MLLT10 in benign and malignant hematopoiesis
2020; Elsevier BV; Volume: 87; Linguagem: Inglês
10.1016/j.exphem.2020.06.002
ISSN1873-2399
AutoresJamie Deutsch, Jessica L. Heath,
Tópico(s)Epigenetics and DNA Methylation
Resumo•MLLT10 is often translocated in leukemia, yet the function is not well described.•Interacting partners implicate MLLT10 in many consequential cellular processes.•MLLT10 may play a role in regulating gene expression during early development.•A more comprehensive understanding of MLLT10 function is essential. Non-random chromosomal translocations involving the putative transcription factor Mixed Lineage Leukemia Translocated to 10 (MLLT10, also known as AF10) are commonly observed in both acute myeloid and lymphoid leukemias and are indicative of a poor prognosis. Despite the well-described actions of oncogenic MLLT10 fusion proteins, the role of wild-type MLLT10 in hematopoiesis is not well characterized. The protein structure and several interacting partners have been described and provide indications as to the potential functions of MLLT10. This review examines these aspects of MLLT10, contextualizing its function in benign and malignant hematopoiesis. Non-random chromosomal translocations involving the putative transcription factor Mixed Lineage Leukemia Translocated to 10 (MLLT10, also known as AF10) are commonly observed in both acute myeloid and lymphoid leukemias and are indicative of a poor prognosis. Despite the well-described actions of oncogenic MLLT10 fusion proteins, the role of wild-type MLLT10 in hematopoiesis is not well characterized. The protein structure and several interacting partners have been described and provide indications as to the potential functions of MLLT10. This review examines these aspects of MLLT10, contextualizing its function in benign and malignant hematopoiesis. Each highly specified, functional member of the hematopoietic system is derived from a common progenitor: the hematopoietic stem cell (HSC) (reviewed in [1Ng AP Alexander WS Haematopoietic stem cells: past, present and future.Cell Death Discov. 2017; 3: 17002Crossref PubMed Scopus (28) Google Scholar,2Pinho S Frenette PS. 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Chromosomal translocations, which occur when two neighboring chromosomes undergo midgene double-stranded breaks and are repaired to the incorrect gene, are one such cytogenetic abnormality that can lead to the development of leukemia [13Zheng J. Oncogenic chromosomal translocations and human cancer (review).Oncol Rep. 2013; 30: 2011-2019Crossref PubMed Scopus (12) Google Scholar,14Nickoloff JA De Haro LP Wray J Hromas R Mechanisms of leukemia translocations.Curr Opin Hematol. 2008; 15: 338-345Crossref PubMed Scopus (0) Google Scholar]. If the chromosomal rearrangement occurs in-frame, translocations can lead to the transcription and translation of a fusion protein, which can retain, lose, or alter functions of both partners [15Rabbitts TH. Chromosomal translocations in human cancer.Nature. 1994; 372: 143-149Crossref PubMed Scopus (1356) Google Scholar]. 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MLLT10 has up to seven different translocation partners found in leukemia to date (Figure 1) [18Dreyling MH Martinez-Climent JA Zheng M Mao J Rowley JD Bohlander SK The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family.Proc Natl Acad Sci USA. 1996; 93: 4804-4809Crossref PubMed Scopus (234) Google Scholar, 19Soler G Kaltenbach S Dobbelstein S et al.Identification of GSX2 and AF10 as NUP98 partner genes in myeloid malignancies.Blood Cancer J. 2013; 3: e124Crossref PubMed Scopus (0) Google Scholar, 20Brandimarte L Pierini V Di Giacomo D et al.New MLLT10 gene recombinations in pediatric T-acute lymphoblastic leukemia.Blood. 2013; 121: 5064-5067Crossref PubMed Scopus (27) Google Scholar, 21Bond J Bergon A Durand A et al.Cryptic XPO1-MLLT10 translocation is associated with HOXA locus deregulation in T-ALL.Blood. 2014; 124: 3023-3025Crossref PubMed Scopus (11) Google Scholar, 22Bond J Touzart A Cieslak A et al.NAP1L1–MLLT10 is a rare recurrent translocation that is associated with HOXA activation and poor treatment response in T-cell acute lymphoblastic leukaemia.Br J Haematol. 