Oncogene (2007) 26, 6838–6849; doi:10.1038/sj.onc.1210766

Mechanisms of transcription factor deregulation in lymphoid cell transformation

J O'Neil1 and A T Look1

1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

Correspondence: Dr AT Look, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Professor of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. E-mail:



The most frequent targets of genetic alterations in human lymphoid leukemias are transcription factor genes with essential functions in blood cell development. TAL1, LYL1, HOX11 and other transcription factors essential for normal hematopoiesis are often misexpressed in the thymus in T-cell acute lymphoblastic leukemia (T-ALL), leading to differentiation arrest and cell transformation. Recent advances in the ability to assess DNA copy number have led to the discovery that the MYB transcription factor oncogene is tandemly duplicated in T-ALL. The NOTCH1 gene, which is essential for key embryonic cell-fate decisions in multicellular organisms, was found to be activated by mutation in a large percentage of T-ALL patients. The gene encoding the FBW7 protein ubiquitin ligase, which regulates the turnover of the intracellular form of NOTCH (ICN), is also mutated in T-ALL, resulting in stabilization of the ICN and activation of the NOTCH signaling pathway. In mature B-lineage ALL and Burkitt lymphoma, the MYC transcription factor oncogene is overexpressed due to translocation into the IG locus. PAX5, a transcription factor essential for B-lineage commitment, is inactivated in 32% of cases of B-progenitor ALL. Translocations resulting in oncogenic fusion transcription factors also occur frequently in this form of ALL. The most frequent transcription factor chimeric fusion, TEL-AML1, is an initiating event in B-progenitor ALL that acts by repressing transcription. Therefore, deregulated transcription and its consequent effects on key developmental pathways play a major role in the molecular pathogenesis of lymphoid malignancy. Once the full complement of cooperating mutations in transformed B- and T-progenitor cells is known, and the deregulated downstream pathways have been elucidated, it will be possible to identify vulnerable components and to target them with small-molecule inhibitors.





Uniform structural and numerical chromosomal abnormalities, such as those resulting in identical rearrangements of IG or TCR genes in patients with acute lymphoblastic leukemia (ALL) (Arnold et al., 1983; Waldmann et al., 1985), are frequently demonstrated in transformed lymphoblasts, establishing the clonality of this disease. Molecular studies on recurrent chromosomal translocations in ALL have indicated a central role for the aberrant expression of transcription factors in the pathobiology of lymphoid leukemia. Deregulated expression of these transcription factors, which are often functionally normal, leads to abnormal proliferation and differentiation arrest of lymphoid progenitors (Cleary, 1991; Rabbitts, 1994; Look, 1997). Although a substantial fraction of oncogenic transcription factors have essential roles in the development of specific cell lineages, many are not normally expressed in lymphocytes, indicating that transformation by these proteins is a result of misexpression (Armstrong and Look, 2005). In some cases, the chromosomal translocations generate chimeric transcription factors with new functions, enabling them to target genes other than those recognized by the intact factors. Here, we focus on the common mechanisms responsible for the aberrant expression of transcription factor genes in lymphoid leukemias.


Aberrant protein expression in T-cell acute lymphoblastic leukemia

In T-cell acute lymphoblastic leukemia (T-ALL), chromosomal break points often involve the TCRbeta enhancer (7q34) or the TCRalpha/delta enhancer (14q11), both of which are highly active in committed T-cell progenitors, resulting in the deregulated expression of transcription factor genes located at the break point on the reciprocal chromosome (Ferrando and Look, 2000). The transcription factors affected by these molecular changes include genes encoding basic helix–loop–helix (bHLH) family members, such as TAL1 (Begley et al., 1989; Chen et al., 1990), TAL2 (Xia et al., 1991), LYL1 (Mellentin et al., 1989), MYC (Finger et al., 1986; McKeithan et al., 1986; Shima et al., 1986) and BHLHB1 (Wang et al., 2000); LIM-only domain (LMO) genes, such as LMO1 and LMO2 (McGuire et al., 1992); and the orphan homeobox genes HOX11 and HOX11L2 (Dube et al., 1991; Hatano et al., 1991; Kennedy et al., 1991; Lu et al., 1991; Dear et al., 1993; Bernard et al., 2001; Ferrando and Look, 2003), the major HOXA locus (Soulier et al., 2005) and MYB in young children (Clappier et al., 2007).

