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REVIEW
MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK
Chromosomal1 translocations are key elements in tumor etiology, as these somatically created abnormal chromosomes have activated oncogenes where the chromosome breakpoints occur (for review, see Rabbitts 1994
). Most often, gene fusions are caused by chromosomal translocations, which frequently break within the exons of the two involved chromosomes, allowing the transcription product to encompass the linked exons, for post-transcriptional processing to splice these exons to create a tumor-specific fusion mRNA and in turn fusion protein. This type of event is common in both leukemias and in sarcomas (Rabbitts 1994; Look 1997). The leukemias divide into chronic and acute forms of cancer. The translocation genes involved can be roughly categorized into distinct types, with those involved in acute leukemia often being transcription regulators (Cleary 1991) whose role as master genes in cell fate determination is a key element in their role in leukemias (Rabbitts 1991). Thus, activated oncogenes or gene fusions influence differentiation in cell-specific ways and the tropism of specific chromosomal translocations for specific cell types is a manifestation of this role.
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The ubiquitous MLL gene and its multitude of chromosomal abnormalities |
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 Top The ubiquitous MLL gene... The MLL protein is...A newly defined threonine...HOX gene regulation by...MLL dimerization as a...Models of MLL fusion-induced...Future prospectivesAcknowledgmentsReferences |
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, 1998; Look 1997; Ayton and Cleary 2001). A gene called the mixed-lineage leukemia gene, MLL (or HTRX, HRX, TRX1, ALL-1; Ziemin-van der Poel et al. 1991; Djabali et al. 1992; Gu et al. 1992; Tkachuk et al. 1992; Domer et al. 1993), is found at the breakpoints of the many and disparate chromosomal translocations of 11q23 (as well as cases of internal duplication of 11q23, often associated with trisomy 11; Schichman et al. 1994, 1995; Caligiuri et al. 1996; Schnittger et al. 2000). Chromosomal breakpoints are found in a consistent region of MLL and cause the synthesis of an MLL fusion protein in the damaged cells, which leads to leukemia of those cells. Chromosomal translocations (or other abnormalities) alter the MLL gene structure, often by creating a fusion between MLL and a gene from a different chromosomal region, and, uniquely among the translocation genes, more than 30 different MLL fusions have been described (for review, see Ayton and Cleary 2001; Collins and Rabbitts 2002). The most frequently found are MLL-AF4 and MLL-AF9 (Fig. 1A). A critical piece of MLL fusion protein biology is the association of specific versions with either acute myeloid leukemias (AML) or acute lymphoid leukemias (ALL). MLL gene abnormalities are found in childhood leukemias (
10% of all pediatric leukemias) and in adults (5% of acute leukemias; Look 1997; Huret et al. 2001).
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45%-75% for AML (Stone 2002) and cure of childhood ALL up to 80% (Downing and Shannon 2002; Pui et al. 2002). However, in addition to spontaneously arising leukemias, there are also MLL-associated leukemias related to the therapies applied to ablate leukemias, which often therefore arise as new leukemias unrelated to the original disease for which the patient was given high-dose chemotherapy (Bloomfield et al. 2002). Around 5%-10% of MLL-associated leukemias are therapy related (t-leukemia). These therapy-related cancers can be acute myeloid leukemia (t-AML) and, more rarely, therapy-related acute lymphoblastic leukemia (t-ALL), myelodysplasia (t-MDS), or chronic myelo-monocytic leukemia (t-CMML). Of these t-leukemias, approximately half are made from various chromosomal translocations and the other half, the most frequent MLL fusion partners, are ELL (eleven nineteen lysine-rich leukaemia gene), AF4 (ALL1 fused gene from chromosome 4), AF9 (ALL1 fused gene from chromosome 9), and AF10 (ALL1 fused gene from chromosome 10; Fig. 1B; Huret et al. 2001). These MLL-associated t-leukemias occur after treatment with topoisomerase II targeting drugs (Felix 2001) but also occur with a variety of other treatments including radiotherapy and regardless of the primary cancer type, that is, leukemias, sarcomas, and solid tumors (Bhatia and Sklar 2002). |
