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

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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.

Original languageEnglish (US)
Pages (from-to)6544-6552
Number of pages9
JournalBlood
Volume118
Issue number25
DOIs
StatePublished - Dec 15 2011
Externally publishedYes

Fingerprint

Nucleic Acid Regulatory Sequences
Leukemia
Genes
Protein Methyltransferases
Mutation
Proteasome Endopeptidase Complex
Histones
Lysine
Transcription Factors
Degradation
DNA
Frameshift Mutation
Hematopoiesis
Missense Mutation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations. / Huang, Gang; Zhao, Xinghui; Wang, Lan; Elf, Shannon; Xu, Hao; Zhao, Xinyang; Sashida, Goro; Zhang, Yue; Liu, Yan; Lee, Jennifer; Menendez, Silvia; Yang, Youyang; Yan, Xiaomei; Zhang, Pu; Tenen, Daniel G.; Osato, Motomi; Hsieh, James J D; Nimer, Stephen D.

In: Blood, Vol. 118, No. 25, 15.12.2011, p. 6544-6552.

Research output: Contribution to journalArticle

Huang, G, Zhao, X, Wang, L, Elf, S, Xu, H, Zhao, X, Sashida, G, Zhang, Y, Liu, Y, Lee, J, Menendez, S, Yang, Y, Yan, X, Zhang, P, Tenen, DG, Osato, M, Hsieh, JJD & Nimer, SD 2011, 'The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations', Blood, vol. 118, no. 25, pp. 6544-6552. https://doi.org/10.1182/blood-2010-11-317909
Huang, Gang ; Zhao, Xinghui ; Wang, Lan ; Elf, Shannon ; Xu, Hao ; Zhao, Xinyang ; Sashida, Goro ; Zhang, Yue ; Liu, Yan ; Lee, Jennifer ; Menendez, Silvia ; Yang, Youyang ; Yan, Xiaomei ; Zhang, Pu ; Tenen, Daniel G. ; Osato, Motomi ; Hsieh, James J D ; Nimer, Stephen D. / The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations. In: Blood. 2011 ; Vol. 118, No. 25. pp. 6544-6552.
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AU - Sashida, Goro

AU - Zhang, Yue

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AU - Lee, Jennifer

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AU - Yang, Youyang

AU - Yan, Xiaomei

AU - Zhang, Pu

AU - Tenen, Daniel G.

AU - Osato, Motomi

AU - Hsieh, James J D

AU - Nimer, Stephen D.

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