Protein arginine-methyltransferase-dependent oncogenesis

Cheung, Nicole W. T.; Li, Chan; Thompson, Alexander; Cleary, Michael L.; So, Chi Wai Eric

doi:10.1038/ncb1642

Cited by 271 publications

(265 citation statements)

References 34 publications

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“…Functional dissection of protein complexes associated with oncogenic transcription factors, which often represent the initiating events in acute leukemia (24), is critical for understanding the transformation mechanisms and identifying potential therapeutic targets for intervention of self-renewal pathways corrupted in cancer stem cells (20,22,(25)(26)(27). CBF␤, which plays an important role for wild-type AML1 functions, in part by increasing its DNA binding ability (28) and stability (29), has been thought to be a critical component and potential target for AE-mediated transformation (1,10).…”

Section: Discussionmentioning

confidence: 99%

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Transforming activity of AML1-ETO is independent of CBFβ and ETO interaction but requires formation of homo-oligomeric complexes

Kwok

Zeisig

Qiu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Although both heterodimeric subunits of core binding factors (AML1/RUNX1 and CBF␤) essential for normal hematopoiesis are frequently mutated to form different chimeric fusion proteins in acute leukemia, the underlying molecular mechanisms and structural domains required for cellular transformation remain largely unknown. Despite the critical role of CBF␤ for wild-type AML1 function and its direct involvement in chromosomal translocation, we demonstrate that both the expression and interaction with CBF␤ are superfluous for AML1-ETO (AE)-mediated transformation of primary hematopoietic cells. Similarly, the hetero-oligomeric interaction with transcriptional repressor ETO family proteins and the highly conserved NHR1 domain in AE fusion are also dispensable for transforming activity. In contrast, AE-mediated transformation is critically dependent on the DNA binding and homo-oligomeric properties of the fusion. Abolishment of homooligomerization by a small-molecule inhibitor could specifically suppress AML1 fusion-mediated transformation of primary hematopoietic cells. Together, these results not only identify the essential molecular components but also potential avenues for therapeutic targeting of AE-mediated leukemogenesis.A ML1/RUNX1 and CBF␤ are 2 critical transcription factors essential for generation of hematopoietic stem cells (HSCs) (1, 2). Mice deficient in AML1 or CBF␤ have almost identical phenotypes; they completely lack definitive hematopoiesis and die at approximately embryonic day 12.5. In acute myeloid leukemia in which leukemic stem cells have been functionally identified, AML1 and CBF␤ represent the most commonly mutated targets (1, 2). t(8;21) resulting in AML1-ETO (AE) fusion can be found in up to 40% of AML-M2; and inv(16) leading to CBF␤-SHMMC fusion constitutes approximately 30% of AML-M4. AML1 is also fused to TEL as a result of t(12;21) in approximately 25% of childhood leukemia, the most common form of childhood cancers. Although animal modeling clearly indicates that AML1 fusions per se are not sufficient for induction of full-blown leukemia, they function to enhance self-renewal and expand targeted HSCs and early progenitors for cooperative secondary mutations to take place (3-5).While enhanced self-renewal has emerged as a critical feature associated with various oncogenic transcription factors involved in acute leukemia (6-8), much less is known about the underlying molecular mechanisms. It is clear that most, if not all, of the transcription factors do not work as monomers but need to complex with various proteins for full activity and specificity, although the molecular composition of the associated transcriptional complexes required for self-renewal remains largely unknown. At the molecular level, AE encodes the DNA-binding runt homology domain (RHD) fused in-frame with almost the entire transcriptional repressor protein ETO containing 4 different Nervy homology regions (NHRs) (Fig. 1A), suggesting a gain of transcriptional repressor function by the oncogenic fusion (9). A well-reco...

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Section: Discussionmentioning

confidence: 99%

“…RTTA was performed as previously described (20,22,25). In vitro transformation was defined as enhanced self-renewal of primary hematopoietic cells beyond 3 rounds of plating in the serial replating assay.…”

Section: Methodsmentioning

confidence: 99%

Transforming activity of AML1-ETO is independent of CBFβ and ETO interaction but requires formation of homo-oligomeric complexes

Kwok

Zeisig

Qiu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…In the case of the cytoplasmatic MLL translocation partner EEN, histone arginine methylation catalyzed by PRMT1 has been shown to be critically important for transformation. 123 It may be that even the molecularly defined group of MLL-rearranged leukemias will undergo further subdivision. An important future goal will be to establish chromatin maps for leukemia propagating (stem) cells.…”

