The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations.
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.
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. gang.huang@cchmc.org
Gang
G
Huang
Xinghui
X
Zhao
Lan
L
Wang
Shannon
S
Elf
Hao
H
Xu
Xinyang
X
Zhao
Goro
G
Sashida
Yue
Y
Zhang
Yan
Y
Liu
Jennifer
J
Lee
Silvia
S
Menendez
Youyang
Y
Yang
Xiaomei
X
Yan
Pu
P
Zhang
Daniel G
DG
Tenen
Motomi
M
Osato
James J-D
JJ
Hsieh
Stephen D
SD
Nimer
D000208:Acute Disease; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D008239:Lysine; D051788:Myeloid-Lymphoid Leukemia Protein; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C493692:CBFB protein, human; C497422:KMT2A protein, human; C493728:RUNX1 protein, human