Mini Review

Leukemia (2005) 19, 183–190. doi:10.1038/sj.leu.2403602 Published online 16 December 2004

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

Correspondence: Dr D-P Liu, National 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 100005, PR China. Fax: +8610 65105093; E-mail:

Received 22 July 2004; Accepted 15 October 2004; Published online 16 December 2004.



Rearrangements of the MLL gene (ALL1, HRX, and Hrtx) located at chromosome band 11q23 are commonly involved in adult and pediatric cases of primary acute leukemias and also found in cases of therapy-related secondary leukemias. Studies on mouse models of MLL translocation and cell lines containing MLL rearrangements showed that the MLL gene linked chromosomal rearrangements to cellular differentiation and tumor tropism. Moreover, recent structural/functional studies on MLL and aberrant MLL proteins provided new clues and suggested that different mechanisms might be included in leukemogenesis by MLL rearrangements. The connection between these different mechanisms will help us understand globally how aberrant MLL oncogenes affect the normal cellular processes at molecular level.


MLL, leukemia, molecular mechanisms



Leukemia is a heterogeneous disease at the molecular level resulting from a variety of alterations in numerous genes important for cell growth, differentiation, and cell death. Identification and characterization of these genetic rearrangements have been proved invaluable for appropriate diagnosis and prognosis, especially in acute leukemia. Rearrangements of the MLL gene (ALL1, HRX, and Hrtx) located at chromosome band 11q23 are commonly involved in acute leukemia. These rearrangements have been shown to be associated with some adult1, 2, 3 and pediatric4, 5, 6 cases of primary acute leukemias and also are found in the majority of patients with secondary leukemias after prior treatment with DNA topoisomerase II inhibitors (eg, etoposide).7, 8 Unlike many other types of leukemia, the presence of an MLL translocation predicts early relapse and poor prognosis.9, 10 Frequently, leukemic blasts are characterized by the expression of lymphoid and myeloid surface markers, defining MLL or Mixed Lineage Leukemia gene.11

The Mixed-Lineage Leukemia gene (MLL/HRX/ALL1) consists of at least 36 exons, encoding a 3969 amino-acid nuclear protein with a molecular weight of nearly 430 kDa that is thought to function as a positive regulator of gene expression in early embryonic development and hematopoiesis. MLL translocation breakpoints cluster within an 8.3-kb region spanning exons 5–11.12 To date, over 60 chromosome partners of 11q23 have been described, and 33 of the presumptive gene partners of MLL cloned and analyzed at the molecular level.13 The mechanisms by which these rearrangements result in leukemia remain largely unknown.

In addition to chromosomal translocations, other mechanisms of MLL rearrangement have been demonstrated in patients with acute leukemia. The partial tandem duplication (PTD) of MLL is present in approximately 10% of patients with acute myeloid leukemia (AML) and normal cytogenetics14 and in the majority of patients with AML and trisomy 11 as the sole cytogenetic abnormality.15 This rearrangement is characterized by an internal duplication of MLL spanning exons 2–6 or 2–8.16 Amplification within chromosome arm 11q involving MLL gene locus is a rare but recurrent aberration in AML and myelodysplastic syndrome (AML/MDS).17, 18, 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, is sufficient to promote leukemogenesis.


Functions of normal MLL protein

MLL, a human homologue of the epigenetic transcriptional regulator Trithorax of Drosophila,20 is an upstream transcriptional effector of HOX genes.21, 22 The importance of normal MLL protein for normal axial-skeletal developmental process and HOX gene regulation has been demonstrated in the embryos of heterozygous and homozygous MLL knockout21 and MLL truncation mutant mice.23 Furthermore, expression of MLL protein is not necessary for turning on transcription of certain HOX genes, but for the maintenance of their transcription.22 Experiments in vitro using hematopoietic progenitors from embryos of homozygous MLL knockout mice24, 25 or mice with MLL mutant26 showed that MLL was also critical for hematopoietic development. Recent findings suggested that MLL is required during embryogenesis for the specification or expansion of hematopoietic stem cells.27 As HOX genes also play a key role in the regulation of hematopoietic development,28 the hematopoietic dysfunction of MLL null cells is likely to be attributed to deregulated patterns of HOX gene expression in hematopoietic stem cells or progenitors. This link between MLL, HOX gene regulation, and hematopoiesis is of particular importance.