Section: Spotlightmentioning

confidence: 99%

Chromatin maps, histone modifications and leukemia

Neff

Armstrong

2009

Leukemia

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“…Several Trx and PcG genes encode lysine methyltransferases that contain a suppressor of variegation, enhancer of zeste, and Trithorax (SET) domain and target histone proteins to activate or repress transcription, respectively. Genetic alterations of several Trx and PcG genes, including members of the mixed lineage leukemia (MLL) family, have been linked to oncogenesis in mammals and are especially prevalent in hematological malignancies (3)(4)(5)(6)(7)(8).…”

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“…Arginine methylation influences protein nuclear localization and intermolecular interactions, thereby affecting various cellular processes, including mRNA splicing and gene transcription. Currently, eight genes have been identified that encode active protein-arginine methyltransferases (PRMTs) in mammals (PRMTs 1,2,3,4,5,6,7, and 8) (24,25). These enzymes mediate mono-and dimethylation of arginine residues and are classified as Type I (PRMTs 1, 2, 3, 4, 6, 7, and 8) or Type II (PRMT 5) enzymes based on their ability to cata-* This work was supported, in whole or in part, by National Institutes of Health Training Grants T32 CA00929930 and T32 CA929931A1 (to J. S.…”

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confidence: 99%

Protein-arginine Methyltransferase 1 (PRMT1) Methylates Ash2L, a Shared Component of Mammalian Histone H3K4 Methyltransferase Complexes

Butler

Zurita-Lopez

Clarke

et al. 2011

Journal of Biological Chemistry

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Multiple enzymes and enzymatic complexes coordinately regulate the addition and removal of post-translational modifications on histone proteins. The oncoprotein Ash2L is a component of the mixed lineage leukemia (MLL) family members 1-4, Setd1A, and Setd1B mammalian histone H3K4 methyltransferase complexes and is essential to maintain global trimethylation of histone H3K4. However, regulation of these complexes at the level of expression and activity remains poorly understood. In this report, we demonstrate that Ash2L is methylated on arginine residues both in vitro and in cells. We found that both protein-arginine methyltransferases 1 and 5 methylate Arg-296 within Ash2L. These findings are the first to demonstrate that post-translational modifications occur on the Ash2L protein and provide a novel example of cross-talk between chromatinmodifying enzyme complexes.Changes in gene expression are brought about in part by dynamic regulation of chromatin structure and govern numerous cellular processes, including differentiation. In this manner, transcription of the developmental Hox gene cluster is temporally and spatially regulated by the opposing action of chromatin modifiers belonging to the Trithorax (Trx) 2 and Polycomb group (PcG) families (1, 2). Several Trx and PcG genes encode lysine methyltransferases that contain a suppressor of variegation, enhancer of zeste, and Trithorax (SET) domain and target histone proteins to activate or repress transcription, respectively. Genetic alterations of several Trx and PcG genes, including members of the mixed lineage leukemia (MLL) family, have been linked to oncogenesis in mammals and are especially prevalent in hematological malignancies (3-8).MLL, Setd1A, and Setd1B methyltransferase complexes catalyze mono-, di-, and trimethylation of histone H3K4 (9 -15). The absent, small, homeotic discs 2-like (Ash2L) protein functions at the molecular level along with WDR5 and RbBP5 to form a submodule of the Setd1A, Setd1B, and MLL methyltransferase complexes. Interestingly, the Ash2L, RbBP5, WDR5, DPY30 submodule was shown to possess an intrinsic methyltransferase activity toward histone H3K4 in vitro that is independent of MLL, although none of these proteins contain a catalytic SET domain (16). Furthermore, depletion of Ash2L in cell lines leads to decreased global levels of histone H3K4me3, whereas global levels of histone H3K4 methylation are unchanged in the absence of MLL (9, 17, 18). Likewise, MLL complexes reconstituted in vitro that lack Ash2L exhibit reduced di-and trimethyltransferase activity toward recombinant histone H3 (16,17,19). These results demonstrate that Ash2L is necessary to maintain histone H3K4 methylation levels in vivo, although the molecular mechanism whereby Ash2L promotes lysine di-and trimethylation remains unclear.Ash2 is a member of the Trx family and was identified in a screen for Drosophila mutants exhibiting imaginal disc abnormalities and late larval/early pupal lethality (20). Ash2L is ubiquitously expressed in humans with the highest lev...

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Protein arginine-methyltransferase-dependent oncogenesis

Cited by 271 publications

References 34 publications

Transforming activity of AML1-ETO is independent of CBFβ and ETO interaction but requires formation of homo-oligomeric complexes

Transforming activity of AML1-ETO is independent of CBFβ and ETO interaction but requires formation of homo-oligomeric complexes

Chromatin maps, histone modifications and leukemia

Protein-arginine Methyltransferase 1 (PRMT1) Methylates Ash2L, a Shared Component of Mammalian Histone H3K4 Methyltransferase Complexes

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