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

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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

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Leukemia
Myeloid-Lymphoid Leukemia Protein
Protein-Arginine N-Methyltransferases
Cyclin-Dependent Kinase Inhibitor p21
human PRMT2 protein
Gene Fusion
Methyltransferases
Hematologic Neoplasms
Acute Myeloid Leukemia
Genome
Genes

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. / Kaushik, S.; Liu, Fan; Veazey, K. J.; Gao, G.; Das, P.; Neves, L. F.; Lin, K.; Zhong, Y.; Lu, Y.; Giuliani, V.; Bedford, M. T.; Nimer, Stephen D; Santos, M. A.

In: Leukemia, Vol. 32, No. 2, 01.02.2018, p. 499-509.

Research output: Contribution to journalArticle

Kaushik, S, Liu, F, Veazey, KJ, Gao, G, Das, P, Neves, LF, Lin, K, Zhong, Y, Lu, Y, Giuliani, V, Bedford, MT, Nimer, SD & Santos, MA 2018, 'Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML', Leukemia, vol. 32, no. 2, pp. 499-509. https://doi.org/10.1038/leu.2017.206
Kaushik, S. ; Liu, Fan ; Veazey, K. J. ; Gao, G. ; Das, P. ; Neves, L. F. ; Lin, K. ; Zhong, Y. ; Lu, Y. ; Giuliani, V. ; Bedford, M. T. ; Nimer, Stephen D ; Santos, M. A. / Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. In: Leukemia. 2018 ; Vol. 32, No. 2. pp. 499-509.
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