2016; 174: 470-473Crossref PubMed Scopus (2) Google Scholar, 23Chaplin T Ayton P Bernard OA et al.A novel class of zinc finger/leucine zipper genes identified from the molecular cloning of the t(10;11) translocation in acute leukemia.Blood. 1995; 85: 1435-1441Crossref PubMed Google Scholar]. 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MLLT10 is frequently translocated in leukemia, but the role it plays in normal hematopoiesis is not well characterized. This review summarizes what is known about wild-type MLLT10 in the context of hematopoiesis and sheds light on how its dysregulation through chromosomal translocation leads to the development of leukemia. Transcription factors are modular proteins with DNA-interacting segments and other domains for recruiting effector proteins [8Frietze S Farnham PJ Transcription factor effector domains.Subcell Biochem. 2011; 52: 261-277Crossref PubMed Scopus (17) Google Scholar]. MLLT10 functions as a transcription factor that interacts directly with DNA, the histone complex, and other transcription factors through its five described domains [36Linder B Newman R Jones LK et al.Biochemical analyses of the AF10 protein: the extended LAP/PHD-finger mediates oligomerisation.J Mol Biol. 2000; 299: 369-378Crossref PubMed Scopus (59) Google Scholar]. MLLT10 has an N-terminal PHD finger, zinc knuckle, and extended PHD finger (PZP) domain [37Saha V Chaplin T Gregorini A Ayton P Young BD The leukemia-associated-protein (LAP) domain, a cysteine-rich motif, is present in a wide range of proteins, including MLL, AF10, and MLLT6 proteins.Proc Natl Acad Sci USA. 1995; 92: 9737-9741Crossref PubMed Scopus (0) Google Scholar]. These two PHD fingers are collectively referred to as a leukemia-associated-protein finger (LAP finger) and have been reported to mediate protein–protein interactions and homo-oligomerization of recombinant MLLT10 in vitro [36Linder B Newman R Jones LK et al.Biochemical analyses of the AF10 protein: the extended LAP/PHD-finger mediates oligomerisation.J Mol Biol. 2000; 299: 369-378Crossref PubMed Scopus (59) Google Scholar,37Saha V Chaplin T Gregorini A Ayton P Young BD The leukemia-associated-protein (LAP) domain, a cysteine-rich motif, is present in a wide range of proteins, including MLL, AF10, and MLLT6 proteins.Proc Natl Acad Sci USA. 1995; 92: 9737-9741Crossref PubMed Scopus (0) Google Scholar]. Accumulating evidence of homo-oligomerization allows for speculation that oligomerization of MLLT10 is intrinsic to its function. In 2000, Linder et al. [36Linder B Newman R Jones LK et al.Biochemical analyses of the AF10 protein: the extended LAP/PHD-finger mediates oligomerisation.J Mol Biol. 2000; 299: 369-378Crossref PubMed Scopus (59) Google Scholar] performed many biochemical assays which forms the foundation of our current understanding of MLLT10. Using FLAG-tagged, full-length MLLT10, they observed a higher-molecular-weight species after crosslinking immunopurified samples with ethylene glycol bis(succinimidyl succinate) (EGS). These results were affirmed with size-elution chromatography and electron microscopy, indicating that pure MLLT10 can form tetramers in solution. In 2007, Forissier et al. [38Forissier S Razanajaona D Ay AS Martel S Bartholin L Rimokh R AF10-dependent transcription is enhanced by its interaction with FLRG.Biol Cell. 2007; 99: 563-571Crossref PubMed Scopus (0) Google Scholar] determined that this homo-oligomerization in vitro, as well as the transactivation potential of MLLT10, was enhanced by the interaction between MLLT10 and follistatin-related gene (FLRG) [39Hayette S Gadoux M Martel S et al.FLRG (follistatin-related gene), a new target of chromosomal rearrangement in malignant blood disorders.Oncogene. 