2. Academic Validation
  3. Targeting PRMT1-mediated FLT3 methylation disrupts maintenance of MLL-rearranged acute lymphoblastic leukemia

Targeting PRMT1-mediated FLT3 methylation disrupts maintenance of MLL-rearranged acute lymphoblastic leukemia

  • Blood. 2019 Oct 10;134(15):1257-1268. doi: 10.1182/blood.2019002457.
Yinghui Zhu 1,  Xin He 1,  Yi-Chun Lin 2,  Haojie Dong 1,  Lei Zhang 3,  Xianwei Chen 4,  Zhihao Wang 5,  Yudao Shen 6,  Min Li 7,  Hanying Wang 1,  Jie Sun 1,  Le Xuan Nguyen 1,  Han Zhang 2,  Wenjuan Jiang 2,  Yanzhong Yang 5,  Jianjun Chen 8,  Markus Müschen 8,  Chun-Wei Chen 8,  Marina Y Konopleva 9,  Weili Sun 10,  Jian Jin 6,  Nadia Carlesso 1,  Guido Marcucci 1,  Yun Luo 2,  Ling Li 1
Affiliations

Affiliations

  • 1 Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope Medical Center, Duarte, CA.
  • 2 College of Pharmacy, Western University of Health Sciences, Pomona, CA.
  • 3 Translational Biomarker Discovery Core.
  • 4 Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, and.
  • 5 Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope Medical Center, Duarte, CA.
  • 6 Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences and Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
  • 7 Department of Information Sciences, Beckman Research Institute, City of Hope Medical Center, Duarte, CA.
  • 8 Department of Systems Biology and The Gehr Family Center for Leukemia Research, Beckman Research Institute, City of Hope Medical Center, Monrovia, CA.
  • 9 Department of Leukemia, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX; and.
  • 10 Department of Pediatrics, City of Hope Medical Center, Duarte, CA.
PMID: 31395602 DOI: 10.1182/blood.2019002457
Abstract

Relapse remains the main cause of MLL-rearranged (MLL-r) acute lymphoblastic leukemia (ALL) treatment failure resulting from persistence of drug-resistant clones after conventional chemotherapy treatment or targeted therapy. Thus, defining mechanisms underlying MLL-r ALL maintenance is critical for developing effective therapy. PRMT1, which deposits an asymmetric dimethylarginine 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 Fms-like receptor tyrosine kinase 3 (FLT3) at arginine (R) residues 972 and 973 (R972/973), 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 (Y969) 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. These results indicate that abolishing FLT3 arginine methylation through PRMT1 inhibition represents a promising strategy to target MLL-r ALL cells.

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