MLL translocations, histone modifications and leukaemia stem-cell development

Krivtsov, Andrei V.; Armstrong, Scott A.

doi:10.1038/nrc2253

Cited by 1,049 publications

(1,092 citation statements)

References 115 publications

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“…MLL-rearranged mixed lineage leukaemia is driven by chromosomal translocations that result in an oncogenic fusion protein comprising the amino terminal region of MLL and the carboxy terminus of one of B70 translocation partners 14 , and pharmacological targeting of MLL translocation complexes was recently shown to reverse oncogenic activity of MLL fusion proteins in leukemia 15 . A subset of MLL fusion partners, including AF4, AF9 and AF10, aberrantly recruit DOT1L to select genomic loci leading to increased H3K79 methylation and transcriptional activation of genes essential for leukemogenesis 16 .…”

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confidence: 99%

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

et al. 2012

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Selective inhibition of protein methyltransferases is a promising new approach to drug discovery. An attractive strategy towards this goal is the development of compounds that selectively inhibit binding of the cofactor, S-adenosylmethionine, within specific protein methyltransferases. Here we report the three-dimensional structure of the protein methyltransferase DOT1L bound to EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy. This structure and those of four new analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage leukaemia cells, in which DOT1L is aberrantly localized via interaction with an oncogenic MLL fusion protein. These data provide important new insight into mechanisms of cell-active S-adenosylmethioninecompetitive protein methyltransferase inhibitors, and establish a foundation for the further development of drug-like inhibitors of DOT1L for cancer therapy.

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confidence: 99%

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

et al. 2012

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“…The PML/RARa fusion protein has been demonstrated to recruit not only HDACs but also DNMT activity to its target genes, such as RARb2, thereby rendering this gene in a silenced state through promoter hypermethylation and by imposing an inactive chromatin structure (Di Croce et al, 2002;Fazi et al, 2007). Several MLL (mixed-lineage leukemia) fusion proteins have also been extensively characterized as recruiters of chromatin-modifying enzymes (Krivtsov and Armstrong, 2007). Furthermore, the AML-specific fusion protein AML1/ETO recruits HDAC activity to target genes, and is under investigation as a protein rendering the CpG islands of its target genes hypermethylated through DNMT recruitment (Liu et al, 2005;Fazi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

et al. 2011

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The chromosomal translocation (8;21) fuses the hematopoietic transcription factor AML1 (RUNX1) with ETO (RUNX1T1, MTG8), resulting in the leukemia-specific chimeric protein AML1/ETO. This fusion protein has been implicated in epigenetic silencing, recruiting histone deacetylases (HDACs) and DNA methyltransferases to target promoters. Previously, we have identified a novel in vivo AML1/ETO target gene, LAT2 (NTAL/LAB/ WBSCR5), which is involved in FceR I, c-Kit, B-cell and T-cell receptor signalling. We have now addressed the molecular mechanisms of AML1/ETO-mediated LAT2 repression. In Kasumi-1 cells, where AML1/ETO bound to the LAT2 gene, small interfering RNA (siRNA)-mediated AML1/ETO depletion caused upregulation of LAT2, suggesting a possible direct mechanism of repression. Expression of AML1/ETO was associated with a decrease in acetylation of histones H3, H3K9 and H4, and an increase in H3K9 and H3K27 trimethylation. The class I-specific HDAC inhibitors entinostat (MS-275) and mocetinostat (MGCD0103) induced LAT2 expression specifically in AML1/ETO-expressing cells, resulting in induction of several activating histone marks on the LAT2 gene, including trimethylation of histone H3K4. The combination of entinostat and decitabine increased acetylation of histones H3 and H4, as well as LAT2 mRNA expression, in an at least additive fashion. In conclusion, several repressive histone modifications mark the LAT2 gene in the presence of AML1/ETO, and LAT2 gene derepression is achieved by pharmacological inhibition of HDACs.

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“…MLL and MOZ genes can be rearranged as a consequence of a chromosomal translocation in human acute leukemias (Krivtsov and Armstrong, 2007;Yang and Ullah, 2007). We mapped the MLL-binding domain also to the MYST domain of MOZ.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

et al. 2010

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MOZ and MLL, encoding a histone acetyltransferase (HAT) and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. In MOZ (MOnocytic leukemia Zinc-finger protein)/CBP-or mixed lineage leukemia (MLL)-rearranged leukemias, abnormal levels of HOX transcription factors have been found to be critical for leukemogenesis. We show that MOZ and MLL cooperate to regulate these key genes in human cord blood CD34 þ cells. These chromatinmodifying enzymes interact, colocalize and functionally cooperate, and both are recruited to multiple HOX promoters. We also found that WDR5, an adaptor protein essential for lysine 4 trimethylation of histone H3 (H3K4me3) by MLL, colocalizes and interacts with MOZ. We detected the binding of the HAT MOZ to H3K4me3, thus linking histone methylation to acetylation. In CD34 þ cells, depletion of MLL causes release of MOZ from HOX promoters, which is correlated to defective histone activation marks, leading to repression of HOX gene expression and alteration of commitment of CD34 þ cells into myeloid progenitors. Thus, our results unveil the role of the interaction between MOZ and MLL in CD34 þ cells in which both proteins have a critical role in hematopoietic cell-fate decision, suggesting a new molecular mechanism by which MOZ or MLL deregulation leads to leukemogenesis.

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MLL translocations, histone modifications and leukaemia stem-cell development

Cited by 1,049 publications

References 115 publications

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

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