The MLL protein is large, multidomain, and versatile |
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TopThe ubiquitous MLL gene...The MLL protein is...A newly defined threonine...HOX gene regulation by...MLL dimerization as a...Models of MLL fusion-induced...Future prospectivesAcknowledgmentsReferences |
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100 kb, and chromosomal abnormalities involved in this gene (translocations, inversions, and interstitial duplications) are clustered in a major break region (MBR) just after the repression domain (Fig. 2A). The most remarkable feature of MLL in leukemias is the diversity of fusion partners (Ayton and Cleary 2001; Collins and Rabbitts 2002). MLL can fuse to at least 36 partner genes with more than 60 recurrent chromosomal translocations (Huret et al. 2001; see also Atlas of Genetics and Cytogenetics in Oncology and Haematology, http://www.infobiogen.fr/services/chromcancer/Anomalies/11q23ID1030.html). However, chromosomal translocations are not the only mechanism of conversion of MLL into an oncogene, as other recurrent events have been found, most especially a partial tandem duplication close to the plant homeodomain (PHD) domain (Schichman et al. 1994; Caligiuri et al. 1996; Schnittger et al. 2000; Fig. 2B). Translocations, inversions, and interstitial duplications are present in patients with myeloid or lymphoid leukemias.
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). Three AT hooks are found near the N terminus of MLL that mediate binding to the minor groove of AT-rich DNA (Zeleznik-Le et al. 1994), and the transcriptional repression domain (Fig. 2A, RD1, RD2) contains a DNMT1 DNA methyltransferase homology domain including the CXXC zinc-finger domain (Ma et al. 1993; Prasad et al. 1995; Xia et al. 2003). This domain remains in all MLL fusions following translocations and is required for transformation capacity of the fusion proteins (Slany et al. 1998). MLL is a member of the trithorax family and recruits the polycomb repressor proteins HPC2 and BMI-1, as well as the corepressor protein CTBP, providing repression activity independent from RD2 (Xia et al. 2003). RD2 mediates transcriptional repression through recruitment of histone deacetylases HDAC1 and HDAC2, which can also interact with part of RD1 directly (Xia et al. 2003). Thus, the MLL super-complex remodels, acetylates and deacetylates, and methylates nucleosome-attached histone (Ernst et al. 2001; Milne et al. 2002; Nakamura et al. 2002; Xia et al. 2003). However, following chromosomal translocations, the histone H3-K4 methylation, which occurs through the C-terminal SET [Su(var)3-9, Enhancer-of-zeste, Trithorax] domain of MLL (Milne et al. 2002; Nakamura et al. 2002), is lost, to be replaced by a fusion partner. Following chromosomal translocations, the main region of gene fusion lies just beyond the exons encoding the C-terminal side of the repression domain, defining the MBR (Fig. 2A), which is adjacent to PHD zinc-finger regions and the BROMO domain (Rowley 1998). This has consequences for target gene activity as the MLL-mediated H3 and H4 methylation of the HOXA9 and Hoxc8 promoter cannot occur after chromosomal translocations (Milne et al. 2002; Nakamura et al. 2002), although it could theoretically do so in the cases of trisomy 11 with the internal duplication of MLL (Fig. 2B). |
A newly defined threonine protease cleaves MLL downstream of the MBR |
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). Biochemical studies of MLL protein synthesis showed that indeed the native protein is cleaved post-translationally into two parts and thus does not accumulate in cells in its 500-kD native form (Nakamura et al. 2002; Yokoyama et al. 2002; Hsieh et al. 2003b). Elegant biochemical isolation work has recently resulted in isolation and gene cloning of a novel threonine protease, designated taspase 1 (an endopeptidase with an asparaginase 2 homology domain), responsible for proteolysis of MLL (Hsieh et al. 2003a). The mature MLL protein is cleaved by taspase 1 at amino acid residues 2666/2667 (CS1) and 2718/2719 (CS2; Fig. 2A; Hsieh et al. 2003a) yielding N300/320- and C180-terminal polypeptides. These fragments reassociate through the FYRN domain (amino acids 1975-2158) and FYRC domain plus part of the SET domain(amino acids 3656-3876; Hsieh et al. 2003b). The break region is located upstream of the taspase 1 sites; thus, MLL fusion proteins are not a substrate for this protease. In