The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations Journal Article

Authors: Huang, G.; Zhao, X.; Wang, L.; Elf, S.; Xu, H.; Sashida, G.; Zhang, Y.; Liu, Y.; Lee, J.; Menendez, S.; Yang, Y.; Yan, X.; Zhang, P.; Tenen, D. G.; Osato, M.; Hsieh, J. J. D.; Nimer, S. D.
Article Title: The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations
Abstract: The mixed-lineage leukemia (MLL) H3K4 methyltransferase protein, and the heterodimeric RUNX1/CBFβ transcription factor complex, are critical for definitive and adult hematopoiesis, and both are frequently targeted in human acute leukemia. We identified a physical and functional interaction between RUNX1 (AML1) and MLL and show that both are required to maintain the histone lysine 4 trimethyl mark (H3K4me3) at 2 critical regulatory regions of the AML1 target gene PU.1. Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation. Furthermore, a subset of previously uncharacterized frame-shift and missense mutations at the N terminus of AML1, found in MDS and AML patients, impairs its interaction with MLL, resulting in loss of the H3K4me3 mark within PU.1 regulatory regions, and decreased PU.1 expression. The interaction between MLL and AML1 provides a mechanism for the sequence-specific binding of MLL to DNA, and identifies RUNX1 target genes as potential effectors of MLL function. © 2011 by The American Society of Hematology.
Keywords: unclassified drug; human cell; methylation; frameshift mutation; missense mutation; mutation; proto-oncogene proteins; nonhuman; mouse; gene expression; protein degradation; cell line; animal experiment; animal model; protein binding; cell line, tumor; blotting, western; amino terminal sequence; reverse transcriptase polymerase chain reaction; chromatin immunoprecipitation; histone h3; leukemia, myeloid; trans-activators; histones; lysine; myelodysplastic syndromes; core binding factor alpha 2 subunit; acute disease; transcription factor runx1; regulatory sequences, nucleic acid; hek293 cells; histone methylation; mixed lineage leukemia protein; myeloid-lymphoid leukemia protein; histone h3k4; core binding factor beta subunit
Journal Title: Blood
Volume: 118
Issue: 25
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2011-12-15
Start Page: 6544
End Page: 6552
Language: English
DOI: 10.1182/blood-2010-11-317909
PROVIDER: scopus
PMCID: PMC3242717
PUBMED: 22012064
Notes: --- - "Export Date: 1 February 2012" - "CODEN: BLOOA" - "Source: Scopus"
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MSK Authors
  1. Xiaomei Yan
    3 Yan
  2. Gang Huang
    12 Huang
  3. Goro Sashida
    14 Sashida
  4. Stephen D Nimer
    345 Nimer
  5. Yan Liu
    23 Liu
  6. Lan Wang
    14 Wang
  7. Hao Xu
    5 Xu
  8. Shannon E Elf
    12 Elf
  9. Youyang Yang
    4 Yang
  10. Jennifer May Lee
    5 Lee