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MINI REVIEW New Insight Into the Molecular Mechanisms of MLL

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MINI REVIEW New Insight Into the Molecular Mechanisms of MLL Leukemia (2005) 19, 183–190 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu MINI REVIEW New insight into the molecular mechanisms of MLL-associated leukemia Z-Y Li1, D-P Liu1 and C-C Liang1 1National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, PR China Rearrangements of the MLL gene (ALL1, HRX, and Hrtx) located have been described, and 33 of the presumptive gene partners of at chromosome band 11q23 are commonly involved in adult MLL cloned and analyzed at the molecular level.13 The and pediatric cases of primary acute leukemias and also found in cases of therapy-related secondary leukemias. Studies on mechanisms by which these rearrangements result in leukemia mouse models of MLL translocation and cell lines containing remain largely unknown. MLL rearrangements showed that the MLL gene linked In addition to chromosomal translocations, other mechanisms chromosomal rearrangements to cellular differentiation and of MLL rearrangement have been demonstrated in patients with tumor tropism. Moreover, recent structural/functional studies acute leukemia. The partial tandem duplication (PTD) of MLL is on MLL and aberrant MLL proteins provided new clues and present in approximately 10% of patients with acute myeloid suggested that different mechanisms might be included in 14 leukemogenesis by MLL rearrangements. The connection leukemia (AML) and normal cytogenetics and in the majority between these different mechanisms will help us understand of patients with AML and trisomy 11 as the sole cytogenetic 15 globally how aberrant MLL oncogenes affect the normal cellular abnormality. This rearrangement is characterized by an processes at molecular level. internal duplication of MLL spanning exons 2–6 or 2–8.16 Leukemia (2005) 19, 183–190. doi:10.1038/sj.leu.2403602 Amplification within chromosome arm 11q involving MLL gene Published online 16 December 2004 locus is a rare but recurrent aberration in AML and myelodys- Keywords: ; leukemia; molecular mechanisms MLL plastic syndrome (AML/MDS).17–19 These alternative classes of MLL mutants presumably promote leukemogenesis without the concomitant requirement for fusion of MLL to a partner protein, suggesting that alteration of MLL alone, in some circumstances, Introduction is sufficient to promote leukemogenesis. Leukemia is a heterogeneous disease at the molecular level resulting from a variety of alterations in numerous genes Functions of normal MLL protein important for cell growth, differentiation, and cell death. Identification and characterization of these genetic rearrange- MLL, a human homologue of the epigenetic transcriptional ments have been proved invaluable for appropriate diagnosis regulator Trithorax of Drosophila,20 is an upstream transcrip- and prognosis, especially in acute leukemia. Rearrangements of tional effector of HOX genes.21,22 The importance of normal the MLL gene (ALL1, HRX, and Hrtx) located at chromosome MLL protein for normal axial-skeletal developmental process band 11q23 are commonly involved in acute leukemia. These and HOX gene regulation has been demonstrated in the rearrangements have been shown to be associated with some embryos of heterozygous and homozygous MLL knockout21 1–3 4–6 adult and pediatric cases of primary acute leukemias and and MLL truncation mutant mice.23 Furthermore, expression of also are found in the majority of patients with secondary MLL protein is not necessary for turning on transcription of leukemias after prior treatment with DNA topoisomerase II certain HOX genes, but for the maintenance of their transcrip- 7,8 inhibitors (eg, etoposide). Unlike many other types of tion.22 Experiments in vitro using hematopoietic progenitors leukemia, the presence of an MLL translocation predicts early from embryos of homozygous MLL knockout mice24,25 or mice 9,10 relapse and poor prognosis. Frequently, leukemic blasts are with MLL mutant26 showed that MLL was also critical for characterized by the expression of lymphoid and myeloid hematopoietic development. Recent findings suggested that surface markers, defining MLL or Mixed Lineage Leukemia MLL is required during embryogenesis for the specification or 11 gene. expansion of hematopoietic stem cells.27 As HOX genes also The Mixed-Lineage Leukemia gene (MLL/HRX/ALL1) consists play a key role in the regulation of hematopoietic develop- of at least 36 exons, encoding a 3969 amino-acid nuclear ment,28 the hematopoietic dysfunction of MLL null cells is likely protein with a molecular weight of nearly 430 kDa that is to be attributed to deregulated patterns of HOX gene expression thought to function as a positive regulator of gene expression in in hematopoietic stem cells or progenitors. This link between early embryonic development and hematopoiesis. MLL translo- MLL, HOX gene regulation, and hematopoiesis is of particular cation breakpoints cluster within an 8.3-kb region spanning importance. 