1998; 16: 2949-2954Crossref PubMed Google Scholar]. Most recently, Song et al. [40Song X Yang L Wang M et al.A higher-order configuration of the heterodimeric DOT1L-AF10 coiled-coil domains potentiates their leukemogenenic activity.Proc Natl Acad Sci USA. 2019; 116: 19917-19923Crossref PubMed Scopus (1) Google Scholar] suggested that the DOT1L–MLLT10 dimer forms a tetramer complex that is critical for wild-type MLLT10 function. The PZP region also senses and interacts with unmodified H3K27 within the histone complex, as both acetylation and methylation of H3K27 inhibit this contact [41Chen S Yang Z Wilkinson AW et al.The PZP domain of AF10 senses unmodified H3K27 to regulate DOT1L-mediated methylation of H3K79.Mol Cell. 2015; 60: 319-327Abstract Full Text Full Text PDF PubMed Google Scholar]. MLLT10 is therefore targeted to a poised histone where it can recruit effector proteins to catalyze alterations to the histone, modulating transcription epigenetically [42Creyghton MP Cheng AW Welstead GG et al.Histone H3K27ac separates active from poised enhancers and predicts developmental state.Proc Natl Acad Sci USA. 2010; 107: 21931-21936Crossref PubMed Scopus (1789) Google Scholar]. MLLT10 binds type C cruciform DNA via the AT-hook motif, a structure-specific interaction consistent with the role of MLLT10 in regulating gene expression and replication [36Linder B Newman R Jones LK et al.Biochemical analyses of the AF10 protein: the extended LAP/PHD-finger mediates oligomerisation.J Mol Biol. 2000; 299: 369-378Crossref PubMed Scopus (59) Google Scholar,43Brázda V Laister RC Jagelská EB Arrowsmith C Cruciform structures are a common DNA feature important for regulating biological processes.BMC Mol Biol. 2011; 12: 33Crossref PubMed Scopus (108) Google Scholar]. To allow for the regulation of MLLT10 function via specific localization within the cell, there are three putative bipartite nuclear localization signals (NLSs). Of these, Linder et al. [36Linder B Newman R Jones LK et al.Biochemical analyses of the AF10 protein: the extended LAP/PHD-finger mediates oligomerisation.J Mol Biol. 2000; 299: 369-378Crossref PubMed Scopus (59) Google Scholar] determined that the most N-terminal NLS is responsible for nuclear targeting. Multiple groups have confirmed a nuclear localization of MLLT10 with immunofluorescence; however, an early publication reported the presence of MLLT10 in both cytoplasmic and nuclear extracts by Western blot [44Greif PA Tizazu B Krause A Kremmer E Bohlander SK The leukemogenic CALM/AF10 fusion protein alters the subcellular localization of the lymphoid regulator Ikaros.Oncogene. 2008; 27: 2886-2896Crossref PubMed Scopus (0) Google Scholar, 45Conway AE Scotland PB Lavau CP Wechsler DS A CALM-derived nuclear export signal is essential for CALM-AF10-mediated leukemogenesis.Blood. 2013; 121: 4758-4768Crossref PubMed Scopus (0) Google Scholar, 46Suzuki M Yamagata K Shino M et al.Nuclear export signal within CALM is necessary for CALM-AF10-induced leukemia.Cancer Sci. 2014; 105: 315-323Crossref PubMed Scopus (5) Google Scholar, 47Linder B Jones LK Chaplin T et al.Expression pattern and cellular distribution of the murine homologue of AF10.Biochim Biophys Acta. 1998; 1443: 285-296Crossref PubMed Scopus (21) Google Scholar]. Perhaps the most well-characterized domain of MLLT10 is the highly conserved octapeptide motif (EQLLERQW), followed by a partially conserved leucine zipper known as the OM/LZ domain [48Chaplin T Bernard O Beverloo HB Beverloo et al.The t(10;11) translocation in acute myeloid leukemia (M5) consistently fuses the leucine zipper motif of AF10 onto the HRX gene.Blood. 1995; 86: 2073-2076Crossref PubMed Google Scholar,49DiMartino JF Ayton PM Chen EH Nafzger CC Young BD Cleary ML The AF10 leucine zipper is required for leukemic transformation of myeloid progenitors by MLL-AF10.Blood. 2002; 99: 3780-3785Crossref PubMed Scopus (0) Google Scholar]. This motif is responsible for interaction of MLLT10 with several protein partners, such as DOT1L, IKAROS, and GAS41 [44Greif PA Tizazu B Krause A Kremmer E Bohlander SK The leukemogenic CALM/AF10 fusion protein alters the subcellular localization of the lymphoid regulator Ikaros.Oncogene. 2008; 27: 2886-2896Crossref PubMed Scopus (0) Google Scholar,50Debernardi S Bassini A Jones LK et al.The MLL fusion partner AF10 binds GAS41, a protein that interacts with the human SWI/SNF complex.Blood. 2002; 99: 275-281Crossref PubMed Scopus (0) Google Scholar,51Okada Y Feng Q Lin Y et al.hDOT1L links histone methylation to leukemogenesis.Cell. 2005; 121: 167-178Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar]. This domain is necessary and sufficient for MLLT10 to induce leukemogenesis [49DiMartino JF Ayton PM Chen EH Nafzger CC Young BD Cleary ML The AF10 leucine zipper is required for leukemic transformation of myeloid progenitors by MLL-AF10.Blood. 