Structural/functional studies on normal MLL protein also provide some information on MLL functions. MLL protein possesses some functional domains that could confer significant functional activity (Figure 1). Of these functional domains, AT hooks and MT domain have DNA-binding activity that could be involved in the regulation of gene transcription through direct binding to DNA. The AT hook, with homology to the high-mobility group I (HMG-I) protein, binds to AT-rich regions of the minor groove of the DNA, but it recognizes DNA structure rather than specific consensus sequences.29 The MT domain is a cysteine-rich CXXC region with homology to a DNA methyltransferase and methyl-CpG-binding protein 1 (MBD1).29, 30 Like 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 to have transcriptional repression activity by recruiting repressor complex(es) such as HDAC or polycomb group proteins such as HPC2 or BMI-1 through MT domain.32

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

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 5' 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.

Full figure and legend (104K)

For most proteins with PHD finger domain are components of chromatin remodeling/transcriptional regulation complexes, at least some part of chromatin remodeling/transcriptional regulation activities of normal MLL protein may be associated with PHD fingers.33 In addition, nuclear cyclophilin Cyp33 can bind to the PHD finger of MLL, and overexpression of Cyp33 is known to have some effects on the expression pattern of HOX genes.34 MLL also has a transcriptional activation domain (TAD) between the PHD fingers and C-terminal SET domain. This activation domain of MLL can bind directly to CBP and facilitate the binding of CBP with CREB to promote transcriptional activation.35 The SET domain is also an evolutionarily highly conserved region and has activity as a lysine-directed histone methyltransferase that impacts on chromatin structure and transcriptional regulation of HOX genes.36, 37 Wild-type MLL contains self-association motifs in the PHD fingers34 and SET domain,38 suggesting that MLL normally functions as a dimer or oligomer. Besides these domains, MLL also has nuclear localization signals in its N-terminal that determine a punctate localization pattern of the proteins in the nucleus.39


The maturation of MLL protein

Full-length MLL protein can be cleaved post-translationally by a protease, taspase 1, at two conserved amino-acid motifs (CS1: D/GADD; CS2: D/GVDD).40 Thus, MLL protein is cleaved into two fragments – an N-termninal 320 kDa (amino acids 1–2666; N320) fragment with transcriptional repression activity and a C-terminal 180 kDa (amino acids 2719–3969; C180) fragment with strong transcriptional activation properties.41 The N-terminal fragment comprises a series of AT-hook motifs: the SNL1 and SNL2 (speckled nuclear localization signals 1 and 2) regions; the MT domain, and the PHD zinc-finger domain. The C-terminal fragment contains the SET domain and the TAD domain. The FYRN domain (amino acids 1979–2130) located in N320 interacts with the FYRC and SET domains (amino acids 3656–3969) located in C180 (Figure 1), thus the two complex MLL peptides build the basic structure required for an MLL multiprotein supercomplex (MLL MPSC)37 that consists of both MLL peptides that confers protein stability and subnuclear localization42 and at least 27 additional proteins.


The recurrent forms of MLL rearrangements

MLL translocation and MLL fusion partners

In contrast to the majority of other fusion oncoproteins, MLL N terminus fuses with a puzzling number of nonrelated proteins, and they form chimeric proteins. MLL partners can be divided into two groups. The first group is nuclear fusion partners, including AF4, AF9, AF10, ENL, ELL, AF17, FKHRL1, AFX1, CBP, p300, and so on, which are associated with various aspects of transcriptional regulation. The second group is mainly cytoplasmic and frequently associated with cytoskeleton-depended signal transduction, including AF6, Septin 6, ABI-1, EEN, FBP17, and so on, possessing structural domains responsible for protein–protein interaction (Table 1).13

