department of Molecular Sciences, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London and MRC Clinical Sciences Centre, Du Cane Road, London W12 0NN, UK.
authors.forename: Boris
authors.initials: B
authors.lastname: Lenhard
authors.affiliation: Department of Pathology, The University of Hong Kong, Pokfulam Road, Hong Kong.
authors.forename: Li Chong
authors.initials: LC
authors.lastname: Chan
authors.affiliation: Leukemia and Stem Cell Biology Group, Division of Cancer Studies, Department of Haematological Medicine, King's College London, Denmark Hill Campus, London SE5 9NU, UK. Electronic address: eric.so@kcl.ac.uk.
authors.forename: Chi Wai Eric
authors.initials: CW
authors.lastname: So
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics
chemical_list: C413655:KDM4C protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; C544194:Jmjd2c protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; D010089:Oxidoreductases, N-Demethylating; C099988:PRMT1 protein, human; C546338:Prmt1 protein, mouse; D011484:Protein-Arginine N-Methyltransferases
keywords: AML; KDM; KDM4C; KMT; MLL fusions; MOZ-TIF2; PMT; PRMT1; acute myeloid leukemia; histone demethylase; histone methyltransferase; leukemia epigenetics