Advertisement

Targeting PRMT1-Mediated FLT3 Methylation Disrupts Maintenance of MLL- rearranged Acute Lymphoblastic Leukemia

Yinghui Zhu, Xin He, Yi-Chun Lin, Haojie Dong, Lei Zhang, Xianwei Chen, Zhihao Wang, Yudao Shen, Min Li, Hanying Wang, Jie Sun, Le Xuan Nguyen, Han Zhang, Wenjuan Jiang, Yanzhong Yang, Jianjun Chen, Markus Müschen, Chun-Wei Chen, Marina Y. Konopleva, Weili Sun, Jian Jin, Nadia Carlesso, Guido Marcucci, Yun Luo and Ling Li

Key Points

  • PRMT1, FLT3 methylation, MLL-r ALL maintenance

Abstract

Relapse remains the main cause of MLL-r Acute Lymphoblastic Leukemia (ALL) treatment failure due to persistence of drug-resistant clones after conventional chemo-treatment or targeted therapy. Thus defining mechanisms underlying MLL-r ALL maintenance is critical to develop effective therapy. PRMT1, which deposits an asymmetric dimethylarginine (ADMA) mark on histone/non-histone proteins, is reportedly overexpressed in various cancers. Here, we demonstrate elevated PRMT1 levels in MLL-r ALL cells and show that inhibition of PRMT1 significantly suppresses leukemic cell growth and survival. Mechanistically, we reveal that PRMT1 methylates FLT3 at arginine (R) residues 972 and 973, and its oncogenic function in MLL-r ALL cells is FLT3 methylation-dependent. Both biochemistry and computational analysis demonstrate that R972/973 methylation could facilitate recruitment of adaptor proteins to FLT3 in a phospho-tyrosine (Y) residue 969 dependent or independent manner. Cells expressing R972/973 methylation-deficient FLT3 exhibited more robust apoptosis and growth inhibition than did Y969 phosphorylation-deficient FLT3-transduced cells. We also show that the capacity of the type I PRMT inhibitor MS023 to inhibit leukemia cell viability parallels baseline FLT3 R972/973 methylation levels. Finally, combining FLT3 tyrosine kinase inhibitor-PKC412 with MS023 treatment enhanced elimination of MLL-r ALL cells relative to PKC412 treatment alone in patient-derived mouse xenografts (PDXs). These results indicate that abolishing FLT3 arginine methylation through PRMT1 inhibition represents a promising strategy to target MLL-r ALL cells.

  • Submitted July 12, 2019.
  • Revision received August 7, 2019.
  • Accepted July 25, 2019.