MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia

Kerry, Jon; Godfrey, Laura; Repapi, Emmanouela; Tapia, Marta; Blackledge, Neil P.; Ma, Helen; Ballabio, Erica; O’Byrne, Sorcha; Ponthan, Frida; Heidenreich, Olaf; Roy, Anindita; Roberts, Irene; Konopleva, Marina; Klose, Robert J.; Geng, Huimin; Milne, Thomas A.

doi:10.1016/j.celrep.2016.12.054

Cited by 73 publications

(153 citation statements)

References 40 publications

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“…To verify this, we assessed MLL occupancy at Hox genes in lin 2 cells harvested from Psip1-depleted cells through ChIP-qPCR. In line with earlier reports, 24,41 ChIP-qPCR analyses demonstrated that MLL occupancy at HoxA9 and HoxA7 promoters was decreased about twofold in Psip…”

Section: Hoxa9 and Eya1 In Psipsupporting

confidence: 92%

“…Several studies show that the latter tethers wild-type MLL and/or MLL-FP complexes to chromatin ( Figure 1A). 16,24,41 Several approaches have been taken to interfere with the function of MLL-fusion complexes, including DOT1L or BET protein inhibitors that target the fusion moiety of MLL-FPs. [47][48][49][50] On the other hand, others directly target the MLL fragment of the fusion.…”

Section: Discussionmentioning

confidence: 99%

“…16 In contrast, recent studies from the same group and others showed that knockdown of LEDGF/p75 led to increased MLL-FP recruitment. 24,41 The authors suggested an independent role for LEDGF/p75 in the wild-type complex, which in turn competes with MLL-FP for chromatin-binding sites. Similar to Zhu et al, we observed a significant reduction of wildtype MLL binding to HoxA9 and HoxA7 promoter regions upon LEDGF/p75 depletion.…”

Section: Discussionmentioning

confidence: 99%

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LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis

Ashkar¹,

Schwaller²,

Pieters³

et al. 2017

Blood

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K E Y P O I N T Sl LEDGF/p75, an important cofactor required for MLLrearranged leukemia, is not essential for steady-state hematopoiesis.l Loss of LEDGF/p75 blocks the development of MLLrearranged leukemia supporting the MLL-LEDGF/p75 interaction as a new therapeutic target.Mixed lineage leukemia (MLL) represents a genetically distinct and aggressive subset of human acute leukemia carrying chromosomal translocations of the MLL gene. These translocations result in oncogenic fusions that mediate aberrant recruitment of the transcription machinery to MLL target genes. The N-terminus of MLL and MLL-fusions form a complex with lens epithelium-derived growth factor (LEDGF/p75; encoded by the PSIP1 gene) and MENIN. This complex contributes to the association of MLL and MLL-fusion multiprotein complexes with the chromatin. Several studies have shown that both MENIN and LEDGF/p75 are required for efficient MLL-fusion-mediated transformation and for the expression of downstream MLL-regulated genes such as HOXA9 and MEIS1. In light of developing a therapeutic strategy targeting this complex, understanding the function of LEDGF/p75 in normal hematopoiesis is crucial. We generated a conditional Psip1 knockout mouse model in the hematopoietic compartment and examined the effects of LEDGF/p75 depletion in postnatal hematopoiesis and the initiation of MLL leukemogenesis. Psip1 knockout mice were viable but showed several defects in hematopoiesis, reduced colonyforming activity in vitro, decreased expression of Hox genes in the hematopoietic stem cells, and decreased MLL occupancy at MLL target genes. Finally, in vitro and in vivo experiments showed that LEDGF/ p75 is dispensable for steady-state hematopoiesis but essential for the initiation of MLL-mediated leukemia. These data corroborate the MLL-LEDGF/p75 interaction as novel target for the treatment of MLL-rearranged leukemia. (Blood. 2018;131(1):95-107)

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Section: Hoxa9 and Eya1 In Psipsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis

Ashkar¹,

Schwaller²,

Pieters³

et al. 2017

Blood

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“…Chromatin Immunoprecipitation. ChIP-qPCR and ChIP-seq experiments were conducted as previously described 49,83 . Briefly, double-fixed samples (2 mM disuccinimidyl glutarate (Sigma) for 30 min followed by 1 % formaldehyde (Sigma) for 30 min) were sonicated in batches of 10 7 cells using a Covaris (Woburn, MA) following the manufacturer's recommendations.…”

Section: Methodsmentioning

confidence: 99%

“…To assess the direct effects of BRD4 inhibition, we chose a 90 min IBET treatment time, based on the qRT-PCR data. We analyzed the global transcriptional response to IBET by sequencing nascent RNA 49 , which provides a much more direct measure of transcriptional output compared to steady state RNA-seq (Fig 2b, Supplementary Table 2). As a comparison, we also sequenced nascent RNA following 24h IBET treatment (Fig 2b, Supplementary Table 2).…”

Section: Loss Of Bet and Mediator Binding Is Associated With Large Trmentioning

confidence: 99%

BET inhibition disrupts transcription but retains enhancer-promoter contact

Crump

Ballabio

Godfrey

et al. 2019

Preprint

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In higher eukaryotes, enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. The formation of phase condensates is thought to be an essential component of enhancer function. Here, we show that pharmacological targeting of cells with inhibitors of BET (Bromodomain and Extra-Terminal domain) proteins can have a strong impact on transcription but very little impact on enhancer-promoter interactions. Treatment with 1,6-hexanediol, which dissolves phase condensate structures and reduces BET and Mediator protein binding at enhancers, can also have a strong effect on gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancerpromoter interactions are separable events. Our findings further suggest that enhancer-promoter interactions are not dependent on high levels of BRD4 (Bromodomain-containing protein 4) and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and loop extrusion by CTCF/cohesin.

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Direct targeted therapy for MLL‐fusion‐driven high‐risk acute leukaemias

Cantilena¹,

Gasparoli²,

Pal

et al. 2022

Clinical & Translational Med

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Direct inhibition of MLL-fusion proteins is a potential therapeutic strategy. MLL-fusion depletion screen identified disulfiram for its ability to ablate MLLfusion protein and block-associated leukaemic phenotype.Disulfiram directly targets the CXXC domain that is essential for all MLL-fusion proteins. Disulfiram prevents the binding to the target genes of the MLL-fusion resulting in rapid decrease in H3K27ac levels.

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MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia

Cited by 73 publications

References 40 publications

LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis

LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis

BET inhibition disrupts transcription but retains enhancer-promoter contact

Direct targeted therapy for MLL‐fusion‐driven high‐risk acute leukaemias

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