Review

Leukemia (2006) 20, 1496–1510. doi:10.1038/sj.leu.2404302; published online 6 July 2006

Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast

C Graux1, J Cools2, L Michaux3, P Vandenberghe3 and A Hagemeijer3

  1. 1Department of Hematology, Cliniques Universitaires St Luc, Catholic University of Louvain, Brussels, Belgium
  2. 2Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), Leuven, Belgium
  3. 3Center for Human Genetics, University of Leuven, Leuven, Belgium

Correspondence: Professor A Hagemeijer, Center for Human Genetics, Catholic University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail: Anne.Hagemeijer@med.kuleuven.be

Received 17 May 2006; Accepted 18 May 2006; Published online 6 July 2006.

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Abstract

For long, T-cell acute lymphoblastic leukemia (T-ALL) remained in the shadow of precursor B-ALL because it was more seldom, and showed a normal karyotype in more than 50% of cases. The last decennia, intense research has been carried out on different fronts. On one side, development of normal thymocyte and its regulation mechanisms have been studied in multiple mouse models and subsequently validated. On the other side, molecular cytogenetics (fluorescence in situ hybridization) and mutation analysis revealed cytogenetically cryptic aberrations in almost all cases of T-ALL. Also, expression microarray analysis disclosed gene expression signatures that recapitulate specific stages of thymocyte development. Investigations are still very much actual, fed by the discovery of new genetic aberrations. In this review, we present a summary of the current cytogenetic changes associated with T-ALL. The genes deregulated by translocations or mutations appear to encode proteins that are also implicated in T-cell development, which prompted us to review the 'normal' and 'leukemogenic' functions of these transcription regulators. To conclude, we show that the paradigm of multistep leukemogenesis is very much applicable to T-ALL and that the different genetic insults collaborate to maintain self-renewal capacity, and induce proliferation and differentiation arrest of T-lymphoblasts. They also open perspectives for targeted therapies.

Keywords:

T-ALL, thymocyte development, cytogenetics, molecular genetics, oncogenes, transcription regulation

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Introduction

T-cell acute lymphoblastic leukemia (T-ALL) is a neoplastic disorder of the lymphoblast committed to the T-cell lineage. T-ALL represents 15% of childhood and 25% of adult ALL.1 It is a heterogeneous disease comprising several clinico-biological entities. Cytogenetic analysis of lymphoblasts reveals recurrent translocations activating a small number of oncogenes in 25–50% of T-ALL but a large proportion of T-ALL shows a normal karyotype.2 In addition, fluorescence in situ hybridization (FISH) frequently demonstrates cytogenetically cryptic abnormalities. Among these, microdeletions leading to the loss of tumor suppressor genes are very frequent. Moreover, T-cell oncogenes are typically overexpressed, often in the absence of the corresponding locus specific chromosomal abnormalities. Expression array analysis has also identified several gene expression signatures indicative of leukemic arrest at specific stages of normal thymocyte development.3, 4 Finally, mutational analysis of oncogenes implicated in T-cell development has shown activating mutations of NOTCH1 in a high proportion of T-ALL.5 Based on these data, several major signaling pathways are emerging that may be responsible for neoplastic transformation.3, 4, 6, 7

In this paper, we review recurrent cytogenetic and molecular genetic alterations in T-ALL, and show how aberrant expression of oncogenes, either or not expressed in normal thymogenesis, can be responsible for various pathways of T-cell leukemogenesis. A summary of T-cell ontogeny will help to clarify these assumptions.

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T-cell ontogeny: the normal T lymphocyte

T-cell receptor and T-cell receptor signaling

Mature T-cells are characterized by the membrane expression of TCR/CD3 complex. T-cell receptor (TCR) is a unique transmembrane heterodimer composed of two chains: either alphabeta or italic gammadelta. The alpha, beta, italic gamma and delta proteins all consist of a variable domain and a constant domain. The variable domains are polymorphic and mediate the unique antigen (Ag) binding properties of each individual TCR. Gene loci encoding alpha- and delta-chains (TCRA and TCRD) are clustered on chromosome 14q11, those encoding the beta-chain (TCRB) and the italic gamma-chain (TCRG) are located on 7q34 and 7p15, respectively. The genomic locus of the various chains contains several gene clusters corresponding with the Variable (V), the Diversity (D), the Joining (J) and the Constant (C) regions. During T-lymphocyte development, strictly ordered gene rearrangements take place leading to the formation of a linear coding unit with exclusion of intervening sequences. Through a random choice between the various V-, D-, J segments and through the deletion or addition of extra nucleotides at the junctions, a broad T-cell repertoire is generated.8 The recombination activating genes RAG-1 and RAG-2 are essential for the rearrangement of variable region genes. The variable region of the alphabetaTCR recognizes antigenic peptides presented on major histocompatibility complex (MHC) molecules by Ag-presenting cells.9

