PRMT1-mediated FLT3 arginine methylation promotes maintenance of FLT3-ITD+ acute myeloid leukemia

Xin He, Yinghui Zhu, Yi-Chun Lin, Min Li, Juan Du, Haojie Dong, Jie Sun, Lei Zhu, Hanying Wang, Zonghui Ding, Lei Zhang, Lianjun Zhang, Dandan Zhao, Zhihao Wang, Herman Wu, Han Zhang, Wenjuan Jiang, Yang Xu, Jian Jin, Yudao Shen, Jeff Perry, Xinyang Zhao, Bin Zhang, Songbai Liu, Sheng-Li Xue, Binghui Shen, Chun-Wei Chen, Jianjun Chen, Samer Khaled, Ya-Huei Kuo, Guido Marcucci, Yun Luo and Ling Li

Key Points

  • PRMT1 promotes survival and growth of FLT3-ITD+ AML cells through methylating FLT3 protein at arginine residues 972 and 973.

  • PRMT1 inhibition enhances elimination of FLT3-ITD+ AML cells by FLT3 TKI treatment.

There is a Blood Commentary on this article in this issue.


The presence of FMS-like receptor tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukemia (AML) is associated with poor clinical outcome. FLT3 tyrosine kinase inhibitors (TKIs), although effective in kinase ablation, do not eliminate primitive FLT3-ITD+ leukemia cells, which are potential sources of relapse. Thus, understanding the mechanisms underlying FLT3-ITD+ AML cell persistence is essential to devise future AML therapies. Here, we show that expression of protein arginine methyltransferase 1 (PRMT1), the primary type I arginine methyltransferase, is increased significantly in AML cells relative to normal hematopoietic cells. Genome-wide analysis, coimmunoprecipitation assay, and PRMT1-knockout mouse studies indicate that PRMT1 preferentially cooperates with FLT3-ITD, contributing to AML maintenance. Genetic or pharmacological inhibition of PRMT1 markedly blocked FLT3-ITD+ AML cell maintenance. Mechanistically, PRMT1 catalyzed FLT3-ITD protein methylation at arginine 972/973, and PRMT1 promoted leukemia cell growth in an FLT3 methylation–dependent manner. Moreover, the effects of FLT3-ITD methylation in AML cells were partially due to cross talk with FLT3-ITD phosphorylation at tyrosine 969. Importantly, FLT3 methylation persisted in FLT3-ITD+ AML cells following kinase inhibition, indicating that methylation occurs independently of kinase activity. Finally, in patient-derived xenograft and murine AML models, combined administration of AC220 with a type I PRMT inhibitor (MS023) enhanced elimination of FLT3-ITD+ AML cells relative to AC220 treatment alone. Our study demonstrates that PRMT1-mediated FLT3 methylation promotes AML maintenance and suggests that combining PRMT1 inhibition with FLT3 TKI treatment could be a promising approach to eliminate FLT3-ITD+ AML cells.

  • Submitted January 23, 2019.
  • Accepted May 29, 2019.
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