TAL1 is overexpressed in T-ALL as a result of the t(1;14) translocation or by site-specific deletions in approximately one-fourth of childhood T-ALL cases (Brown et al., 1990; Aplan et al., 1991, 1992; Bernard et al., 1991; Breit et al., 1993; Bash et al., 1995). However, these two mechanisms cannot account for all instances of TAL1 overexpression in this disease, as the gene is aberrantly expressed in the leukemic cells of 60% of children and 45% of adults with T-ALL. An attractive hypothesis, based on observations of biallelic activation of TAL1, is that pathways involved in TAL1 repression during T-cell differentiation are inactivated in T-ALL (Ferrando et al., 2004). As a master regulatory protein active during early hematopoietic development, TAL1 is required for the generation of all blood cell lineages (Robb et al., 1995; Shivdasani et al., 1995), but it is not required for the generation and function of hematopoietic stem cells during adult hematopoiesis (Mikkola et al., 2003). This class II bHLH transcription factor binds to DNA by forming heterodimers with class I bHLH factors such as E2A and HEB (Baer, 1993; O'Neil et al., 2001). The observation that loss of E2A results in T-cell leukemia in mice (Bain et al., 1997; Yan et al., 1997), and that the DNA-binding domain of TAL1 is dispensable for transformation in a transgenic mouse model (O'Neil et al., 2001), supports the notion that TAL1-mediated inhibition of class I bHLH factors plays a critical role in T-ALL pathogenesis (Figure 1). Further support for this hypothesis comes from a study in which accelerated development of T-cell leukemia was observed in Tal1 transgenic mice on an E2A- or HEB-deficient background (O'Neil et al., 2004).

Figure 1.
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TAL1 acts by inhibiting the function of the class I bHLH proteins E47 and HEB. (a) In normal thymocytes, E47 homodimers or E47/HEB heterodimers bind to E-box sequences in DNA, recruit co-activators such as p300, CBP and PCAF, and activate the expression of genes important for T-cell development, including CD4 and pre-Talpha. (b) When TAL1 is misexpressed in the thymus in T-ALL, it interacts with E47 and HEB and disrupts E47 homodimers or E47/HEB heterodimers. TAL1 can bind to E-box sequences as a heterodimer with class I bHLH proteins; however, TAL1 recruits corepressors such as mSin3a, thereby repressing genes important for T-cell development. The repression of these genes results in differentiation arrest in Tal1 transgenic mouse models. bHLH, basic helix–loop–helix.

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The LIM-only domain genes LMO1/RBTN1/TTG1 and LMO2/RBTN2/TTG2 (McGuire et al., 1989, 1992; Boehm et al., 1991; Royer-Pokora et al., 1991) encode proteins that contain duplicated cysteine-rich LIM domains involved in protein–protein interactions. LMO1 and LMO2 can be activated by translocation to the TCR enhancer loci, or in the case of LMO2, by deletion that removes a negative regulator of LMO2 expression (McGuire et al., 1989; Boehm et al., 1991; Royer-Pokora et al., 1991; Van Vlierberghe et al., 2006). LMO2 interacts with TAL1 in erythroid cells and in T-cell leukemias (Valge-Archer et al., 1994; Wadman et al., 1994; Larson et al., 1996). Moreover, homozygous disruption of LMO2 in mice causes the same phenotype as described above for Tal1-deficient mice, indicating that a multiprotein complex involving LMO2, TAL1 and, potentially, other proteins is required for normal hematopoietic development (Warren et al., 1994; Porcher et al., 1996). Finally, overexpression of Lmo1 or Lmo2 transgenes in mouse thymocytes leads to T-cell lymphomas (Fisch et al., 1992; McGuire et al., 1992; Larson et al., 1994, 1995; Neale et al., 1995) and accelerates the onset of leukemia in Tal1 transgenic mice (Larson et al., 1996).

