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Abstract
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.
Highlights
Survival rates for children and adults carrying mutations in the Mixed Lineage Leukemia (MLL) gene continue to have a very poor prognosis
MLL-AF4 activates transcription of BCL-2 and MCL1 A survey of MLL-AF4 Chromatin immunoprecipitation (ChIP)-seq data [17,18,25,26] revealed that only BCL-2 and MCL-1 were bound by MLL-AF4 in three data sets (Fig. 1A)
Because BIM protein levels are significantly increased in MLL-AF4 leukemias [18], we wanted to determine if lack of MLL-AF4 binding to BIM in the Wilkinson/Geng data set [17,26] was due to sensitivity of the ChIP-seq experiment
Summary
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. Survival rates for children diagnosed with acute lymphoblastic leukemia (ALL) have drastically improved and, in some cases, are approaching 90% [1,2]. Even with this progress, adults with ALL still have a very poor prognosis [3], and childhood ALL cases that relapse often exhibit drug resistance and remain difficult to treat [4]. We recently reported that MLL-AF4 activates important gene targets such as RUNX1, HOXA9, and BCL-2 [17,18], mainly through recruitment of the disruptor of telomeric silencing 1-like (DOT1L) protein
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