Signals from TCR are important for lymphocyte survival. TCR is associated at the cell surface with the CD3 complex and the zeta- or eta-chains, which will activate intracellular signaling upon Ag binding. Protein kinases such as p56LCK and p59FYN brought into proximity of TCR/CD3 through interaction with the co-stimulatory molecules CD4 or CD8, phosphorylate the cytoplasmic immunoreceptor tyrosine-based activation motifs present on CD3, zeta or eta. This leads to the recruitment of other kinases such as ZAP-70 and PI3K. The signaling cascades thus activated will induce the transcription of various genes including IL2, a pivotal growth factor supporting clonal expansion of Ag-reactive T-cells. Recent reports suggest the requirement for ABL kinases for the regulation of T-cell receptor mediated signal transduction leading to IL-2 production and cell proliferation.10, 11

Thymocyte development and selection

Common lymphoid progenitors (CLP) migrate from the embryonic liver or from adult bone marrow to colonize the thymus, the site of education and maturation of T-lymphocytes. The commitment to the T-cell lineage depends on signals from the thymic microenvironment, where IL7 is indispensable for survival and proliferation of human T-cell precursors.12 In the thymus, T-cell progenitors rearrange their TCRD, TCRG, TCRB and TCRA loci, which if successful, will lead to expression of a mature TCR. They also undergo a series of selection procedures leading to a repertoire of non-self reactive, MHC-restricted, Ag-specific mature T-cells. The expression of a pre-T-cell receptor (pre-TCR) precedes the expression of the mature alphabeta T-cell receptor (alphabetaTCR).13 The different stages of thymocyte development are detailed and commented in Figure 1.

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 help@nature.com or the author

Thymocyte development. CLP: common lymphoid progenitor; IDP: immature double positive thymocyte; DP: CD8+ CD4+ double positive thymocyte; SP: CD4+ or CD8+ single positive thymocyte; pTalpha: TCRalpha chain 'substitute' for immature T-cells; pre-TCR: pre-T-cell receptor. When CLPs enter into the thymus, they are still able to differentiate into B, T, NK or dendritic cells.150 The commitment to the T-cell lineage is characterised by downregulation of CD34 and sequential upregulation of CD5, CD1a, CD4 and CD8 and rearrangement of genes coding for the TCRD and TCRG first. Thereafter, rearrangement of those coding for TCRB allows the formation and expression of the pre-TCR. The pre-TCR complex is composed of TCRbeta, pTalpha and the CD3 chains. Subsequently, TCRA genes rearrangement leads to the expression of the mature alphabetaTCR.151 The pre-TCR and the mature alphabetaTCR are sequentially expressed and act both as checkpoints.152 Signals from the pre-TCR allow survival, cellular expansion and further differentiation of T-cells with productive rearrangement of the TCRB (beta-selection).153 Signaling from the mature alphabetaTCR, triggered by its interaction with MHC molecules on thymic epithelial cells, allows the selection of alphabetaTCR non-self-reactive thymocytes that recognize self-MHC molecules and the production of single positive mature T-cells (positive and negative selection). The pre-TCR and the alphabetaTCR act through downstream effectors including the SRC family of protein tyrosine kinases LCK and FYN, the tyrosine kinase ABL1,10, 11 the RAS-MAP kinase pathway,154 the antiapoptotic transcription factor NFkappaB,155, 156 and cyclin D3.157 The italic gammadelta lineage diverge from the alphabeta at the pre-T1 stage and does not use the pre-TCR complex to mature. There are many differences between human and mouse thymocyte maturation but they both follow the same main developmental stages.158 The understanding of the role of the thymopoiesis regulators, E2A/HEB, NOTCH1 and Homeobox proteins, in the control of key steps throughout thymocyte development derives mainly from experiments in mice. Also, their site of action as indicated in this figure is an extrapolation to the context of human thymogenesis. The lower part of the figure summarises the critical steps of thymocyte development that can be targeted by oncogenic events.

Full figure and legend (235K)

Thymocytes with alphabetaTCR that recognize self-MHC molecules are rescued from programmed cell death by survival signals from the TCR and progress further towards maturation (positive selection). Others die by neglect. T-cells with strong TCR affinity for endogenous MHC complex are eliminated to avoid self-reactivity (clonal deletion). During positive selection, double positive thymocytes, characterized by CD4+ and CD8+ expression, undergo transition to single positive stages: either CD4+ and MHC class II restricted or CD8+ and MHC class I restricted.