2002; 99: 3780-3785Crossref PubMed Scopus (0) Google Scholar,52Deshpande AJ Rouhi A Lin Y et al.The clathrin-binding domain of CALM and the OM-LZ domain of AF10 are sufficient to induce acute myeloid leukemia in mice.Leukemia. 2011; 25: 1718-1727Crossref PubMed Google Scholar], as will be explained under MLLT10 in Leukemia in this review. Classically, leucine zippers facilitate dimerization or higher-order oligomerization and DNA binding [40Song X Yang L Wang M et al.A higher-order configuration of the heterodimeric DOT1L-AF10 coiled-coil domains potentiates their leukemogenenic activity.Proc Natl Acad Sci USA. 2019; 116: 19917-19923Crossref PubMed Scopus (1) Google Scholar,53Pu WT Struhl K. Dimerization of leucine zippers analyzed by random selection.Nucleic Acids Res. 1993; 21: 4348-4355Crossref PubMed Google Scholar]. As briefly mentioned, the OM/LZ domain of MLLT10 has been well documented in its interaction with DOT1L and has been found to facilitate the formation of MLLT10–DOT1L heterodimers in vitro [40Song X Yang L Wang M et al.A higher-order configuration of the heterodimeric DOT1L-AF10 coiled-coil domains potentiates their leukemogenenic activity.Proc Natl Acad Sci USA. 2019; 116: 19917-19923Crossref PubMed Scopus (1) Google Scholar]. These recent studies, which were performed with constructs consisting only of the OM/LZ domain of MLLT10 and individual coiled-coil domains of DOT1L, have indicated that oligomerization occurs between the leucine zipper domain of MLLT10 and coiled-coil regions of DOT1L [40Song X Yang L Wang M et al.A higher-order configuration of the heterodimeric DOT1L-AF10 coiled-coil domains potentiates their leukemogenenic activity.Proc Natl Acad Sci USA. 2019; 116: 19917-19923Crossref PubMed Scopus (1) Google Scholar]. It has not been determined if full-length MLLT10 and DOT1L form these heterodimers in vivo, whether this would occur via the PHD or OM/LZ domain of full-length MLLT10, nor how this regulates MLLT10 function. Finally, there is an insufficiently characterized glutamine-rich region (Q-rich) located on the C terminus of MLLT10 [36Linder B Newman R Jones LK et al.Biochemical analyses of the AF10 protein: the extended LAP/PHD-finger mediates oligomerisation.J Mol Biol. 2000; 299: 369-378Crossref PubMed Scopus (59) Google Scholar]. Q-Rich regions are commonly found in eukaryotic transcription factors and play a role in regulating their activity [54Gemayel R Chavali S Pougach K et al.Variable glutamine-rich repeats modulate transcription factor activity.Mol Cell. 2015; 59: 615-627Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar]. The structural domains of a transcription factor dictate its function. Transcription factors cannot facilitate alterations in gene expression independently but must interact with other protein partners to modulate the epigenetic state of gene targets [8Frietze S Farnham PJ Transcription factor effector domains.Subcell Biochem. 2011; 52: 261-277Crossref PubMed Scopus (17) Google Scholar]. Although there is no comprehensive understanding of MLLT10 target genes, we can gleam invaluable insight into its role in hematopoiesis and development through examination of its known interacting partners [55Will T Helms V Identifying transcription factor complexes and their roles.Bioinformatics. 2014; 30: i415-i421Crossref PubMed Google Scholar]. The most well-characterized co-factor of wild-type MLLT10 is disruptor of telomeric silencing 1-like (DOT1L), the sole mammalian histone methyltransferase of H3K79 [56Nguyen AT Zhang Y. The diverse functions of Dot1 and H3K79 methylation.Genes Dev. 2011; 25: 1345-1358Crossref PubMed Scopus (318) Google Scholar]. Okada et al. [51Okada Y Feng Q Lin Y et al.hDOT1L links histone methylation to leukemogenesis.Cell. 2005; 121: 167-178Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar] discovered the interaction between MLLT10 and DOT1L in 2005, initially linking dysregulated DOT1L activity to Hoxa upregulation in leukemia. Functionally, DOT1L catalyzes the addition of one, two, or three methyl groups onto H3K79 within the nucleosome. Notably, this residue is unique in the way it is modified within the histone core, instead of the more commonly modified histone tail residues [56Nguyen AT Zhang Y. The diverse functions of Dot1 and H3K79 methylation.Genes Dev. 2011; 25: 1345-1358Crossref PubMed Scopus (318) Google Scholar]. Interestingly, DOT1L does not contain a SET domain as other histone methyltransferases do, and instead binds S-adenosyl methionine (SAM) to act as a methyl donor [56Nguyen AT Zhang Y. The diverse functions of Dot1 and H3K79 methylation.Genes Dev. 2011; 25: 1345-1358Crossref PubMed Scopus (318) Google Scholar]. Deshpande et al. [57Deshpande AJ Deshpande A Sinha AU et al.AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes.Cancer Cell. 2014; 26: 896-908Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar] reported that MLLT10 is required for DOT1L recruitment to target genes and the further methylation of H3K79me1, but not the initial methylation of H3K79. While DOT1L can partner with other proteins to facilitate methylation of H3K79, MLLT10 is responsible for the large majority of this complex's function [57Deshpande AJ Deshpande A Sinha AU et al.AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes.Cancer Cell. 2014; 26: 896-908Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar,58Park G Gong Z Chen J Kim JE Characterization of the DOT1L network: implications of diverse roles for DOT1L.Protein J. 2010; 29: 213-223Crossref PubMed Scopus (33) Google Scholar]. The coiled-coil domain within DOT1L interacts with the OM-LZ domain of MLLT10, an interaction stabilized by zinc [40Song X Yang L Wang M et al.A higher-order configuration of the heterodimeric DOT1L-AF10 coiled-coil domains potentiates their leukemogenenic activity.Proc Natl Acad Sci USA. 2019; 116: 19917-19923Crossref PubMed Scopus (1) Google Scholar]. Loss of MLLT10—and disruption of the MLLT10–DOT1L interaction—results in a genome-wide decrease in H3K79me2 and H3K79me3, correlating with a decrease in genomic stability and disrupted hematopoiesis, mirroring the effects of loss of DOT1L [57Deshpande AJ Deshpande A Sinha AU et al.AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes.Cancer Cell. 2014; 26: 896-908Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar,59Ogoh H Yamagata K Nakao T et al.Mllt10 knockout mouse model reveals critical role of Af10-dependent H3K79 methylation in midfacial development.Sci Rep. 2017; 7: 11922Crossref PubMed Scopus (1) Google Scholar,60Nguyen AT He J Taranova O Zhang Y Essential role of DOT1L in maintaining normal adult hematopoiesis.Cell Res. 2011; 21: 1370-1373Crossref PubMed Scopus (39) Google Scholar]. To date, the relationship between DOT1L and MLLT10 is the most studied aspect of wild-type MLLT10. However, MLLT10 interacts with multiple proteins, and the role it plays in other contexts needs to be considered as well to fully elucidate MLLT10 function. MLLT10-interacting partners are known to be involved in regulating higher-order chromatin structure, the DNA damage response, and the Wnt signaling pathway, so it should be considered that MLLT10 may function in these cellular processes. The evidence indicating the role of MLLT10 in higher-order chromatin structure stems from studies highlighting protein-interacting partners that are well established in this regard. GAS41, TIP60, and IKAROS are all the currently known interacting partners of MLLT10 that play a role in regulating gene expression on a macro level through chromatin remodeling ATPase complexes [50Debernardi S Bassini A Jones LK et al.The MLL fusion partner AF10 binds GAS41, a protein that interacts with the human SWI/SNF complex.Blood. 2002; 99: 275-281Crossref PubMed Scopus (0) Google Scholar,61Kim J Sif S Jones B et al.Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes.Immunity. 1999; 10: 345-355Abstract Full Text Full Text PDF PubMed Google Scholar,62Squatrito M Gorrini C Amati B Tip60 in DNA damage response and growth control: many tricks in one HAT.Trends Cell Biol. 2006; 16: 433-442Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar]. MLLT10 interacts with GAS41, a documented epigenetic reader sensitive to succinylation on histone H3K122, as well as acetylation on H3K27 and H3K14 [63Hsu CC Zhao D Shi J et al.Gas41 links histone acetylation to H2A.Z deposition and maintenance of embryonic stem cell identity.Cell Discov. 2018; 4: 28Crossref PubMed Scopus (5) Google Scholar]. Initially determined to interact with MLLT10 by a yeast two-hybrid screen, the interaction was confirme
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