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

Gang Huang; Xinghui Zhao; Lan Wang; Shannon Elf; Hao Xu; Xinyang Zhao; Goro Sashida; Yue Zhang; Yan Liu; Jennifer Lee; Silvia Menendez; Youyang Yang; Xiaomei Yan; Pu Zhang; Daniel G Tenen; Motomi Osato; James J.-D Hsieh; Stephen D Nimer

doi:10.1182/blood-2010-11-317909

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

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

Gang Huang, Xinghui Zhao, Lan Wang, Shannon Elf, Hao Xu, Xinyang Zhao, Goro Sashida, Yue Zhang, Yan Liu, Jennifer Lee, …

Blood, Vol.118(25), pp.6544-6552

2011-12-15

DOI: https://doi.org/10.1182/blood-2010-11-317909

PMCID: PMC3242717

PMID: 22012064

Abstract

Hematopoiesis and Stem Cells

Myeloid Neoplasia

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.103 Blood Disorders; 1.103.155 Acute Myeloid Leukemia
Web Of Science research areas: Hematology
ESI research areas: Clinical Medicine

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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
Creators: Gang Huang - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Xinghui Zhao - Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Lan Wang - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Shannon Elf - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Hao Xu - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Xinyang Zhao - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Goro Sashida - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Yue Zhang - Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Yan Liu - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Jennifer Lee - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Silvia Menendez - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Youyang Yang - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Xiaomei Yan - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Pu Zhang - Harvard Stem Cell Institute, Harvard Medical School, Boston, MA
Daniel G Tenen - Harvard Stem Cell Institute, Harvard Medical School, Boston, MA
Motomi Osato - Cancer Science Institute, National University of Singapore, Singapore; and
James J.-D Hsieh - Department of Medicine, Washington University School of Medicine, St Louis, MO
Stephen D Nimer - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Publication Details: Blood, Vol.118(25), pp.6544-6552
Publisher: American Society of Hematology; Washington, DC
Grant note: DK52208; CA41456 / National Institutes of Health
Academic Unit: Leadership Department; Miller School of Medicine; Sylvester Comprehensive Cancer Center
Language: English
Resource Type: Journal article
PMID: 22012064
PMCID: PMC3242717
Record Identifier: 991031560943202976