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

Blood
Yinghui ZhuLing Li

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 tha...Continue Reading

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Citations

Aug 9, 2020·Clinical Science·Chunyun Zhang, Shougang Zhuang
Aug 30, 2020·Journal of Experimental & Clinical Cancer Research : CR·Cheng YangLihui Wang
Oct 29, 2020·Archives of Medical Research·Jorge Vela-OjedaElba Reyes-Maldonado
Jan 8, 2021·ACS Chemical Biology·Roberto Di BlasiHarry J Whitwell
May 8, 2020·Current Protein & Peptide Science·Ayad A Al-HamashiRong Huang

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