MLL Targets SET Domain Methyltransferase Activity to Hox Gene Promoters

Milne, Thomas A.; Briggs, Scott; Brock, Hugh W.; Martin, Mary Ellen; Gibbs, Denise; Allis, C. David; Hess, Jay L.

doi:10.1016/s1097-2765(02)00741-4

Cited by 958 publications

(910 citation statements)

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“…29 Transcription factors such as p53 and CTNNB1(b-catenin) are most likely to recruit the MLL complex to initiate RNA synthesis, 26,30 and specific genes, such as the HOX genes, seem to be more dependent on the MLL complex for chromatin modification during transcription than others. 31,32 In MLL rearrangements the breakpoint in MLL is highly conserved and all fusion partners are fused in frame, leading to a gain of function of the MLL complex. The MLL fusion most likely disrupts the MLL complex, leading to inappropriate expression of specific HOX genes, that is, HOXA4, HOXA5, HOXA9 and HOXA10, in pediatric MLL-rearranged AML.…”

Section: Etiology Of Mll Rearrangementsmentioning

confidence: 99%

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

et al. 2011

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Translocations involving the mixed-lineage leukemia (MLL) gene, localized at 11q23, comprise 15 to 20% of all pediatric acute myeloid leukemia (AML) cases. This review summarizes current knowledge about the etiology, biology, clinical characteristics and differences in outcome in MLL-rearranged pediatric AML. Furthermore, we discuss the role of cooperating events in MLL-rearranged pediatric AML, and future therapeutic strategies to improve outcome. We conclude that MLL-rearranged pediatric AML is a heterogeneous disease, and prognosis depends on various factors, for example, translocation partner, age, WBC and additional cytogenetic aberrations. The relationship of outcome with specific translocation partners requires that they be searched for in the diagnostic work-up of AML. To achieve further improvements in outcome, unraveling the biology of MLL-rearranged pediatric AML is warranted.

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Section: Etiology Of Mll Rearrangementsmentioning

confidence: 99%

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

et al. 2011

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“…It is believed that Mll controls Hox gene expression by binding to Hox regulatory elements and association with other transcriptional regulators. Indeed, MLL binding to the promoters of HOXA9 and Hoxc8 was described recently [Milne et al, 2002;Nakamura et al, 2002]. Overexpression of some Hox genes, including Hoxa9, has been linked to leukemia in mouse models.…”

Section: Wild-type Mll Functionmentioning

confidence: 99%

“…Methylation of the lysine residues on histone tails is part of the proposed histone code in which different histone modifications direct the recruitment of transcriptional regulators, ultimately exerting an influence on gene expression [Jenuwein and Allis, 2001]. While the initial studies failed to confirm such enzymatic function in the MLL SET domain, more recently two groups have shown that mouse and human MLL SET domains are indeed able to methylate lysine residues on histone tails [Milne et al, 2002;Nakamura et al, 2002]. The specificity of the MLL SET domain is for lysine 4 (K4) on histone H3.…”

Section: Many Pieces Of the Puzzlementioning

confidence: 99%

MLL: How complex does it get?

Popovic

Zeleznik‐Le

2005

J of Cellular Biochemistry

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The mixed lineage leukemia (MLL) gene encodes a very large nuclear protein homologous to Drosophila trithorax (trx). MLL is required for the proper maintenance of HOX gene expression during development and hematopoiesis. The exact regulatory mechanism of HOX gene expression by MLL is poorly understood, but it is believed that MLL functions at the level of chromatin organization. MLL was identified as a common target of chromosomal translocations associated with human acute leukemias. About 50 different MLL fusion partners have been isolated to date, and while similarities exist between groups of partners, there exists no unifying property shared by all the partners. MLL gene rearrangements are found in leukemias with both lymphoid and myeloid phenotypes and are often associated with infant and secondary leukemias. The immature phenotype of the leukemic blasts suggests an important role for MLL in the early stages of hematopoietic development. Mll homozygous mutant mice are embryonic lethal and exibit deficiencies in yolk sac hematopoiesis. Recently, two different MLL-containing protein complexes have been isolated. These and other gain-and loss-of-function experiments have provided insight into normal MLL function and altered functions of MLL fusion proteins. This article reviews the progress made toward understanding the function of the wild-type MLL protein. While many advances in understanding this multifaceted protein have been made since its discovery, many challenging questions remain to be answered. J. Cell. Biochem. 95: 234-242, 2005. ß 2005 Wiley-Liss, Inc.

