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

Yinghui Zhu1, Xin He1, Yi-Chun Lin2

  • 1Department 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.

Blood
|August 10, 2019
PubMed

Insights

Targeting PRMT1, an enzyme overexpressed in MLL-rearranged (MLL-r) acute lymphoblastic leukemia (ALL), inhibits leukemic cell growth. PRMT1 methylation of FLT3 is crucial for MLL-r ALL survival, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Relapse in MLL-rearranged (MLL-r) acute lymphoblastic leukemia (ALL) is driven by drug-resistant clones.
  • Protein arginine methyltransferase 1 (PRMT1) is overexpressed in cancers and deposits asymmetric dimethylarginine marks.

Purpose of the Study:

  • To investigate the role of PRMT1 in MLL-r ALL maintenance and therapeutic potential.
  • To elucidate the mechanism of PRMT1 action in MLL-r ALL, focusing on Fms-like receptor tyrosine kinase 3 (FLT3).

Main Methods:

  • Assessed PRMT1 levels in MLL-r ALL cells.
  • Investigated the effect of PRMT1 inhibition on leukemic cell growth and survival.
  • Utilized biochemical and computational analyses to study PRMT1-mediated FLT3 methylation at R972/973.
  • Examined the impact of FLT3 methylation-deficient mutants on apoptosis and growth inhibition.
  • Evaluated the combination therapy of a PRMT1 inhibitor (MS023) and a FLT3 inhibitor (PKC412) in patient-derived mouse xenografts.

Main Results:

  • PRMT1 is elevated in MLL-r ALL cells, and its inhibition suppresses leukemic cell growth.
  • PRMT1 methylates FLT3 at R972/973, which is critical for MLL-r ALL oncogenic function.
  • FLT3 R972/973 methylation facilitates adaptor protein recruitment, impacting cell survival.
  • Cells with methylation-deficient FLT3 showed increased apoptosis and growth inhibition compared to phosphorylation-deficient mutants.
  • Combined treatment with MS023 and PKC412 enhanced MLL-r ALL cell elimination in vivo.

Conclusions:

  • PRMT1 plays a critical role in MLL-r ALL pathogenesis by methylating FLT3.
  • Targeting PRMT1-mediated FLT3 arginine methylation is a promising therapeutic strategy for MLL-r ALL.
  • Combination therapy with PRMT1 and FLT3 inhibitors may overcome treatment resistance in MLL-r ALL.

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