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Leukemia (2016) 30, 789799 2016 Macmillan Publishers Limited All rights reserved 0887-6924/16
http://www.nature.com/leu
Web End =www.nature.com/leu
ORIGINAL ARTICLE
The dual epigenetic role of PRMT5 in acute myeloid leukemia: gene activation and repression via histone arginine methylation
SS Tarighat1, R Santhanam2, D Frankhouser2, HS Radomska2, H Lai3, M Anghelina2, H Wang2, X Huang1, L Alinari2, A Walker2, MA Caligiuri2, CM Croce4, L Li5, R Garzon2, C Li3,6, RA Baiocchi2,6 and G Marcucci5,6
Changes in the enzymatic activity of protein arginine methyltransferase (PRMT) 5 have been associated with cancer; however, the proteins role in acute myeloid leukemia (AML) has not been fully evaluated. Here, we show that increased PRMT5 activity enhanced AML growth in vitro and in vivo while PRMT5 downregulation reduced it. In AML cells, PRMT5 interacted with Sp1 in a transcription repressor complex and silenced miR-29b preferentially via dimethylation of histone 4 arginine residue H4R3. As Sp1 is also a bona de target of miR-29b, the miR silencing resulted in increased Sp1. This event in turn led to transcription activation of FLT3, a gene that encodes a receptor tyrosine kinase. Inhibition of PRMT5 via sh/siRNA or a rst-in-class small-molecule inhibitor (HLCL-61) resulted in signicantly increased expression of miR-29b and consequent suppression of Sp1 and FLT3 in AML cells. As a result, signicant antileukemic activity was achieved. Collectively, our data support a novel leukemogenic mechanism in AML where PRMT5 mediates both silencing and transcription of genes that participate in a yin-yang functional network supporting leukemia growth. As FLT3 is often mutated in AML and pharmacologic inhibition of PRMT5 appears feasible, the PRMT5miR-29bFLT3
network should be further explored as a novel therapeutic target for AML.
Leukemia (2016) 30, 789799; doi:http://dx.doi.org/10.1038/leu.2015.308
Web End =10.1038/leu.2015.308
INTRODUCTIONAcute myeloid leukemia (AML) is the most common type of acute leukemia in adults.13 The incidence and mortality rate associated with AML increase with age, and the long-term overall survival achieved by younger (o60 years) and older (60 years) AML patients is ~ 3040 and o10%, respectively.2,4 The highly
heterogeneous nature of this disease (cytogenetically and clinically) complicates treatment and further highlights the signicance of using biomarkers for risk-stratication and treatment guidance.5,6
Aberrant activity of epigenetic modiers, which has been shown to play an important role in malignant transformation, represents a novel class of...