The PAF complex regulation of Prmt5 facilitates the progression and maintenance of MLL fusion leukemia

Oncogene. 2018 Jan 25;37(4):450-460. doi: 10.1038/onc.2017.337. Epub 2017 Sep 25.

Abstract

Acute myeloid leukemia (AML) is a disease associated with epigenetic dysregulation. 11q23 translocations involving the H3K4 methyltransferase MLL1 (KMT2A) generate oncogenic fusion proteins with deregulated transcriptional potential. The polymerase-associated factor complex (PAFc) is an epigenetic co-activator complex that makes direct contact with MLL fusion proteins and is involved in AML, however, its functions are not well understood. Here, we explored the transcriptional targets regulated by the PAFc that facilitate leukemia by performing RNA-sequencing after conditional loss of the PAFc subunit Cdc73. We found Cdc73 promotes expression of an early hematopoietic progenitor gene program that prevents differentiation. Among the target genes, we confirmed the protein arginine methyltransferase Prmt5 is a direct target that is positively regulated by a transcriptional unit that includes the PAFc, MLL1, HOXA9 and STAT5 in leukemic cells. We observed reduced PRMT5-mediated H4R3me2s following excision of Cdc73 placing this histone modification downstream of the PAFc and revealing a novel mechanism between the PAFc and Prmt5. Knockdown or pharmacologic inhibition of Prmt5 causes a G1 arrest and reduced proliferation resulting in extended leukemic disease latency in vivo. Overall, we demonstrate the PAFc regulates Prmt5 to facilitate leukemic progression and is a potential therapeutic target for AMLs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Disease Progression
  • Epigenesis, Genetic
  • Female
  • G1 Phase Cell Cycle Checkpoints / genetics
  • Gene Expression Regulation, Leukemic*
  • Gene Knockdown Techniques
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histones / genetics
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, Transgenic
  • Myeloid Ecotropic Viral Integration Site 1 Protein / genetics
  • Myeloid Ecotropic Viral Integration Site 1 Protein / metabolism
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oncogene Proteins, Fusion / genetics*
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors
  • Protein-Arginine N-Methyltransferases / genetics*
  • Protein-Arginine N-Methyltransferases / metabolism
  • Transcription Factors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • CDC73 protein, human
  • Histones
  • Homeodomain Proteins
  • KMT2A protein, human
  • MEIS1 protein, human
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • PAF1 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • homeobox protein HOXA9
  • Myeloid-Lymphoid Leukemia Protein
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases
  • Histone-Lysine N-Methyltransferase