Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML

S. Kaushik, Fan Liu, K. J. Veazey, G. Gao, P. Das, L. F. Neves, K. Lin, Y. Zhong, Y. Lu, V. Giuliani, M. T. Bedford, Stephen D Nimer, M. A. Santos

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

The hematological malignancies classified as mixed lineage leukemias (MLL) harbor fusions of the MLL1 gene to partners that are members of transcriptional elongation complexes. MLL-rearranged leukemias are associated with extremely poor prognosis, and response to conventional therapies and efforts to identify molecular targets are urgently needed. Using mouse models of MLL-rearranged acute myeloid leukemia, here we show that genetic inactivation or small-molecule inhibition of the protein arginine methyltransferase PRMT5 exhibit anti-tumoral activity in MLL-fusion protein-driven transformation. Genome-wide transcriptional analysis revealed that inhibition of PRMT5 methyltransferase activity overrides the differentiation block in leukemia cells without affecting the expression of MLL-fusion direct oncogenic targets. Furthermore, we find that this differentiation block is mediated by transcriptional silencing of the cyclin-dependent kinase inhibitor p21 (CDKN1a) gene in leukemia cells. Our study provides pre-clinical rationale for targeting PRMT5 using small-molecule inhibitors in the treatment of leukemias harboring MLL rearrangements.

Original languageEnglish (US)
Pages (from-to)499-509
Number of pages11
JournalLeukemia
Volume32
Issue number2
DOIs
StatePublished - Feb 1 2018

    Fingerprint

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Kaushik, S., Liu, F., Veazey, K. J., Gao, G., Das, P., Neves, L. F., Lin, K., Zhong, Y., Lu, Y., Giuliani, V., Bedford, M. T., Nimer, S. D., & Santos, M. A. (2018). Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. Leukemia, 32(2), 499-509. https://doi.org/10.1038/leu.2017.206