HOX11 was originally isolated from the site of the recurrent t(10;14)(q24;q11) translocation in T-ALL (Dube et al., 1991; Hatano et al., 1991; Kennedy et al., 1991; Lu et al., 1991; Dear et al., 1993) and is aberrantly expressed in 3–5% of pediatric and up to 30% of adult T-ALL cases (Berger et al., 2003; Ferrando and Look, 2003; Kees et al., 2003). Similar to other HOX genes, HOX11 plays an important role in embryonic development, and functions as a master transcriptional regulator necessary for the genesis of the spleen (Roberts et al., 1994; Dear et al., 1995). In the mouse embryo, Hox11 expression can be detected in the branchial arches, restricted areas of the hindbrain and the splenic primordium (Raju et al., 1993; Roberts et al., 1995), where it is required for the survival of early splenic progenitors (Dear et al., 1995). The proposed function of HOX11 as a transcriptional regulator is supported by the presence of both a 61-amino acid, helix–turn–helix DNA-binding domain (or homeodomain) and by the localization of the HOX11 protein in the cell nucleus (Neale et al., 1995). HOX11 can also disrupt the G2/M cell-cycle checkpoint through a transcription-independent mechanism, which involves its interaction with the PP2A and PP1 phosphatases (Riz and Hawley, 2005; Owens et al., 2006).

A second HOX11 family member, HOX11L2, has also been implicated in the pathogenesis of human T-ALL through characterization of the cryptic t(5;14)(q35;q32) chromosomal rearrangement (Bernard et al., 2001). This translocation leads to the ectopic expression of HOX11L2, possibly by bringing it under the influence of regulatory elements in the CTIP2/BCL11B gene, which is highly expressed during T-lymphoid differentiation. Expression of HOX11L2 can be detected in 20–25% of children but in only 5% of adults with T-ALL (Ballerini et al., 2002; Mauvieux et al., 2002; Berger et al., 2003; Ferrando and Look, 2003). In mice, Hox11l2 expression is essential for normal development of the ventral medullary respiratory center, supporting its role as a master transcriptional regulator upstream of important pathways involved in cell-fate determination (Shirasawa et al., 2000).


Activation of the NOTCH signaling pathway in T-cell acute lymphoblastic leukemia

The mammalian NOTCH proteins are heterodimeric transmembrane receptors that control cell proliferation, apoptosis and cell fate during the development of diverse cellular lineages (Wilson and Radtke, 2006). In adults, NOTCH signaling regulates stem cell maintenance, binary cell-fate decisions such as B- vs T-lineage differentiation and the differentiation of self-renewing organs (Radtke et al., 2004). NOTCH is synthesized in the endoplasmic reticulum and is transported to the Golgi network, where it is post-translationally modified. A proteolytic cleavage (S1) separates the extracellular portion of the protein from the intracellular form. These two parts of NOTCH then form a heterodimer that is transported to the cell membrane. Binding of NOTCH ligands, such as DELTA and SERRATE, initiates a series of additional proteolytic cleavages in NOTCH, the last of which is catalysed by gamma-secretase, resulting in the release of the intracellular domain of NOTCH (ICN) and its translocation to the nucleus, where it forms part of a multiprotein complex. The ICN interacts with the DNA-binding protein CSL, displaces corepressors and recruits co-activators, thereby converting CSL from a repressor to an activator of gene transcription (Figure 2).

Figure 2.
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Activation of NOTCH signaling via extracellular and intracellular proteolytic cleavage and nuclear translocation of the intracellular NOTCH domain (ICN). Interaction with delta serrate ligand (DSL) stimulates proteolytic cleavage of NOTCH by metalloproteases and gamma-secretase. This leads to the release of the intracellular ICN domain, which translocates to the nucleus where it interacts with the DNA-binding protein CSL, displaces corepressors and recruits co-activators (MAM1), thereby converting CSL from a repressor to an activator of gene expression. Adapted from Armstrong SA, Look AT (2005). Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol 23: 6306–6315, with permission from the American Society of Clinical Oncology.

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The t(7;9) translocation, which places a truncated form of the NOTCH1 gene under control of the TCRbeta locus, is quite rare, occurring in less than 1% of T-ALL cases (Ellisen et al., 1991). Deletion of the extracellular, ligand-binding domain of NOTCH1 by this translocation yields a constitutively active ligand-independent allele. Mice transplanted with cells expressing the activated NOTCH1 allele rapidly develop T-cell leukemia, demonstrating the transforming potential of activated NOTCH signaling (Pear et al., 1996).