addition, there is an apparent discrepancy between loss of the taspase sites after chromosomal translocations and their retention in cases of internal duplication of MLL (Fig. 2B). Part of the explanation may be that stabilization of MLL fusions occurs in the former by loss of taspase proteolysis sites and in the latter by effectively displacing the taspase proteolysis sites to the C-terminal end of a huge, potentially stable protein that would still be 430 kD after taspase cleavage of the C-terminal sites. It is possible that the important event of chromosomal abnormality is disturbance of homeostasis of the MLL supercomplex, which would be a facile explanation for the huge variability of MLL alterations (including the deletion of the simple first PHD finger; Lochner et al. 1996) leading to the deregulation of a very specific set of target genes. |
HOX gene regulation by MLL fusion proteins |
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; Hess et al. 1997; Yagi et al. 1998), accompanied by homeobox (Hox) gene expression abnormalities, which were most significant for Hoxa7, Hoxa9, Hoxa10, Hoxc4, Hoxc8, and Hoxc9 in whole embryos or fetal liver (Yu et al. 1995; Yagi et al. 1998). Analysis of the MLL supercomplex demonstrated direct binding of MLL to HOXA9 and Hoxc8 promoters (Milne et al. 2002; Nakamura et al. 2002). Gene targeting of the mouse homologs of genes encoding fusion partners of MLL gave further evidence of regulators of cell differentiation. The null mutation of the mouse homolog of AF9 showed its importance for embryonic patterning without influencing hematopoiesis (Collins et al. 2002), whereas the mouse Af4 gene influences lymphoid development (Isnard et al. 2000). These observations suggested that the MLL fusion proteins, created by the leukemia-associated chromosomal abnormalities, are themselves transcription regulators that may be determinants of HOX gene expression in abnormal arrangements (Ayton and Cleary 2001; Collins and Rabbitts 2002). Target gene assessment lends very strong support to this model of MLL fusion protein function (Ayton and Cleary 2001; Collins and Rabbitts 2002). An especially pertinent function of MLL, and of its fusion protein derivatives, is as a major regulator of class I HOX gene expression (for review, see Ernst et al. 2002). HOX genes are a major group of transcription factors and participate in the control of embryonic development and hematopoietic cell differentiation with a specific expression pattern in different hematopoietic lineages at various differentiation stages (Sauvageau et al. 1994; Lawrence et al. 1996; Pineault et al. 2002). In leukemias with MLL fusion proteins, disturbance of HOX expression patterns has been observed, subverting a major role of HOX gene expression in hematopoietic lineage regulation (Yu et al. 1995; Hess et al. 1997; Yagi et al. 1998). All three major types of MLL gene aberrations (Fig. 2) are implicated in HOX gene deregulation as the mediator of leukemia.
An important link between Hox gene expression and MLL-ENL (eleven nineteen leukemia) fusion protein-mediated leukemogenesis was made using retroviral transduction of bone marrow progenitors (Ayton and Cleary 2003). In these studies, embryonic stem (ES) cells that were null for Hoxa7 or Hoxa9 had reduced in vitro myeloid immortalization but bone marrow transplantation (BMT) of Hoxa9-/- bone marrow (BM) cells transduced with retroviral expressing MLL-ENL failed to develop leukemias, whereas wild-type BM cells with MLL-ENL developed AML. Finally, the ability of Hoxa9-/- BM cells to become leukemic in vivo was rescued by expression of both Hoxa9 and MLL-ENL. This showed unequivocally that leukemia only occurs if the Hoxa9 gene is present and suggests an absolute requirement of Hoxa9, and possibly of Hoxa7, for the development of AML mediated by MLL-ENL (Ayton and Cleary 2003). However, the situation with Mll-AF9 may be different because Mll-AF9 knock-in mice develop leukemia with similar rates in the presence or the absence of the Hoxa9 gene showing that Hoxa9 is not required for leukemia in the KI (knock-in using homologous recombination) model (Kumar et al. 2004). It is intriguing that the Mll-AF9 leukemias in the absence of Hoxa9 have a more immature phenotype (Kumar et al. 2004). This difference between the outcomes of the two fusions may reflect the different models used (i.e., BMT for MLL-ENL and KI for Mll-AF9) or may reflect biological differences mediated through the two fusion proteins.
