MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia

被引:77
作者
Prange, K. H. M. [1 ]
Mandoli, A. [1 ]
Kuznetsova, T. [1 ]
Wang, S-Y [1 ]
Sotoca, A. M. [1 ]
Marneth, A. E. [2 ]
van der Reijden, B. A. [2 ]
Stunnenberg, H. G. [1 ]
Martens, J. H. A. [1 ]
机构
[1] Radboud Univ Nijmegen, Fac Sci, Radboud Inst Mol Life Sci, Dept Mol Biol, Geert Grootepl 26, NL-6500 HB Nijmegen, Netherlands
[2] Radboud Univ Nijmegen, Dept Lab Med, Lab Hematol, Med Ctr, Nijmegen, Netherlands
关键词
MLL FUSION PROTEINS; H3K79; METHYLATION; TRANSCRIPTION FACTORS; HOX GENES; INHIBITION; CHROMATIN; BET; EXPRESSION; COMPLEX; MEIS1;
D O I
10.1038/onc.2016.488
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In 11q23 leukemias, the N-terminal part of the mixed lineage leukemia (MLL) gene is fused to 460 different partner genes. In order to define a core set of MLL rearranged targets, we investigated the genome-wide binding of the MLL-AF9 and MLL-AF4 fusion proteins and associated epigenetic signatures in acute myeloid leukemia (AML) cell lines THP-1 and MV4-11. We uncovered both common as well as specific MLL-AF9 and MLL-AF4 target genes, which were all marked by H3K79me2, H3K27ac and H3K4me3. Apart from promoter binding, we also identified MLL-AF9 and MLL-AF4 binding at specific subsets of non-overlapping active distal regulatory elements. Despite this differential enhancer binding, MLL-AF9 and MLL-AF4 still direct a common gene program, which represents part of the RUNX1 gene program and constitutes of CD34(+) and monocyte-specific genes. Comparing these data sets identified several zinc finger transcription factors (TFs) as potential MLL-AF9 co-regulators. Together, these results suggest that MLL fusions collaborate with specific subsets of TFs to deregulate the RUNX1 gene program in 11q23 AMLs. Oncogene (2017)
引用
收藏
页码:3346 / 3356
页数:11
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