Despite the heterogeneity of the fusion partners, all known 11q23 translocations delete a large 3' portion of the MLL gene and connect the remaining 5' part in frame with the corresponding partner gene. This leads to the expression of a chimeric protein that has actively transforming properties (Figure 1). Moreover, as a result of reciprocal translocations, the N-terminal fusion portion of MLL contains two different DNA binding domains (AT-hooks and MT-domain) and the critical regions for correct subnuclear localization. Therefore, fusions of the N-terminal portion of the MLL protein with various partner protein sequences should target the same subnuclear compartment, as evidence from independent studies that have demonstrated a nuclear punctate distribution in immunohistochemical studies.39, 43 Patients carrying MLL translocations were shown to exhibit a specific gene expression profile of upregulated and downregulated genes, suggesting a novel and specific disease phenotype.44 The upregulated genes were some recognized targets of MLL including some HOX genes. Deregulated expression of HOX genes typifies certain malignancies.

MLL PTDs and MLL gene amplifications

The so-called PTD leads to fusion of the 5' portion of MLL protein with itself (Figure 1).16 This abnormality is associated with AML, the incidence lying in the range of 3–10% of unselected cases45 but rises to 90% of AML cases with trisomy of chromosome 11.46 The chimeric transcripts code for proteins as potent transcriptional activators with potential oncogenic activity. The finding that partially duplicated forms of MLL also had potent coactivator activity suggests that duplication of potential DNA binding elements such as the AT hooks or DNA methyltrasferase homology region may play an important role in transformation.47 The duplicated DNA binding domains might interfere with corepressor binding to CpG repeats, or AT hook-mediated DNA bending could facilitate transcription factor binding further upstream, or increased affinity might stabilize interactions with coactivators.47 A partial nontandem duplication with the insertion of one AF9 exon that generates three distinct fusion transcripts in B-cell acute lymphoblastic leukemia has been reported.48

MLL gene amplification was recognized as a recurrent aberration in AML and MDS, associated with adverse prognosis and karyotype complexity.17, 18, 19 These patients exhibit intrachromosomal amplification of unrearranged MLL, presumably to facilitate increased MLL expression. Expression analyses identified MLL as a prominent target of 11q23 amplification and support an etiologic role for MLL gain of function in myeloid malignancies.18


The molecular mechanisms of MLL-associated leukemia

There is good evidence that the acquisition of novel properties by the combination of MLL with the fusion partners, rather than the loss of wild-type MLL function, leads to the generation of an active oncoprotein. Simple truncation of MLL at the site of translocation-induced fusion does not lead to development of leukemias in gene-targeted mice49 or in retroviral transduction/transplantation models of MLL-associated myeloid leukemogenesis.50 In a series of knockin studies it was clearly demonstrated that MLL needs a fusion partner to become leukemogenic whereas a simple truncation did not cause leukemias in mice.51, 52 Moreover, several structure–function studies testing the transformation assay found critical contribution of the fusion partners.53, 54, 55 Recent studies provided more details on MLL translocations and suggested that different mechanisms might be involved in the leukemogenesis by MLL fusion proteins. Although the oncogenesis of MLL-associated leukemia is very complicated, this issue can be dissected from the following different aspects.

Transcriptional activation

In many studies, it has been postulated that transcriptional transactivation might be the common denominator of several fusion partners and transactivational domains are indeed found in some fusion partners. FKHRL1 and AFX are two MLL fusion partners that have well-characterized roles in transcriptional regulation.56, 57 They are members of the forkhead subfamily of transcription factors (FKHR family) that contain highly conserved forkhead DNA-binding domains (DBDs).58 Transformation mediated by MLL-forkhead fusion proteins required two conserved transcriptional effector domains (CR2 and CR3), each of which alone is not sufficient to activate MLL.59 A synthetic fusion of MLL with FKHR, a third mammalian forkhead family member that contains both effector domains, is also capable of transforming hematopoietic progenitors in vitro.59 For ENL, the 90 C-terminal amino acids not only constitute a transcriptional activator but they are also the minimal component necessary to convert MLL into a leukemogenic oncoprotein.54 Similarly, structure/function analysis showed that a highly conserved 82-amino-acid portion of AF10, comprising two adjacent alpha-helical domains, exhibited transcriptional activation properties and was sufficient for immortalizing activity when fused to MLL.60 The crucial domain of another MLL fusion partner, ELL, is a protein–protein interaction domain that binds to EAF1 (ELL-associated factor).55 EAF1, in turn, comprises a stretch of amino acids with homology to the transactivator domain of AF4.61 Finally, the MLL partners CBP and p300 are general cofactors in transcriptional activation.62, 63 In another report, Zeisig et al64 provided evidence that a generic transactivator function could replace the authentic MLL fusion partner ENL. These results corroborate the hypothesis that an intrinsic transactivation potential is the common denominator of many MLL fusion partners. Structure/function studies of the respective fusion proteins revealed that the minimal domains required for oncogenesis display transactivation potentials that vary from strong (AFX, FKHR) to weak (ENL, ELL, AF10, CBP). Thus, acquisition of heterologous transcriptional effector domains by MLL may represent a common oncogenic pathway for deregulating its transcriptional functions by some, if not all, of its nuclear fusion partners.

