PRMT4 blocks myeloid differentiation by assembling a Methyl-RUNX1-dependent repressor complex

Ly P. Vu, Fabiana Perna, Lan Wang, Francesca Voza, Maria E. Figueroa, Paul Tempst, Hediye Erdjument-Bromage, Rui Gao, Sisi Chen, Elisabeth Paietta, Tony Deblasio, Ari Melnick, Yan Liu, Xinyang Zhao, Stephen D. Nimer

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Defining the role of epigenetic regulators in hematopoiesis has become critically important, because recurrent mutations or aberrant expression of these genes has been identified in both myeloid and lymphoid hematological malignancies. We found that PRMT4, a type I arginine methyltransferase whose function in normal and malignant hematopoiesis is unknown, is overexpressed in acute myelogenous leukemia patient samples. Overexpression of PRMT4 blocks the myeloid differentiation of human stem/progenitor cells (HSPCs), whereas its knockdown is sufficient to induce myeloid differentiation of HSPCs. We demonstrated that PRMT4 represses the expression of miR-223 in HSPCs via the methylation of RUNX1, which triggers the assembly of a multiprotein repressor complex that includes DPF2. As part of the feedback loop, PRMT4 expression is repressed posttranscriptionally by miR-223. Depletion of PRMT4 results in differentiation of myeloid leukemia cells invitro and their decreased proliferation invivo. Thus, targeting PRMT4 holds potential as a novel therapy for acute myelogenous leukemia.

Original languageEnglish (US)
Pages (from-to)1625-1638
Number of pages14
JournalCell Reports
Volume5
Issue number6
DOIs
StatePublished - Dec 26 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Vu, L. P., Perna, F., Wang, L., Voza, F., Figueroa, M. E., Tempst, P., Erdjument-Bromage, H., Gao, R., Chen, S., Paietta, E., Deblasio, T., Melnick, A., Liu, Y., Zhao, X., & Nimer, S. D. (2013). PRMT4 blocks myeloid differentiation by assembling a Methyl-RUNX1-dependent repressor complex. Cell Reports, 5(6), 1625-1638. https://doi.org/10.1016/j.celrep.2013.11.025