Mature immunocompetent lymphocytes migrate to peripheral lymphoid organs where encounters with Ag lead to cell-mediated immune reactions driven by either cytotoxic CD8+ T-cells or CD4+ helper T-cells.

Key steps of thymocyte development are controlled by several transcriptional regulators.14, 15 Among these, the E proteins E2A and HEB, proteins from the family of Notch receptors, and Homeobox proteins are major players in T-cell ontogeny as well as in T-cell leukemia. Their role in normal thymocyte development will be discussed below together with their role in thymogenesis.

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The leukemic thymocyte: classification

T-ALLs are a heterogeneous group of diseases with regard to immunophenotype, cytogenetics, molecular genetic abnormalities and clinical features, including response to therapy.

Immunophenotype: EGIL classification

Several immunophenotypic classifications have been proposed. Among these, the classification proposed by the European Group for the Immunological Characterization of Leukemias (EGIL) is commonly used in Europe.16 According to EGIL, the presence of cytoplasmic or membrane expression of CD3 defines T-ALL. Four subgroups are proposed: (TI) the immature subgroup or pro-T-ALL is defined by the expression of only CD7; (TII) pre-T-ALL also expresses CD2 and/or CD5 and/or CD8; (TIII) or cortical T-ALL shows CD1a positivity; (TIV) finally, mature T-ALL is characterized by the presence of surface CD3 and CD1a negativity. Depending on the mutually exclusive membrane expression of alphabeta or italic gammadelta TCR, two subgroups, group a and group b, are distinguished.

A classification of T-ALL based on the status of the TCR rearrangement has been proposed but is not used in clinical practice.17

Cytogenetic aberrations in T-ALL

In approximately 50% of T-ALL, structural chromosomal aberrations are identified by conventional karyotyping. Numerical changes are rare, except for tetraploidy which is seen in approximately 5% of cases, and are without prognostic significance. A high percentage of cryptic abnormalities is revealed by FISH, mainly cryptic deletions at 9p21 and at 1p32. In addition, translocations with breakpoints in near terminal regions of chromosomes, for example the t(5;14)(q35;q32), rearrangements of TCRB at 7q34 and 9q34 breakpoints, are often disclosed only using FISH with the appropriate probes as illustrated in 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 help@nature.com or the author

FISH detection of cryptic cytogenetic aberrations in T-ALL. Arrows indicate abnormal chromosome. (a/b) ABL1 containing episomes visible as small dots in between chromosomes and not visible in G-banded metaphase (b). Probe used: LSI-BCR/ABL1 ES (Vysis). (c) Hemizygous deletion of p16 (9p21) detected with LSI-p16/CEP9 (Vysis). (d) Detection of t(5;14) with TLX3 DNA probe/split signal (DAKOcytomation). Sequences labeled in red are translocated to chromosome 14. (e) Detection of inv(7)(p15q34) using BAC probes: RPI-167F23 (in red) and RP5-1200I23 (in green) mapping centromeric and telomeric of the HOXA locus (7p15), respectively. (f) Deletion of SIL resulting in SIL-TAL1 fusion gene, demonstrated with the SIL-TAL1 DNA probe (DAKOcytomation). The SIL probe (in red) is absent on del(1).

Full figure and legend (275K)

Table 1 summarizes recurrent cytogenetic changes observed in T-ALL. Structural rearrangements in T-ALL result in oncogene activation either by promoter swap, usually the consequence of translocations in TCR loci, or by gene fusion encoding chimeric proteins. Deletions are the hallmark for loss of tumor suppressor genes.


Translocations involving TCR loci Breakpoints involving TCR loci are recurrent on 14q11 (TCRA/D) and 7q34 (TCRB). During T-cell development with V(D)J recombination taking place, several other genes transcribed at an early stage of thymocyte development are in 'open' chromatin configuration and vulnerable to the action of recombinase enzymes. Thus, illegitimate recombinations may juxtapose transcription factor genes and strong promoter and enhancer elements of the TCR genes. This may lead to their aberrant expression in developing thymocytes and give rise to T-ALL with differentiation block at various stages of maturation. Altogether, translocations involving the TCR loci are found in about 35% of T-ALL with unidentified partner genes in as of yet 5–10% of cases.18