A recent study has demonstrated a broader role of activated NOTCH signaling in human T-ALL than was originally believed. Activating somatic mutations were found in over 50% of T-ALL patient samples and cell lines (Weng et al., 2004; Grabher et al., 2006). The mutations were found in all subtypes of T-ALL and in two regions of the NOTCH1 protein. Missense mutations in the heterodimerization domain activate NOTCH signaling by altering the interaction between the transmembrane subunit and the inhibitory extracellular subunit of NOTCH1 (Malecki et al., 2006). Frameshift and point mutations in the C-terminal region of the NOTCH1 gene were also observed. These mutations delete the PEST domain, which targets the NOTCH1 protein for degradation by the proteasome, thereby leading to increased ICN stability and increased NOTCH signaling. Similar activating mutations were later found in mouse models of T-ALL, demonstrating the evolutionarily conserved role of NOTCH in T-ALL and providing in vivo models in which to test therapeutic agents that target the NOTCH pathway (Lin et al., 2006; O'Neil et al., 2006). This strategy has considerable appeal, given that T-ALL patients with mutated NOTCH1 have a poorer prognosis than patients with the wild-type gene (Zhu et al., 2006).

The gamma-secretase enzyme that cleaves NOTCH to release the ICN also cleaves the amyloid precursor protein, leading to the production of plaques in Alzheimer's patients. As a result, gamma-secretase inhibitors have already been developed for use as targeted therapy. Treatment of T-ALL cell lines with gamma-secretase inhibitors leads to G0/G1 arrest and apoptosis, demonstrating that the cells are dependent on NOTCH signaling for their growth and suggesting that activation of the NOTCH pathway contributes to T-cell transformation by influencing cell-cycle progression and cell survival (Weng et al., 2004; Lewis et al., 2007). Clinical trials to determine whether gamma-secretase inhibitors will be effective in treating T-ALL are underway.

Several recent studies have shed light on the mechanism of NOTCH-induced T-ALL. Studies in both mouse and human T-ALL cells have identified the MYC oncogene as a direct transcriptional target of NOTCH (Palomero et al., 2006; Sharma et al., 2006; Weng et al., 2006). Reintroduction of MYC into cells that have been treated with gamma-secretase inhibitors rescues their growth, demonstrating the importance of MYC in T-ALL pathogenesis induced by aberrant NOTCH signaling. A microarray screen for the activation of phosphorylation events downstream of NOTCH in T-ALL identified several phosphorylated components of the mammalian target of rapamycin pathway (Chan et al., 2007). Treatment of T-ALL cells with rapamycin, an mammalian target of rapamycin inhibitor, in combination with gamma-secretase inhibitors synergistically inhibited cell growth, suggesting a rational drug combination to treat T-ALL patients (Chan et al., 2007). Another group has demonstrated activation of the nuclear factor-kappaB signaling pathway downstream of NOTCH and has shown that the proteasome inhibitor bortezomib can reduce the IC50 of gamma-secretase inhibitors in T-ALL cell lines (Vilimas et al., 2007). These observations underscore an emerging concept in evaluations of pathway-targeted therapeutics; although revision of a single genetic abnormality may be adequate to inhibit tumor growth, eradication of the malignant clone will likely require pathway manipulation at multiple points.


Mutation of FBW7 in T-cell acute lymphoblastic leukemia

We and others have recently discovered that the FBW7 protein ubiquitin ligase is mutated in human T-ALL cell lines and patient samples (Malyukova et al., 2007; Maser et al., 2007; O'Neil et al., 2007; Thompson et al., 2007). The missense mutations occur in arginine residues in the substrate-binding domain of FBW7, whose substrates include NOTCH, MYC and cyclin E. We demonstrate that the mutant forms of FBW7 cannot bind to the ICN, resulting in increased levels of ICN in T-ALL cell lines with mutations in FBW7. Mutated FBW7 can bind to MYC but does not promote its degradation. Therefore, FBW7 mutations likely contribute to T-ALL pathogenesis by increasing the stability of the ICN and MYC. Interestingly, all T-ALL cell lines with mutations in FBW7 are resistant to gamma-secretase inhibitor treatment. We find sustained expression of NOTCH target genes in these cell lines after gamma-secretase inhibitor treatment, suggesting that NOTCH signaling is maintained due to decreased turnover of the ICN (O'Neil et al., 2007).


