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Survival rates for children and adults carrying mutations in the Mixed Lineage Leukemia (MLL) gene continue to have a very poor prognosis. The most common MLL mutation in acute lymphoblastic leukemia is the t(4;11)(q21;q23) chromosome translocation that fuses MLL in-frame with the AF4 gene producing MLL-AF4 and AF4-MLL fusion proteins. Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. In the study described here, we performed a detailed analysis of MLL-AF4 regulation of the entire BCL-2 family. By measuring nascent RNA production in MLL-AF4 knockdowns, we found that of all the BCL-2 family genes, MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 and also represses BIM via binding of the polycomb group repressor 1 (PRC1) complex component CBX8. We further analyzed MLL-AF4 activation of the BCL-2 gene using Capture-C and identified a BCL-2-specific enhancer, consisting of two clusters of H3K27Ac at the 3' end of the gene. Loss of MLL-AF4 activity results in a reduction of H3K79me3 levels in the gene body and H3K27Ac levels at the 3' BCL-2 enhancer, revealing a novel regulatory link between these two histone marks and MLL-AF4-mediated activation of BCL-2.

Original publication

DOI

10.1016/j.exphem.2016.11.003

Type

Journal article

Journal

Exp Hematol

Publication Date

03/2017

Volume

47

Pages

64 - 75

Keywords

Acetylation, Bcl-2-Like Protein 11, Cell Cycle Proteins, Cell Line, Tumor, Chromatin Immunoprecipitation, Enhancer Elements, Genetic, Gene Expression Profiling, Gene Expression Regulation, Leukemic, High-Throughput Nucleotide Sequencing, Histones, Humans, Myeloid Cell Leukemia Sequence 1 Protein, Myeloid-Lymphoid Leukemia Protein, Oncogene Proteins, Fusion, Polycomb Repressive Complex 1, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-bcl-2, Translocation, Genetic