Targeting Aberrant Epigenetic Networks Mediated by PRMT1 and KDM4C in Acute Myeloid Leukemia

Publication date: 11 January 2016
Source:Cancer Cell, Volume 29, Issue 1
Author(s): Ngai Cheung, Tsz Kan Fung, Bernd B. Zeisig, Katie Holmes, Jayant K. Rane, Kerri A. Mowen, Michael G. Finn, Boris Lenhard, Li Chong Chan, Chi Wai Eric So
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.

Graphical abstract

Teaser

Cheung et al. show that PRMT1 is necessary but insufficient for acute myeloid leukemia induction by chimeric transcription factors, which also recruit KDM4C for epigenetic reprogramming. Pharmacological inhibition of KDM4C/PRMT1 suppresses transcription and transformation abilities of the MOZ-TIF2 and MLL fusions.


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