Duplication of the MYB oncogene in T-cell acute lymphoblastic leukemia

The MYB transcription factor is the cellular counterpart of the v-Myb oncogene of the acutely transforming avian myeloblastosis virus, which causes a fatal monoblastic leukemia in chickens (Klempnauer et al., 1982). Mouse knockout studies have demonstrated that Myb is essential for normal hematopoiesis, including T-cell development (Mucenski et al., 1991; Pearson and Weston, 2000). Overexpression of v-Myb in the thymus causes T-ALL (Badiani et al., 1996), and retroviral insertion and transcriptional activation of the Myb locus represents one of the most frequent accelerating events in several different murine models of T-ALL ( Very recently, MYB duplication and translocation were demonstrated in human T-ALL (Clappier et al., 2007; Lahortiga et al., 2007; J O'Neil et al., unpublished data). We have shown that the duplication of MYB occurs through homologous recombination mediated by Alu elements flanking the MYB locus. We detect the tandem duplication of MYB in a low percentage of peripheral blood cells of healthy individuals, suggesting that MYB duplication is selected for in the pathogenesis of T-ALL (J O'Neil et al., unpublished data). Knockdown of MYB in T-ALL cell lines affects T-cell differentiation, and when combined with inhibitors of the NOTCH signaling pathway, inhibits cell proliferation, demonstrating that increased expression of MYB contributes to T-cell transformation (Lahortiga et al., 2007).


Activation of MYC in mature B-cell T-cell acute lymphoblastic leukemia

In mature B-cell acute leukemia and Burkitt lymphoma, MYC is overexpressed due to translocation of one allele into the vicinity of an IG gene, either the heavy-chain gene on chromosome 14q32 or the kappa- and lambda-light-chain genes on chromosomes 2 and 22 (Dalla-Favera et al., 1982; Taub et al., 1982, 1984; Adams et al., 1983; Croce et al., 1983; Erikson et al., 1983; Emanuel et al., 1984; Hollis et al., 1984; Rappold et al., 1984). MYC is a bHLH protein that binds to canonical E-box DNA sequences (5'-CACGTG-3') as an MYC:MAX heterodimer and activates transcription (Grandori et al., 1996), leading to cell proliferation. MAX can also heterodimerize with other bHLHZip proteins, including MAD (Ayer et al., 1993). This interaction inhibits MYC function by competing with MYC for binding to MAX and by directly inhibiting transcription. Deregulated expression of MYC due to the t(8;14) results in a higher concentration of MYC:MAX complexes relative to MAX:MAD and hence to transcriptional cell proliferation. MYC has many target genes that are involved in diverse cellular functions including cell-cycle regulation, apoptosis, metabolism and signaling pathways. Chromatin immunoprecipitation experiments have shown that MYC can bind to as much as 15% of all promoter regions (Fernandez et al., 2003; Li et al., 2003; Orian et al., 2003). It is likely that a combination of these targets contributes to the oncogenic function of MYC. A recent study suggests that MYC may also contribute to transformation by controlling DNA replication independent of its transcriptional activity (Dominguez-Sola et al., 2007).


PAX5 inactivation in B-progenitor acute lymphoblastic leukemia

The advent of genome-wide technologies to assess gene copy number, such as single-nucleotide polymorphism arrays and comparative genome hybridization (array CGH), has allowed investigators to identify novel genes involved in the pathogenesis of lymphoid leukemia. A recent search for somatic mutations in 242 cases of pediatric ALL, using DNA microarrays containing probes for approximately 350 000 genetic loci, uncovered deletions, amplifications, point mutations or structural rearrangements in numerous genes that are essential for B-cell development (Mullighan et al., 2007). Among these genes, the transcription factor PAX5 was the most commonly altered, either by deletion or by point mutation. The PAX5-mutant proteins displayed reduced transcriptional activity in a reporter assay, demonstrating that the mutations result in loss of function (Mullighan et al., 2007). The PAX5 gene is also involved in several chromosomal translocations that occur in cases of B-progenitor ALL including PAX5-ETV6, PAX5-EVI3 and PAX5-ELN (Cobaleda et al., 2007). Although it is not clear as to how all of these translocations contribute to leukemic transformation, it has been shown that the PAX5-ENL protein inhibits the function of the wild-type PAX5 protein (Bousquet et al., 2007).


