Abstract
SummaryTranscriptional 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.
Highlights
Human leukemia is characterized by the prevalence of recurrent chromosomal translocations, resulting in the generation of chimeric fusion proteins with aberrant oncogenic activities (Look, 1997)
With the exception of acute promyelocytic leukemia (APL) for which targeted therapy has been developed, transforming it from a highly fatal disease to a manageable condition (Arteaga et al, 2015; Wang and Chen, 2008), all acute myeloid leukemia (AML) patients still receive the same chemotherapy treatment developed more than half a century ago, which only induces long-term complete remission in less than 40% of young patients and is generally too toxic to use in patients aged older than 60 years (Zeisig et al, 2012)
Identification of Prmt1-Dependent Leukemia Fusion Proteins To define the functional involvement of Prmt1 in leukemias, we performed a systematic functional screen by retroviral transduction and transformation assay (RTTA) using validated Prmt1 small hairpin RNAs on more than ten different MLL and non-MLL oncogenic transcription factors
Summary
Human leukemia is characterized by the prevalence of recurrent chromosomal translocations, resulting in the generation of chimeric fusion proteins with aberrant oncogenic activities (Look, 1997). There has been very little progress in targeting classically intractable oncogenic transcription factors, which are the common drivers for many other malignancies including acute myeloid leukemia (AML) (Zeisig et al, 2012). In contrast to kinases that already have functional enzymatic activities, transcription factors need to work in tandem with other co-factors to orchestrate an array of epigenetic modifications for regulating gene expression. Among these factors are protein methyltransferases (PMTs), consisting of lysine methyltransferases (KMTs) and arginine methyltransferases (PRMTs), which have recently taken the center stage as key players in Significance
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