Dimerization or oligomerization

However, not all MLL translocation partners appear to be transcriptional activators. Some are cytoplasmic proteins that are unlikely to have a nuclear function. The presence of self-association motifs in some MLL translocation partners has prompted several investigators to propose that dimerization of truncated MLL may be transforming.65, 66, 67 There is abundant indirect evidence for this mechanism. AF10 and AF17 contain leucine zipper motifs that are required for transformation60, 67 and AF10 is a homotetramer.68 AF3p21 homo-oligomerizes66 and guanine monophosphate synthetase is a tetramer.69 In addition, LCX,70 SEPTING,71 and EEN72 all contain alpha-helical coiled-coil regions that are retained in fusion proteins. These coiled-coil self-association domains resemble the rod-like domains that mediate dimerization of myosin chains and therefore are also likely to self-associate. Experimental evidence for dimerization model is the finding that MLL-LacZ knockin mice developed both lymphoid and myeloid leukemias, albeit with a long latency period.52 beta-Galactosidase has no known transcriptional activity nor is it homologous to any known MLL translocation partner. However, in its active form, the enzyme is a tetramer in solution,73 implying that the primary role of the translocation partner in these experimental leukemias is to oligomerize MLL.

MLL normally maintains HOX gene transcription in part by targeting SET domain methyltransferase activity to HOX gene promoters,36 but this domain and the TAD domain are lost in leukemogenic MLL fusion proteins. Forced dimerization/oligomerization may alter the association of a DNA binding protein for its transcriptional cofactors, or the dimerization motifs themselves may constitutively recruit transcriptional effector molecules. Oligomerized chimeras may also sequester essential partners or cofactors to exert dominant-negative effects on target gene expression.

Moreover, recent experimental data support this MLL dimerization/oligomerization model. Simple dimerization of MLL by a cytoplasmic fusion partner (either GAS7 or AF1p) activates its transcriptional and oncogenic properties.74 Similarly, a coiled-coil dimerization domain of EEN retained in MLL-EEN fusion protein is critical for leukemogenesis caused by MLL-EEN.72 In addition, MLL-EEN might act as a potential transcriptional factor that transactivates the promoter of HOXA7, a potential target gene of MLL.72 Another article showed that the small oligomerization domain of gephyrin converts MLL to an oncogene.75 Forced dimerization of MLL may lead to the inappropriate recruitment of accessory factors and create a transcriptional activator complex capable of stimulating HOX expression in the absence of histone methylation. This model may also account for the oncogenicity of a class of transforming 'self-fusion' MLL proteins, which arise through an intrachromosomal tandem duplication of N-terminal MLL sequences, effectively producing a tethered homodimer of this region fused to the remainder of the MLL coding sequences.47

Chromatin structure changes

As discussed above, patients carrying MLL translocations were shown to exhibit a specific gene expression profile, suggesting a novel and specific disease phenotype. And why? Chromatin structure changes of downstream genes essentially account for the leukemogenesis by MLL fusion proteins. MLL itself is a human homologue of the epigenetic transcriptional regulator Trithorax (TRX) in Drosophila melanogaster.20 MLL is part of nuclear regulatory mechanism that establishes an epigenetic transcriptional memory system.76 This system is based on high molecular weight protein complexes that exert histone/chromatin-modifying/remodeling and transactivating/repressing activities.77 MLL, as a component of MPSC, has been shown that it binds directly to HOXA9 and HOXC8 regulatory regions in chromatin immunoprecipitation assays and by the demonstration that the SET domain of MLL is a histone H3 (lysine-4)-specific methyltransferase whose activity is associated with HOX gene activation.36, 37 As a result, specific gene expression patterns will be established and maintained throughout subsequent mitotic cell cycles, which in turn will allow cells to cope with their cellular fate, or their specific developmental or differentiation pathways.