E2A-PBX1 fusion gene in pre-B-cell acute lymphoblastic leukemia

The E2A-PBX1 fusion gene results from the t(1;19)(q23;p13) chromosomal translocation present in 3–5% of all B-lineage ALLs and in 25% of cases with a pre-B phenotype (Ferrando and Look, 2000). This translocation fuses the E2A gene on chromosome 19 to a homeobox gene (PBX1) on chromosome 1, leading to the expression of several forms of hybrid E2A-PBX1 oncoproteins. PBX1 is related to the Drosophila exd gene, a homeotic gene that plays a role in segmental development through its ability to heterodimerize with and alter the downstream regulatory programs of the products of the HOM-C major homeobox genes. The hybrid proteins resulting from the t(1;19) contain the N-terminal transactivation domains of E2A (AD1 and AD2) (Kamps et al., 1990; Mellentin et al., 1990; Nourse et al., 1990) and the DNA-binding domain of PBX1, enabling the fusion proteins to function as chimeric transcription factors (Van Dijk et al., 1993; LeBrun and Cleary, 1994; Lu et al., 1994).

Expression of the E2A-PBX1 fusion gene in the bone marrow of lethally irradiated mice results in acute myeloid leukemia (AML), demonstrating its oncogenic potential (Kamps and Baltimore, 1993). E2A-PBX can also transform NIH-3T3 fibroblasts and induce T-cell lymphomas in transgenic mice (Dedera et al., 1993; Monica et al., 1994). Deletion of one of the E2A activation domains diminishes its transforming activity, while deletion of the PBX1 homeodomain has no effect (Kamps and Baltimore, 1993; Monica et al., 1994). However, the homeodomain and flanking sequences are required for interactions with other HOX proteins and for optimal binding of E2A-PBX1 to specific DNA sequences (Chang et al., 1995, 1997; Knoepfler and Kamps, 1995; Lu et al., 1995; van Dijk et al., 1995). Hence, it is likely that interactions between E2A-PBX1 and other HOX proteins target the fusion protein to specific target genes whose activation is critical to lymphoid cell transformation.


E2A-HLF fusion gene in B-progenitor acute lymphoblastic leukemia

The t(17;19) is a rare recurrent chromosomal translocation that fuses the N-terminal transactivation domains of E2A to the C-terminal DNA-binding and dimerization domains of hepatic leukemia factor (HLF) (Hunger et al., 1992; Inaba et al., 1992), a member of the PAR subfamily of bZIP transcription factors. Although E2A-HLF can bind DNA either as a homodimer or as a heterodimer with HLF and related proteins, no other PAR proteins are expressed at detectable levels in leukemic cells, and the E2A-HLF fusion product appears to bind DNA as a homodimer in cells harboring the t(17;19). Similar to E2A-PBX1, E2A-HLF can transform NIH-3T3 fibroblasts and induce lymphoid tumors in transgenic mice (Yoshihara et al., 1995; Hunger, 1996).

Hepatic leukemia factor is the mammalian homologue of the nematode protein cell death specification family member 2 (CES-2), which regulates the death of a specific pair of serotoninergic neurons during Caenorhabditis elegans development (Inaba et al., 1996; Metzstein et al., 1996; Thompson, 1996). CES-2 induces apoptosis by inhibiting the expression of ces-1, a prosurvival gene that normally inhibits programmed cell death by antagonizing the activity of the proapoptotic factor EGL-1. In contrast to the proapoptotic role of CES-2 in the worm via repression of ces-1, E2A-HLF blocks apoptosis by inducing the expression of SLUG, a ces-1 homologue normally responsible for protecting hematopoietic progenitors from DNA-damage-induced apoptosis (Inukai et al., 1999; Metzstein and Horvitz, 1999; Inoue et al., 2002; Wu et al., 2005). Expression of a dominant-negative form of E2A-HLF in t(17;19)-carrying cell lines blocks E2A-HLF function and results in apoptosis (Inaba et al., 1996; Figure 3).

