Targeting Recruitment of Disruptor of Telomeric Silencing 1-like (DOT1L)

Shen, Chenxi; Jo, Stephanie Y.; Liao, Chenzhong; Hess, Jay L.; Nikolovska‐Coleska, Zaneta

doi:10.1074/jbc.m113.457135

Cited by 30 publications

(18 citation statements)

References 34 publications

(56 reference statements)

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“…Each of the DOT1L sites interacting with AF9 is predicted to be disordered (Figure S1C), suggesting that there is a mutual synergistic folding between AF9 and DOT1L at each of these binding sites. Our binding measurements of DOT1L (Site 2) with AF9 yielded K d values significantly different from those reported in a recent publication that biochemically mapped the interaction of this particular DOT1L site with AF9, but did not identify the interactions of the other DOT1L sites (Shen et al, 2013). As is the case with many intrinsically disordered proteins, the AF9 AHD has a propensity to aggregate, requiring significant care in the concentrations and conditions employed for binding measurements, perhaps suggesting a rationale for the difference in the measured binding affinities.…”

Section: Resultscontrasting

confidence: 99%

“…The protein-protein interaction between AF9 and DOT1L has been roughly mapped (Biswas et al, 2011; Shen et al, 2013; Yokoyama et al, 2010; Zhang et al, 2006), but there is a lack of structural characterization of this interaction and functional effects of the direct recruitment of DOT1L. To that end, we now show that there are three separate regions in DOT1L that interact with AF9 and fold into structurally similar complexes.…”

Section: Introductionmentioning

confidence: 76%

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Degree of Recruitment of DOT1L to MLL-AF9 Defines Level of H3K79 Di- and Tri-methylation on Target Genes and Transformation Potential

Kuntimaddi¹,

Achille²,

Thorpe³

et al. 2015

Cell Reports

105

115

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SUMMARY The MLL gene is a common target of chromosomal translocations found in human leukemia. MLL-fusion leukemia has a consistently poor outcome. One of the most common translocation partners is AF9 (MLLT3). MLL-AF9 recruits DOT1L, a histone 3 lysine 79 methyltransferase (H3K79me1/me2/me3), leading to aberrant gene transcription. We show that DOT1L has three AF9 binding sites, and present the NMR solution structure of a DOT1L-AF9 complex. We generate structure-guided point mutations and find they have graded effects on recruitment of DOT1L to MLL-AF9. ChIP-Seq analyses of H3K79me2 and H3K79me3 show that graded reduction of the DOT1L interaction with MLL-AF9 results in differential loss of H3K79me2 and me3 at MLL-AF9 target genes. Furthermore, the degree of DOT1L recruitment is linked to the level of MLL-AF9 hematopoietic transformation.

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Section: Resultscontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 76%

Degree of Recruitment of DOT1L to MLL-AF9 Defines Level of H3K79 Di- and Tri-methylation on Target Genes and Transformation Potential

Kuntimaddi¹,

Achille²,

Thorpe³

et al. 2015

Cell Reports

105

115

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“…From a systems standpoint, our functional proteomics data indicate that dimerized MLL recruits a network of protein complexes analogous to direct fusion of MLL with transcriptional activators. This suggests that targeting the epigenetic modulator DOT1L 48 , 49 , 58 should have efficacy for all MLL-driven leukemia’s. Conversely, an engineered MLL fusion with an FKBP domain capable of dimerization driven by a synthetic small molecule did not elicit robust H2K79 methylation 59 , and may therefore not associate with DOT1L.…”

Section: Discussionmentioning

confidence: 99%

Evolution of AF6-RAS association and its implications in mixed-lineage leukemia

et al. 2017

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Elucidation of activation mechanisms governing protein fusions is essential for therapeutic development. MLL undergoes rearrangement with numerous partners, including a recurrent translocation fusing the epigenetic regulator to a cytoplasmic RAS effector, AF6/afadin. We show here that AF6 employs a non-canonical, evolutionarily conserved α-helix to bind RAS, unique to AF6 and the classical RASSF effectors. Further, all patients with MLL-AF6 translocations express fusion proteins missing only this helix from AF6, resulting in exposure of hydrophobic residues that induce dimerization. We provide evidence that oligomerization is the dominant mechanism driving oncogenesis from rare MLL translocation partners and employ our mechanistic understanding of MLL-AF6 to examine how dimers induce leukemia. Proteomic data resolve association of dimerized MLL with gene expression modulators, and inhibiting dimerization disrupts formation of these complexes while completely abrogating leukemogenesis in mice. Oncogenic gene translocations are thus selected under pressure from protein structure/function, underscoring the complex nature of chromosomal rearrangements.

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“…A genome-wide study showed that inactivation of DOT1L leads to down-regulation of MLL-AF9 direct targets and an MLL1 translocation-associated gene expression signature [80]. Importantly, the AF9-binding site in DOT1L was mapped to 2 regions of human DOT1L (628–653 and 863–900 residues), and the interaction of DOT1L with the C-terminus of AF9 (present in MLL-AF9 fusion protein) is required for transformation by MLL-AF9 [127, 134]. These data suggest that MLL1-translocations create chimeric proteins that link MLL1 to other functionally distinct protein complexes including the super elongation complex (SEC) and the DOT1L-H3K79 methyltransferase complex and thus contribute to the ectopic expression of a homeobox gene-centric leukemic program (Fig.…”

Section: Molecular Basis Of Mll1-rearranged Leukemiasmentioning

confidence: 99%

Targeting DOT1L and HOX gene expression in MLL-rearranged leukemia and beyond

Chen

Armstrong

2015

Experimental Hematology

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Leukemias harboring mixed lineage leukemia (MLL1) gene abnormalities are associated with poor clinical outcomes and new therapeutic approaches are desperately needed. Rearrangement of the MLL1 gene generates chimeric proteins that fuse the NH3-terminus of MLL1 to the COOH-terminus of its translocation partners. These MLL1-fusion oncoproteins drive the expression of homeobox genes such as HOXA cluster genes and MEIS1, which are known to induce leukemic transformation of hematopoietic progenitors. Genome-wide histone methylation studies have revealed that the abnormal expression of MLL1-fusion target genes is associated with high levels of H3K79 methylation at these gene loci. The only known enzyme that catalyzes methylation of H3K79 is disruptor of telomeric-silencing 1-like (DOT1L). Loss-of-function mouse models as well as small molecular inhibitors of DOT1L demonstrate that leukemias driven by MLL1-translocations are dependent on DOT1L enzymatic activity for proliferation and for the maintenance of HOXA gene expression. Furthermore, DOT1L also appears to be important for HOXA gene expression in other settings including leukemias with select genetic abnormalities. These discoveries have established a foundation for disease-specific therapies that target chromatin modifications in highly malignant leukemias harboring specific genetic abnormalities. This review focuses on the molecular mechanisms underlying MLL1-translocation-driven leukemogenesis, and the latest progress on DOT1L-targeted epigenetic therapies for MLL1-rearranged and other leukemias.

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Targeting Recruitment of Disruptor of Telomeric Silencing 1-like (DOT1L)

Cited by 30 publications

References 34 publications

Degree of Recruitment of DOT1L to MLL-AF9 Defines Level of H3K79 Di- and Tri-methylation on Target Genes and Transformation Potential

Degree of Recruitment of DOT1L to MLL-AF9 Defines Level of H3K79 Di- and Tri-methylation on Target Genes and Transformation Potential

Evolution of AF6-RAS association and its implications in mixed-lineage leukemia

Targeting DOT1L and HOX gene expression in MLL-rearranged leukemia and beyond

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