However, when translocation occurs, the normal epigenetic transcriptional functions of MLL are disrupted and aberrant epigenetic transcriptional functions are contributed by its fusion partners. The minimal essential domains of ENL as well as of AF9 recruit the novel polycomb protein Pc3.78 In addition, novel SWI/SNF chromatin-remodeling complexes contain ENL have been identified. The resultant MLL-ENL fusion protein associates and cooperates with SWI/SNF complexes to activate transcription of the promoter of HOXA7.79 Two more fusion partners, ABI1 and AF10, are also connected to ENL either by a direct interaction or via the GAS41 protein, an ENL homologue that interacts with the human SWI/SNF complex.80, 81 Polycomb proteins and SWI/SNF complex in turn are known to be members of machines that have been connected mostly, but not exclusively, with transcriptional silencing. It might be possible that, by unknown mechanisms, the assembly of an MLL-ENL-chromatin remodeling complex leads to chromatin structure changes that cause a persistent and strong activation of target genes. Chromatin structure changes maybe are also the underlying mechanism in CBP and p300 fusion partners achieving their transactivation effect.

Association with signal transduction

SH3 (Src homology 3) domain, a well-known domain contained in many proteins intermediating signal transduction, plays an important and intriguing role in MLL fusion partners. EBP, a novel EEN binding protein, interacts with the SH3 domain of EEN through a proline-rich motif PPERP.82 EBP is a ubiquitous protein that is normally expressed in the cytoplasm but is recruited to the nucleus by MLL-EEN with a punctate localization pattern characteristic of the MLL chimeric proteins.82 EBP interacts simultaneously with EEN and Sos, a guanine-nucleotide exchange factor for Ras. Coexpression of EBP with EEN leads to suppression of Ras-induced cellular transformation and Ras-mediated activation of Elk-1.82 Taken together, these findings suggest a new mechanism for MLL-EEN-mediated leukemogenesis in which MLL-EEN interferes with the Ras-suppressing activities of EBP through direct interaction. Moreover, SH3 domains of EEN and ABI-1 can interact with different proline-rich domains of synaptojanin,83 a member of the inositol phosphatase family that has recently been shown to regulate cell proliferation and survival. Similarly, the AF3p21 gene encodes a protein consisting of 722 amino acids, which has an SH3 domain, a proline-rich domain, and a bipartite nuclear localization signal. The structural characteristics suggest the possibility that AF3p21 protein plays a role in signal transduction in the nucleus.84 Another MLL fusion partner AF17 was identified as a downstream gene of the beta-catenin/T-cell factor pathway. AF17 gene product is likely to be involved in the beta-catenin-T-cell factor/lymphoid enhancer factor signaling pathway and to function as a growth-promoting, oncogenic protein.85 Similarly, FKHRL1 and AFX are downstream targets of protein kinase B (PKB/Akt) in a conserved signaling pathway that regulates expression of cell cycle regulatory and proapoptotic genes.86 A putative guanine nucleotide exchange factor (GEF), termed leukemia-associated RhoGEF (LARG), was recently identified upon fusion to the coding sequence of the MLL gene in AML.87 Although the function of LARG is still unknown, it exhibits a number of structural domains suggestive of a role in signal transduction, including a PDZ domain, an LH/RGS domain, and a Dbl homology/pleckstrin homology domain.88 LARG can activate Rho in vivo.87 Furthermore, LARG is an integral component of a novel biochemical route whereby G protein-coupled receptors (GPCRs) and heterotrimeric G proteins of the G alpha(12) family stimulate Rho-dependent signaling pathways.88 Taken together, these findings suggest a potential link between MLL fusion-mediated leukemogenesis and the different signal pathways.