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“…Several reports have detailed how deregulation of methylation can be the direct cause or result of cellular dysfunction. For example, in certain cancers, hyper-and hypomethylation of specific regions of DNA by DNMTs and rearrangement of chromatin due to HMTs are observed routinely and serve to silence and activate genes related to cell growth and malignancy [11][12][13][14][15][16].The study of methyltransferase activity and its regulation continues to be an important and promising area of research in fields from oncology to neurology. Thus, there currently is a demand for the ability to screen large compound libraries to identify and optimize small molecules that modulate methyltransferase activity.…”

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A universal competitive fluorescence polarization activity assay for S-adenosylmethionine utilizing methyltransferases

Graves

Zhang

Scott

2008

Analytical Biochemistry

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A high-throughput, competitive fluorescence polarization immunoassay has been developed for the detection of methyltransferase activity. The assay was designed to detect Sadenosylhomocysteine (AdoHcy), a product of all S-adenosylmethionine (AdoMet)-utilizing methyltransferase reactions. We employed commercially available anti-AdoHcy antibody and fluorescein-AdoHcy conjugate tracer to measure AdoHcy generated as a result of methyltransferase activity. AdoHcy competes with tracer in the antibody/tracer complex. The release of tracer results in a decrease in fluorescence polarization. Under optimized conditions, AdoHcy and AdoMet titrations demonstrated that the antibody had more than a 150-fold preference for binding AdoHcy relative to AdoMet. Mock methyltransferase reactions using both AdoHcy and AdoMet indicated that the assay tolerated 1 to 3 μM AdoMet. The limit of detection was approximately 5 nM (0.15 pmol) AdoHcy in the presence of 3 μM AdoMet. To validate the assay's ability to quantitate methyltransferase activity, the methyltransferase catechol-Omethyltransferase (COMT) and a known selective inhibitor of COMT activity were used in proofof-principle experiments. A time-and enzyme concentration-dependent decrease in fluorescence polarization was observed in the COMT assay that was developed. The IC 50 value obtained using a selective COMT inhibitor was consistent with previously published data. Thus, this sensitive and homogeneous assay is amenable for screening compounds for inhibitors of methyltransferase activity. KeywordsFluorescence polarization; Methyltransferase; S-Adenosylhomocysteine; S-Adenosylmethionine; Catechol-O-methyltransferase Methyltransferases are a diverse class of enzymes that catalyze the transfer of a single methyl group from a methyl donor molecule to a methyl acceptor. The vast majority use Sadenosylmethionine (AdoMet) 1 as the methyl donor [1,2]. AdoMet is the second most HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscriptwidely used substrate molecule in the cell after ATP. Methylation is an essential and highly choreographed regulatory metabolic process. Small organic molecules and peptides and most types of cellular macromolecules, including DNA, RNA, protein, and lipids, can serve as substrates for methylation (for detailed reviews, see Refs. [2][3][4][5][6][7]).A rapidly growing area of methyltransferase research focuses on methylation of histone tails by histone methyltransferases (HMTs) (for reviews, see Refs. [8,9]). Histone methylation is an epigenetic modification that has a role in formation of heterochromatin, X chromosome inactivation, and modification of gene expression patterns. Histone methylation occurs on arginine and lysine residues and is catalyzed by methyltransferases belonging to three distinct families of proteins: the protein arginine N-methyltransferase 1 (PRMT1) family, the SET-domain-containing protein family, and the non-SET-domain proteins DOT1/DOT1L. This histone methylation alters chromatin structure and, thus, regulates...

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MLL Targets SET Domain Methyltransferase Activity to Hox Gene Promoters

Cited by 958 publications

References 48 publications

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

MLL: How complex does it get?

A universal competitive fluorescence polarization activity assay for S-adenosylmethionine utilizing methyltransferases

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