Hoxa7 and Hoxa9 expression was also observed in BMT in vitro models with fusion proteins MLL-GAS7, MLL-AF1P, MLL-AF9, and dimerized MLL. In addition, Hoxa7 and a9 gene expression was reversibly deregulated in a dimerization model in which MLL dimerization was required for a blockage of BM myeloid cell differentiation (see below; Martin et al. 2003). Addition of the inducer of dimerization caused MLL fusion to bind with the Hoxa9 promoter, linking MLL-induced leukemogenesis with HOX gene regulation. An intriguing feature of Hox gene expression profiles in these Mll fusion gene models is that the Hox gene expression is very similar in all models regardless of which fusion partner was expressed in the chimeric protein. This suggests that the MLL fusion gene characteristics are the dominant feature of this type of leukemia, as opposed to other transformation mechanisms. Data from gene expression profiling studies with human leukemias strengthen this conclusion. All MLL-associated leukemia subtypes had HOXA9 and MEIS1 expression (Armstrong et al. 2002; Yeoh et al. 2002; Debernardi et al. 2003; Ferrando and Look 2003). Different MLL tumor lineages share very similar deregulated HOX gene expression patterns (Armstrong et al. 2002; Yeoh et al. 2002; Debernardi et al. 2003; Ferrando and Look 2003), and the pattern is independent from the specific fusion partner, as found for the mouse models. ALLs were divided into subgroups according to their chromosomal translocation associated with a highly specific cluster of overexpressed genes (Armstrong et al. 2002; Yeoh et al. 2002; Ferrando and Look 2003). Thus, the profiling data suggest that HOX genes are targeted by the MLL fusions, but the nature of the fusion partner does not contribute to the specificity of the HOX gene subset target.
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MLL dimerization as a mechanism of leukemogenesis |
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TopThe ubiquitous MLL gene...The MLL protein is...A newly defined threonine...HOX gene regulation by...MLL dimerization as a...Models of MLL fusion-induced...Future prospectivesAcknowledgmentsReferences |
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; Caligiuri et al. 1996; Schnittger et al. 2000), which are effectively duplications of the N-terminal region to just ahead of the PHD fingers (Fig. 2B). In addition, a subgroup of MLL fusion partners that are joined by chromosomal translocations have oligomerization domains such as leucine zippers and 
-helical coiled-coil domains (Prasad et al. 1994; Chaplin et al. 1995; Saha et al. 1995; Linder et al. 2000; Pegram et al. 2000; Sano 2001; DiMartino et al. 2002; Ono et al. 2002; Slater et al. 2002). The first experimental evidence for molecular dimerization as a mode of MLL tumorigenicity came from the finding that mice with the lacZ gene (encoding 
-galactosidase) knocked into Mll at the place corresponding to the break region of human MLL developed AML (Dobson et al. 2000) and that these mice express Mll--galactosidase protein with -galactosidase enzyme (which is a tetramer) activity. Furthermore, an N-terminal segment of Mll has no transforming capacity, as an artificially created truncation of Mll at exon 8 in the break region has no influence on hematopoietic differentiation or on tumor propensity (Corral et al. 1996). This suggested that addition of material to the N-terminal portion of MLL may be a mechanism to elicit a tumorigenic effect and that stabilization of the N-terminal MLL protein and dimerization could be the functional consequence of such fusions (Prasad et al. 1994; Chaplin et al. 1995; Dobson et al. 2000).
In recent publications, dimerization of MLL has been directly tested as a biochemical function involved in tumorigenicity. Two fusion partners of MLL are GAS7 and AF1P (So et al. 2003b), which are normally cytoplasmic proteins with different functions but both possessing coiled-coil domains capable of oligomer formation, potentially creating nuclear, oligomerized MLL fusions. This was directly tested using retroviral transduction of BM hematopoietic stem cells followed by transplantation into recipient mice (So et al. 2003b). Both fusion products resulted in leukemia but, significantly, the presence of the GAS7 or AF1P coiled-coil domains fused to the MLL portion was sufficient for transformation in mice. Further, an inducible dimerization of N-terminal MLL affected hematopoietic differentiation, which was reversible by withdrawing a pharmacological dimerization agent (Martin et al. 2003; using retroviral transduction of mouse BM cells with the MLL fusion partner FKBP12, which is a FK506 binding protein that oligomerizes in the presence of AP20187). These studies support the conclusions about the earlier Mll-lacZ KI mice that MLL dimerization is a key element of its leukemogenic function (Dobson et al. 2000). As first observed with the Mll-lacZ KI model (Dobson et al. 2000), all of these models of MLL oligomerization have reduced oncogenicity, compared with "normal" Mll fusions, which suggests further specific biological contributions of the fusion partners in dynamics and penetrance of tumorigenesis.
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Models of MLL fusion-induced leukemia in mice |
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TopThe ubiquitous MLL gene...The MLL protein is...A newly defined threonine...HOX gene regulation by...MLL dimerization as a...Models of MLL fusion-induced...Future prospectivesAcknowledgmentsReferences |
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; Fig. 3A, designated pro-B and pro-T, respectively). Myeloid cells (granulocytes and monocyte lineage) emanate from the granulocyte-monocyte precursor (GMP) and erythrocytes and megakaryocytes from their precursor (MEP). MLL fusions created somatically in this tissue can be instructive or noninstructive in determining tumor phenotype. In the instructive model, the acquisition of a fusion is followed by a developmental signal through the MLL fusion protein (Fig. 3B). Thus, for instance, MLL-AF4, which typically occurs in B-lymphoid tumors, would provide proliferative signals for B-cell differentiation. This would imply that MLL-AF4 translocations occur in the HSC or progeny. Alternatively, MLL-AF9 has a cell fate effect giving rise to myeloproliferation and eventual myeloid leukemias (Fig. 3B). A variant of this model is the postulate of a biphenotypic cell that comes from the HSC and is the target of MLL fusions (Cumano et al. 1992; Montecino-Rodriguez et al. 2001; Fig. 3C), leading to either ALL or AML depending on which fusion is found. Finally, the noninstructive model attributes no cell fate decisions to the fusion but rather indicates that translocations will be oncogenic when in a permissive cell (Fig. 3D). Thus, MLL-AF9 would be oncogenic in the myeloid precursors and MLL-AF4 in lymphoid precursors.
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). An important feature was that the Mll-AF9 fusion elicited an early myelo-proliferation, which preceded the onset of AML in both chimeric and heterozygous KI mice, and could be detected as early as 6 d after birth (Corral et al. 1996; Dobson et al. 1999). Myelo-proliferative impairment could be detected prenatally but was not sufficient at any time point (prenatally or postnatally) to induce leukemia in transplantation experiments. The late onset of overt leukemia suggests that secondary mutational events (not directly on Mll) were necessary for the malignant transformation of the myelo-proliferative cell pool. Similarly, the use of retroviral transduction of BM progenitors and transplantation of such cells into syngeneic mouse recipients models lineage specific leukemia (Ayton and Cleary 2001). In this way, transduction of hematopoietic stem cells with retrovirus expressing the MLL-ENL fusion caused leukemia and myelo-proliferation preceding the leukemia (Lavau et al. 1997; Slany et al. 1998).