As a summary, these different mechanisms may explain some of the heterogeneity in MLL-mediated leukemogenesis. For some nuclear fusion partners, transcriptional activation may be prevailing because acquisition of heterologous transcriptional effector domains from these fusion partners will directly influence downstream gene expression at transcriptional level. But for some cytoplasmic fusion partners that are unlikely to have a nuclear function, dimerization or oligomerization will better explain the leukemogenesis by these MLL fusion proteins because the coiled-coil self-association domains retained in MLL fusion proteins may facilitate the dimerization of MLL fusion proteins and alter the normal transcriptional regulation activities. Forced dimerization/oligomerization may alter the association between MLL and its transcriptional cofactors, or the dimerization motifs themselves may constitutively recruit transcriptional effector molecules or accessory factors and create a transcriptional activator complex exert dominant-negative effects on target gene expression.

Furthermore, MLL fusion partners will result in the remodeling of MPSC, the altered MPSC will recruit some accessory factors that may influence gene expression at transcriptional level or influence signal transduction in expanded range. Due to the heterogeneity of MLL fusion partners, the components of MPSC alter from one to another and different mechanisms will mediate the oncogenesis of MLL-associated leukemias.

Though mechanisms of leukemogenesis by MLL fusion proteins are various, there is the same result – the alteration of gene expression profiles. Certainly, different MLL fusion proteins will result in different gene expression profiles, but the establishment of these expression profiles is ultimately achieved through the epigenetic regulation.


Conclusions and perspective

Different mechanisms may be involved in the leukemogenesis by different aberrant MLL proteins and there is some connection between these mechanisms: (1) As discussed above, dimerization (or oligomerization) might be the common mechanism for leukemogenesis by aberrant MLL proteins derived from different MLL rearrangements (including MLL fusion with some cytoplasmic partners, MLL PTD or MLL gene amplification);47(2) aberrant MLL MPSC will recruit some chromatin-remodeling complexes that result in chromatin structure changes and even aberrant gene expression profiles; (3) some MLL fusion proteins derived from MLL fusion with some cytoplasmic partners can act as transcription regulator via dimerization (eg MLL-EEN);72 (4) some fusion partners may link some signal molecules to MLL MPSC and may result in extensive alteration in gene expression profiles. Thus, the aberrant MLL proteins presumably affect normal cellular control mechanisms, including signal transduction, cell cycle, and so on, possibly by a direct action on its target genes (eg HOX gene) expression occurring at the level of chromatin-mediated activation or by an indirect action on other nontargeted genes (Figure 2).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Multiple roles of normal and aberrant MLL proteins in development programming. Normal MLL protein is required for maintaining for normal gene expression profile and normal development programming. However, aberrant MLL proteins derived from MLL translocation, MLL partial tandem duplication or MLL gene amplification will result in aberrant gene expression profile and aberrant development programming and eventually will result in leukemia. Different mechanisms are involved in leukemogenesis by aberrant MLL proteins and there are some connections among them.

Full figure and legend (95K)

In order to study leukemogenesis of aberrant MLL proteins, loss-of-function models and gain-of-function models are often put to use to analyze gene expression patterns. Dysregulation of HOX gene family members is implicated as a dominant mechanism of leukemic transformation induced by chimeric MLL oncogenes.89 The strategy of comparing patterns of gene expression in loss-of-function models to gain-of-function models and leukemic cells harboring MLL fusion (or MLL partial duplication or MLL amplification) oncogenes will not only help us understand globally the mechanism by which aberrant MLL oncogenes affect the normal cellular processes but also provide more details in antileukemia therapies. To clarify the heterogeneity of leukemogenesis by different aberrant MLL proteins derived from different chromosomal rearrangements, investigation on diversification of MPSC components will provide more information to us. As discussed above, some evidence suggests a potential link between MLL fusion-mediated leukemogenesis and the different signal pathways. To testify this possibility, study on MPSC composition combined with the information from the study of signal transduction will be helpful.



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We thank Dr Gong-Hong Wei and other colleagues for helpful discussion and critical reading of the manuscript. We apologize for any errors or omissions in this review. This work was supported by a grant from the National Natural Science Foundation of China (N0. 30393110).