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 language | English (US) |
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Pages (from-to) | 1625-1638 |
Number of pages | 14 |
Journal | Cell reports |
Volume | 5 |
Issue number | 6 |
DOIs | |
State | Published - Dec 26 2013 |
Funding
We thank Michael Kharas, Minkui Luo, Ross Levine, and the members of the Nimer laboratory for providing thoughtful suggestions and comments. We thank the MSKCC Flow Cytometry core facility for their assistance and the Eastern Cooperative Oncology Group (ECOG) bank for making their database of AML patient samples available. The mass spectrometry work was supported by NCI Cancer Center support grant P30 CA08748 to Microchemistry and Proteomics Core Laboratory, MSKCC. We would like to thank Elizabeth Chang for help with mass spectrometry sample preparation. This study was funded by a grant from the National Institutes of Health (R01CA166835) and by the American Society of Hematology Scholar Award (to F.P.).
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology