Elsevier

Experimental Hematology

Volume 47, March 2017, Pages 64-75
Experimental Hematology

Malignant Hematopoiesis
MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation

https://doi.org/10.1016/j.exphem.2016.11.003Get rights and content
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open access

Highlights

  • Mixed lineage leukemia (MLL)-AF4 directly controls the active transcription of both BCL-2 and MCL-1.

  • MLL-AF4 represses BIM via recruitment of the polycomb group repressor 1 member CBX8.

  • Capture-C and chromatin immunoprecipitation sequencing are used to identify a BCL-2-specific enhancer.

  • The BCL-2 enhancer consists of two clusters of H3K27Ac at the 3′ end of the gene.

  • MLL-AF4 controls H3K79me3 in the BCL-2 gene body and H3K27Ac at the enhancer.

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.

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