12 exons 5–11. To date, over 60 chromosome partners of 11q23 Structural/functional studies on normal MLL protein also provide some information on MLL functions. MLL protein Correspondence: Dr D-P Liu, National Laboratory of Medical possesses some functional domains that could confer significant Molecular Biology, Institute of Basic Medical Sciences, Chinese functional activity (Figure 1). Of these functional domains, AT Academy of Medical Sciences and Peking Union Medical College, 5 hooks and MT domain have DNA-binding activity that could be Dong Dan San Tiao, Beijing 100005, PR China; Fax: þ 8610 65105093; E-mail: [email protected] involved in the regulation of gene transcription through direct Received 22 July 2004; accepted 15 October 2004; Published online binding to DNA. The AT hook, with homology to the high- 16 December 2004 mobility group I (HMG-I) protein, binds to AT-rich regions of the Molecular mechanisms of MLL-associated leukemia Z-Y Li et al 184 Figure 1 Schematic depictions of wild type and aberrant MLL proteins. As MLL translocation occurs, MLL N terminus fuses with other nonrelated proteins, and they will form chimeric proteins. However, in the normal process, MLL will be cleaved into two fragments. The partial tandem duplication of MLL leads to fusion of the 50 portion of MLL protein with itself. Various putative functional domains are shown as colored boxes and labeled as follows: AT hooks, AT hook DNA binding motifs; SNL 1 and 2, speckled nuclear localization signals 1 and 2; CxxC (MT), cysteine-rich motif homologous to DNA methyltransferase and MBD1; PHD 1–3, PHD fingers 1, 2 and 3; BROMO, BROMO domain; FYRN, F/Y- rich region, N-terminus; FYRC, F/Y-rich region, C-terminus; TAD, transactivation domain; SET, SET domain. Regions structurally conserved with Trithorax of Drosophila are indicated by the (TRX) label. minor groove of the DNA, but it recognizes DNA structure domain,38 suggesting that MLL normally functions as a dimer or rather than specific consensus sequences.29 The MT domain is a oligomer. Besides these domains, MLL also has nuclear cysteine-rich CXXC region with homology to a DNA methyl- localization signals in its N-terminal that determine a punctate transferase and methyl-CpG-binding protein 1 (MBD1).29,30 Like localization pattern of the proteins in the nucleus.39 these proteins, the MT domain of MLL has DNA-binding activity to unmethylated CpG sequences, in contrast to MBD1, which binds methylated CpG sequences.31 MLL protein is also known The maturation of MLL protein to have transcriptional repression activity by recruiting repressor complex(es) such as HDAC or polycomb group proteins such as Full-length MLL protein can be cleaved post-translationally by a HPC2 or BMI-1 through MT domain.32 protease, taspase 1, at two conserved amino-acid motifs (CS1: For most proteins with PHD finger domain are components of D/GADD; CS2: D/GVDD).40 Thus, MLL protein is cleaved into chromatin remodeling/transcriptional regulation complexes, at two fragments – an N-termninal 320 kDa (amino acids 1–2666; least some part of chromatin remodeling/transcriptional regula- N320) fragment with transcriptional repression activity and a C- tion activities of normal MLL protein may be associated with terminal 180 kDa (amino acids 2719–3969; C180) fragment PHD fingers.33 In addition, nuclear cyclophilin Cyp33 can bind with strong transcriptional activation properties.41 The N- to the PHD finger of MLL, and overexpression of Cyp33 is terminal fragment comprises a series of AT-hook motifs: the known to have some effects on the expression pattern of HOX SNL1 and SNL2 (speckled nuclear localization signals 1 and 2) genes.34 MLL also has a transcriptional activation domain (TAD) regions; the MT domain, and the PHD zinc-finger domain. The between the PHD fingers and C-terminal SET domain. This C-terminal fragment contains the SET domain and the TAD activation domain of MLL can bind directly to CBP and facilitate domain. The FYRN domain (amino acids 1979–2130) located in the binding of CBP with CREB to promote transcriptional N320 interacts with the FYRC and SET domains (amino acids activation.35 The SET domain is also an evolutionarily highly 3656–3969) located in C180 (Figure 1), thus the two complex conserved region and has activity as a lysine-directed histone MLL peptides build the basic structure required for an MLL methyltransferase that impacts on chromatin structure and multiprotein supercomplex (MLL MPSC)37 that consists of both transcriptional
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