Skip to Content
MilliporeSigma
  • Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML.

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

Leukemia (2017-07-01)
S Kaushik, F Liu, K J Veazey, G Gao, P Das, L F Neves, K Lin, Y Zhong, Y Lu, V Giuliani, M T Bedford, S D Nimer, M A Santos
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-trimethyl-Histone H3 (Lys4) Antibody, clone MC315, rabbit monoclonal, culture supernatant, clone MC315, Upstate®
Sigma-Aldrich
Anti-trimethyl-Histone H3 (Lys27) Antibody, Upstate®, from rabbit
Sigma-Aldrich
Anti-β-Actin antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture
Sigma-Aldrich
Normal Rabbit IgG, Normal Rabbit IgG Polyclonal Antibody control validated for use in Immunoprecipitation & Western Blotting.