title: Histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia.
abstract: Mixed-lineage leukemia (MLL) fusions are potent oncogenes that initiate aggressive forms of acute leukemia. As aberrant transcriptional regulators, MLL-fusion proteins alter gene expression in hematopoietic cells through interactions with the histone H3 lysine 79 (H3K79) methyltransferase DOT1L. Notably, interference with MLL-fusion cofactors like DOT1L is an emerging therapeutic strategy in this disease. Here, we identify the histone H2B E3 ubiquitin ligase ring finger protein 20 (RNF20) as an additional chromatin regulator that is necessary for MLL-fusion-mediated leukemogenesis. Suppressing the expression of Rnf20 in diverse models of MLL-rearranged leukemia leads to inhibition of cell proliferation, under tissue culture conditions as well as in vivo. Rnf20 knockdown leads to reduced expression of MLL-fusion target genes, effects resembling Dot1l inhibition. Using ChIP-seq, we found that H2B ubiquitination is enriched in the body of MLL-fusion target genes, correlating with sites of H3K79 methylation and transcription elongation. Furthermore, Rnf20 is required to maintain local levels of H3K79 methylation by Dot1l at Hoxa9 and Meis1. These findings support a model whereby cotranscriptional recruitment of Rnf20 at MLL-fusion target genes leads to amplification of Dot1l-mediated H3K79 methylation, thereby rendering leukemia cells dependent on Rnf20 to maintain their oncogenic transcriptional program.
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors: Eric
authors: E
authors: Wang
authors: Shinpei
authors: S
authors: Kawaoka
authors: Ming
authors: M
authors: Yu
authors: Junwei
authors: J
authors: Shi
authors: Ting
authors: T
authors: Ni
authors: Wenjing
authors: W
authors: Yang
authors: Jun
authors: J
authors: Zhu
authors: Robert G
authors: RG
authors: Roeder
authors: Christopher R
authors: CR
authors: Vakoc
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics; D055785:Gene Knockdown Techniques; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011519:Proto-Oncogenes; D034741:RNA, Small Interfering / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004273:DNA, Neoplasm; D006657:Histones; C497422:KMT2A protein, human; C474558:MLL-AF9 fusion protein, human; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; C506646:RNF20 protein, human; C571257:RNF20 protein, mouse; D044767:Ubiquitin-Protein Ligases