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Molecular targets for therapy

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

Leukemia volume 32, pages 499–509 (2018)Cite this article

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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.

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Acknowledgements

We thank all members of the MA Santos’s laboratory; we thank Na Man from SD Nimer lab for all the technical help; P Jones for discussions, P Whitney for flow cytometry; C Perez for imaging; P Huskey and all members of the Smithville animal facility for animal care; L Coletta for RNA-seq; and J Zuber for MLL-ENL/NrasG12D cells. RASF-Smithville, Laboratory Animal Genetic Services, RHPI—Pathology and Imaging Services were supported by NIH CA16672; the Science Park NGS core by CPRIT RP120348. This work was supported by an American Cancer Society Institutional Research Grant to FL and a CPRIT Recruitment of First-time Tenure-Track Faculty Award (RR150039), a Sidney Kimmel Foundation—Kimmel Scholar Award (SKF-16–061) and a NCI Cancer Center Support Grant (CCSG) New Faculty Award to MAS.

Author contributions

SK, FL, KV, VG, MTB, SDN and MAS participated in the study design. SK, FL, GG, PD and LN performed mouse breeding, hematopoietic stem cell analysis, transplantation and leukemia experiments, and analyzed data. KV led all the ChIP experiments and analyzed data. KL, YZ and YL performed computational experiments. SK, FL, SDN and MAS wrote the manuscript and all authors reviewed it. MAS supervised the project.

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Author notes

  1. S Kaushik and F Liu: These authors contributed equally to this work.

  2. S D Nimer and M A Santos: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S Kaushik, K J Veazey, G Gao, P Das, L F Neves, K Lin, Y Zhong, Y Lu, M T Bedford & M A Santos

  2. Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA

    F Liu & S D Nimer

  3. Center for Cancer Epigenetics, Houston, TX, USA

    K Lin, Y Zhong, Y Lu, M T Bedford & M A Santos

  4. Institute for Applied Cancer Science/Center for Co-clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    V Giuliani

  5. Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA

    S D Nimer

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  1. S Kaushik
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Kaushik, S., Liu, F., Veazey, K. et al. Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. Leukemia 32, 499–509 (2018). https://doi.org/10.1038/leu.2017.206

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