Figure 3.
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Models of conserved cell-death specification pathways and the role of E2A-HLF in leukemogenesis. In the nematode C. elegans, the CES-2 protein negatively regulates ces-1 to induce the activation of a cell-death pathway that results in the apoptosis of two serotononergic neurons (NSM sisters). This pathway presumably involves the transcriptional activation of egl1, whose product is a proapoptotic factor that binds to and inhibits CED-9, preventing it from inhibiting the CED-4 and CED-3 cell-death effectors. In humans, a similar cell-death pathway regulates the survival of myeloid progenitors during hematopoiesis. In this system, a CES-2 homologue negatively controls the expression of SLUG (ces-1 homologue), which presumably downregulates apoptosis by inhibiting a BH3-only family member (egl1 homologue). In the absence of SLUG, the upregulation of this BH3-only factor blocks the activity of antiapoptotic molecules such as BCL2 and BCLXL, triggering the release of cytochrome c from the mitochondria and the activation of downstream apoptotic effector molecules (APAF1, caspase-9). Because E2A-HLF and CES-2 recognize the same DNA sequence, expression of this chimeric oncoprotein with its strong transactivation domains induces expression of SLUG, whose activity subsequently inhibits the expression of a BH3-only gene responsible for cell-death activation in pro-B cells. Reprinted from Ferramdo AA, Look AT (2005). Hematology, In: Hoffman (ed). Pathobiology of Acute Lymphoblastic Leukemia, 4th edn, chapter 63, with permission from Elsevier.

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MLL fusion genes

Translocations involving the MLL gene on chromosome 11 band q23 occur in approximately 80% of infant ALL cases (Ferrando and Look, 2000). MLL encodes a protein that shares significant sequence homology with trithorax, a Drosophila regulator of homeotic gene function that is required for normal head, thorax and abdomen development during fly embryogenesis (Ziemin-van der Poel et al., 1991; Djabali et al., 1992; Gu et al., 1992; Tkachuk et al., 1992). The mixed-lineage leukemia (MLL) protein shares three regions of homology with trithorax, including two central zinc-finger domains and a 210-amino acid C-terminal sur (var) 3-9, enhancer of zeste and tritho-rax (SET) domain. The MLL SET domain contains a histone H3/lysine 4 methyl transferase activity that plays a critical role in the regulation of HOX gene expression (Milne et al., 2002; Yokoyama et al., 2004). Other structural features of MLL include three A-T hook domains near the N terminus that are thought to bind the minor groove of DNA in AT-rich regions, and a 47-amino acid region of homology with the non-catalytic domains of human DNA methyltransferase (Reeves and Nissen, 1990; Ma et al., 1993). Mll heterozygous mice exhibit anemia, thrombocytopenia and reduced numbers of B lymphocytes. The mice also display homeotic transformations of the cervical, thoracic and lumbar regions that reflect shifts in the pattern of Hox gene expression, establishing a crucial role for Mll in Hox gene regulation. Mice with homozygous loss of Mll die in utero and lack Hox gene expression, further supporting a key role for Mll in Hox gene regulation (Yu et al., 1998).

The translocation break points cluster in an 8.5-kilobase region of MLL between exons 5 and 11, and fuse the N-terminal region of MLL, containing the A-T hook and methyltransferase domains, to a variety of partner proteins. Although the role of each partner protein in leukemogenesis has not been fully elucidated, some of them may contribute functional domains to the fusion protein. For example, the t(4;11), t(9;11) and t(11;19)(q23;p13.3) fuse MLL to AF-4, AF-9 and ENL, respectively. All three of these partners are small serine/proline-rich proteins with nuclear localization signals, suggesting that they may function as transcriptional transactivators. An RNA polymerase II elongation factor, ELL, is fused to MLL by the t(11;19)(q23;p13.1) (Thirman et al., 1994; Mitani et al., 1995; Shilatifard et al., 1996). Still other partners have no transcriptional activity but contain a dimerization domain that results in homo-oligomerization of the N-terminal portion of MLL (Hsu and Look, 2003; So et al., 2003).