In different circumstances, retroviral transduction of BM has also been used to show that both MLL-ENL and MLL-GAS7 can induce a biphenotypic leukemia using controlled culture conditions (So et al. 2003a; Zeisig et al. 2003). Transplantation gave biphenotypic tumors expressing lymphoid and myeloid cell surface markers and displaying biphenotypic gene expression profiles (So et al. 2003a; Zeisig et al. 2003). Similarly, when murine hematopoietic stem cells enriched for early progenitors were transduced with the MLL-GAS7 fusion gene and directly transplanted into syngeneic mice, oligoclonal AML (80%) and ALL (10%) and multiclonal acute biphenotypic leukemia (ABL; 10%) resulted. Multiclonality of the latter suggests that the transduction procedure affected several different progenitors resulting in multilineage leukemia and supports a noninstructive model (Fig. 3D). This approach has been taken further with refined experiments transducing MLL-ENL-expressing retrovirus in purified, committed myeloid progenitors (CMP and GMP; Cozzio et al. 2003) as well as multipotent HSC. In these experiments, myeloid leukemias resulted in each case, implying that the "permissive" environment for oncogenicity of MLL-ENL fusion proteins is provided by both noncommitted progenitors or committed progeny (Cozzio et al. 2003).
The limitation of the KI gene fusion and BMT is circumvented by the translocator mouse model in which chromosomal translocations are produced de novo (Smith et al. 1995; van Deursen et al. 1995) during mouse development (Buchholz et al. 2000; Collins et al. 2000). Mll-involved translocations were evaluated in a translocator model of Mll-Enl gene fusions (Forster et al. 2003). Somatically occurring reciprocal translocations involving rearrangement between Mll and Enl loci were achieved using Cre-mediated interchromosomal recombination between loxP sites introduced in intronic regions of mouse Mll and Enl, corresponding to human breakpoints (Forster et al. 2003). This experimental strategy results in de novo Mll-Enl chromosomal translocations and fusion genes in their normal genomic context and under control of their normal transcriptional controlling elements. This led to myeloid leukemias with a rapid onset in all mice (mean survival 2-4 mo; Forster et al. 2003). Reciprocal translocations were present in all tumor cells and could be detected as early as 12 d after birth suggesting that the translocation events occur early and frequently to allow time for disease manifestation (Forster et al. 2003). These results were obtained using a Cre-expressing mouse line in which Cre was expressed in stem cells and early progenitors from the Lmo2 promoter (Warren et al. 1994), suggesting that the translocations (which appeared very early) can occur in uncommitted cells and thus supporting an instructive role for Mll-Enl fusion in this setting. Continued study of the cells of origin of the translocations in this model will shed light on this issue. Furthermore, additional mouse models are needed to investigate the possible specifying effects of the fusion partners, ideally translocators with different Cre-expressing mice; thus, lineage-specific Cre expression would be informative about the accessibility of hematopoietic cells at different stages of differentiation to the influence of the Mll fusion proteins. A good test for the instructive vs. noninstructive models should be an Mll-Af4 translocator mouse, as MLL-AF4 in humans typically manifests as an ALL phenotype.
The diverse MLL fusions, and related mutations, found in human leukemias shows the disparate means by which chromosomal abnormalities can affect gene structure to result in malignant transformation. Because MLL fusions have been found in leukemias with various hematopoietic phenotypes, the function of this mixed lineage gene in leukemogenesis remains a conundrum. Several different mouse models and many molecular studies have yet to clarify definitively whether MLL fusions work by instructing cell fate decisions or whether these fusion proteins are only oncogenic in specific cellular environments. Furthermore, a mixed situation may be invoked, whereby a particular fusion is instructive if the chromosomal abnormality occurs in a multipotential precursor and noninstructive (i.e., simply oncogenic) if the chromosomal abnormality occurs in a committed cell of the permissive phenotype. Either way, noninstructive models would not allow for oncogenicity of a particular fusion in a committed cell of the nonpermissive phenotype.
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Future prospectives |
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Acknowledgments |
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TopThe ubiquitous MLL gene...The MLL protein is...A newly defined threonine...HOX gene regulation by...MLL dimerization as a...Models of MLL fusion-induced...Future prospectivesAcknowledgmentsReferences |
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Footnotes |
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1 Corresponding author.
E-MAIL thr{at}mrc-lm.cam.ac.uk; FAX 44-0-1223-412178. 
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References |
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