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

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.

Jmjd2/Kdm4 demethylases are required for expression ofIl3raand survival of acute myeloid leukemia cells

“…4B). Although the phenotype that we observed upon Jmjd2/Kdm4 depletion was not dependent on deregulated Hoxa9 and Meis1 transcription, Jmjd2c was found to bind to the promoter of Meis1 and Hoxa9, in agreement with Cheung et al (2016) (Supplemental Fig. 3A,B).…”

“…This is underscored by the fact that coexpression of Hoxa9 and Meis1 is sufficient to induce transformation of GMPs (Kroon et al 1998;Wang et al 2010). In a recent study published while this work was in preparation, it was reported that Jmjd2c binds to MLL-AF9 and is an essential cofactor for the transcriptional activation of Hoxa9 and Meis1 during leukemic transformation (Cheung et al 2016). According to this study, Jmjd2c is recruited to the TSSs of Hoxa9 and Meis1, where it can demethylate H3K9me3 (Cheung et al 2016).…”

“…In a recent study published while this work was in preparation, it was reported that Jmjd2c binds to MLL-AF9 and is an essential cofactor for the transcriptional activation of Hoxa9 and Meis1 during leukemic transformation (Cheung et al 2016). According to this study, Jmjd2c is recruited to the TSSs of Hoxa9 and Meis1, where it can demethylate H3K9me3 (Cheung et al 2016). Additionally, it was reported that Jmjd2c alone is required for leukemic transformation by MLL-AF9 (Cheung et al 2016), a conclusion that contrasts with our data showing that deletion of Jmjd2c alone has no effect on leukemic transformation, while only the simultaneous deletion of Jmjd2a, Jmjd2b, and Jmjd2c results in attenuation of leukemic growth.…”

“…According to this study, Jmjd2c is recruited to the TSSs of Hoxa9 and Meis1, where it can demethylate H3K9me3 (Cheung et al 2016). Additionally, it was reported that Jmjd2c alone is required for leukemic transformation by MLL-AF9 (Cheung et al 2016), a conclusion that contrasts with our data showing that deletion of Jmjd2c alone has no effect on leukemic transformation, while only the simultaneous deletion of Jmjd2a, Jmjd2b, and Jmjd2c results in attenuation of leukemic growth. To understand whether transcription of Hoxa9 and Meis1 was affected upon genetic inactivation of Jmjd2a, Jmjd2b, and Jmjd2c, we performed RT-qPCR analysis on L-MA9-2c and L-MA9-2abc cells.…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…For example, PRMT1 is necessary for leukemic transformation, which requires co-recruitment of KDM4C, an H3K9 demethylase. 75,104 Lysine demethylases Histone methylation is also dynamically controlled by histone/ protein lysine demethylases (KDMs), enzymes that remove the methyl group(s) from a methylated lysine side chain (Fig. 1).…”