Murine models of MLL-induced leukemias have demonstrated the oncogenic role of MLL fusions. Chimeric mice harboring aN MLL-AF9 fusion gene developed leukemias with a latency of 4–12 months (Corral et al., 1996). Retroviral transduction of MLL-ENL, MLL-ELL and MLL-CBP fusion genes in hematopoietic precursors induces transformation upon transplantation into recipient mice (Lavau et al., 2000a, 2000b; Zeisig et al., 2003). Similar results were obtained with models in which chromosomal translocations involving the Mll locus are induced by directed interchromosomal recombination in mice, a strategy that reproduces experimentally the initiating events in the pathogenesis of MLL-rearranged leukemias (Forster et al., 2003; Drynan et al., 2005; Metzler et al., 2006). Microarray gene-expression analysis of MLL-rearranged B- and T-cell ALLs has uncovered a characteristic gene-expression signature that includes the upregulation of several HOX genes including HOXA9, HOXA10, HOXC6 and the HOX gene regulator MEIS1 (Armstrong et al., 2002; Yeoh et al., 2002; Ferrando et al., 2003). HOXA9 is required for the transformation of hemopoietic precursors by MLL fusion oncogenes in murine leukemia models (Ayton and Cleary, 2003), demonstrating the central role of HOX gene deregulation in the pathogenesis of MLL-rearranged leukemias.


TEL-AML1 (ETV6-RUNX1) fusion gene in B-progenitor acute lymphoblastic leukemia

The t(12;21) translocation that creates the TEL-AML1 fusion gene is the most common genetic lesion in pediatric ALL, occurring in 20–25% of B-lineage cases, but is much less common in adult ALL (Ferrando and Look, 2000). The chimeric protein contains an HLH domain of TEL fused to nearly all of AML1, including both the transactivation domain and the DNA- and protein-binding Runt homology domain. TEL-AML1 expression in the mouse does not induce leukemia but does increase the self-renewal of B-cell progenitors (Andreasson et al., 2001; Morrow et al., 2004; Tsuzuki et al., 2004), suggesting that additional hits are necessary to induce leukemia. Supporting this hypothesis, TEL-AML1 transgenic zebrafish develops B-ALL at a low frequency (3%) and after a long latency (Sabaawy et al., 2006). The TEL-AML1 translocation appears to be an initiating event in B-ALL as it can be detected prenatally (Greaves and Wiemels, 2003).

Lack of expression of genes normally upregulated by AML1 likely plays a role in TEL-AML1-induced transformation. Evidence in support of this model includes the interference of AML1-dependent transcriptional transactivation by TEL-AML1 in vitro (Hiebert et al., 1996), and the interaction of TEL-AML1, but not normal AML1, with N-Cor, a component of the nuclear coreceptor complex with histone deacetylase activity. In fact, TEL-AML1-mediated gene repression can be reversed by treatment with histone deacetylase (HDAC) inhibitors, suggesting that these drugs may be useful therapeutic agents for TEL-AML1 patients (Fenrick et al., 1999). The observation that the non-translocated copy of TEL is frequently deleted as a secondary event in TEL-AML1 leukemias suggests that the leukemogenic effect of TEL-AML1 may be mediated, at least in part, by loss of function of the TEL gene (McLean et al., 1996; Cave et al., 1997; Jousset et al., 1997; Takeuchi et al., 1997). In fact, overexpression of TEL in cell lines reduces proliferation by inducing a G1 cell-cycle arrest (Rompaey et al., 2000). Recent studies in the mouse have demonstrated that several domains of TEL-AML1 from both TEL and AML1 are required for self-renewal of B-cell precursors highlighting the complex function of this fusion gene in B-cell transformation (Morrow et al., 2007).


Summary and future directions

Deregulation of transcription factors plays a major role in lymphoid cell transformation. Cloning translocation break points that occur between T-cell receptor loci and transcription factors with essential roles in blood cell development have identified a number of oncogenic T-cell transcription factors, but such rearrangements are relatively rare. Other techniques such as quantitative reverse transcription–PCR and genomic sequencing have revealed that oncogenes are activated or overexpressed in a much higher percentage of ALL patients than previously believed. The application of emerging technologies such as single-nucleotide polymorphism arrays and array comparative genome hybridization to samples of T- and B-cell ALL has expanded the list of candidate oncogenes in these diseases. Detailed study of their activities has begun to generate a more complete picture of the molecular events required for leukemic transformation in a given blast cell. Most exciting, perhaps, is the opportunity to develop new drugs that target the aberrant signaling pathways now being identified in ALL. It is our hope that future therapy for ALL will be tailored to the genetic changes that characterize each patient's leukemia, resulting in more efficient elimination of transformed blast cells and less toxicity to normal tissues.



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A Thomas Look is supported by the NIH (CA109901). Jennifer O'Neil is supported by a Harvard Medical School Hematology Training Grant.

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