Generation of fusion genes A second type of rearrangement, mostly translocations, results in formation of 'fusion genes'. Parts of both genes located at the chromosomal breakpoints are fused 'in frame' and encode a new chimeric protein with oncogenic properties. The SIL-TAL1 fusion gene results from a cryptic interstitial deletion at 1p32 and is found in 9–30% of childhood T-ALL, with decreasing frequency in adults. The t(10;11)(p13;q14) encoding CALM-AF10 is found in about 10% of cases, but is often cryptic.19 Translocations implicating MLL with various partners represent about 8% of cases,20 and translocations of ABL1 are rare except for NUP214-ABL1 fusion recently identified in up to 6% of T-ALL as a result of episomal formation with amplification.21 Recurrent translocations involving NUP98, another protein of the nucleopore complex, are reported very rarely.22, 23

Deletions
 

Cryptic deletions are frequent and may be concomitant with other changes. The most frequent is loss of the INK4/ARF locus at 9p21 that leads to loss of G1 control of cell cycle.24 Another recurrent aberration is del(6)(q) of variable size. The common deleted region focuses around 6q16 but the target gene(s) have not yet been formally identified.25

Molecular classification: gene expression signature

Recent investigations using quantitative RT-PCR and expression microarrays have shown that different T-cell oncogenes (mainly transcription factors) can also be aberrantly expressed in T-ALL, in the absence of chromosomal locus specific abnormalities.7 Large-scale expression profiling of T-ALL has identified several gene expression signatures indicative of leukemic arrest at specific stages of normal thymocyte development.3, 4 For example, LYL1+ signature corresponds to immature thymocytes (pro-T), TLX1+ to early cortical and TAL1+ to late cortical thymocytes.3 Genomic characterization and expression analysis of TCR, pre-TCR and RAG-1 also demonstrated that T-ALL have normal cellular counterparts and recapitulate the stages of normal thymogenesis.17

Table 2 summarizes the different developmental stages of normal thymocytes matched with corresponding T-ALL counterparts.


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Aberrant expression of oncogenes and deregulation of thymopoiesis regulators in T-ALL

Key steps of thymocyte development are controlled by several transcriptional regulators. The presence of some of them at the breakpoint region of recurrent chromosomal abnormalities in T-ALL provides a direct link with leukemogenesis.

NOTCH signaling deregulation

NOTCH family proteins are transmembrane receptors involved in regulation of cell fate in a broad spectrum of tissues and species.26 NOTCH signaling regulates hematopoietic stem cell maintenance (self-renewal)27 and plays a critical role in T-cell development.28

NOTCH1 is an important player in T-cell commitment decisions of the CLP29 and in the assembly and signaling of pre-TCR in immature thymocytes.30, 31 NOTCH1 could also play a role in differentiation by controlling the turnover of E2A proteins.32

Mature NOTCH1 is a heterodimeric transmembrane receptor consisting of extracellular (NEC) and transmembrane (NTM) subunits that are noncovalently associated by the heterodimerization domain (HD). Binding of the ligand from the Delta-Serrate-Lag2 (DSL) family to the NEC initiates a cascade of proteolytic cleavages of the NTM resulting in removal of NEC and NOTCH1 activation. The final cleavage is catalyzed by the italic gamma-secretase complex of proteases, and generates intracellular NOTCH1 (ICN). ICN translocates to the nucleus where it becomes part of a large transcription activator complex. ICN has a C-terminal PEST domain, a motif implicated in protein turnover and responsible for the short half-life of the protein.33

Mice transplanted with bone marrow expressing activated NOTCH1 develop T-cell neoplasms.34

In T-ALL, NOTCH1 was identified as a fusion partner of TCRB in the rare t(7;9)(q34;q34.3) leading to the formation of N-terminally truncated constitutively active NOTCH1 peptides.35

Recently, NOTCH1 activating mutations have been found in the HD domain and the PEST domain in 56% of T-ALL from all molecular subtypes.5 Mutations in HD, observed in 44% of T-ALL, result in ligand independent ICN production; mutations in PEST, observed in 30% of T-ALL, extend the half-life of ICN transcription activator complex. Combined HD and PEST mutations were found in 17% of cases and were shown to have a synergistic effect on NOTCH1 activation.5

The finding of NOTCH1 mutations in all molecular subtypes of T-ALL suggests that they occur in immature progenitors. The mechanism of NOTCH1 transforming activity is still unclear and results probably from the deregulation of its normal functions during T-cell development36 and its role in maintenance of self-renewal capacity of stem cells.27

E-proteins deregulation

The basic helix–loop–helix (bHLH) family of transcription factors share the bHLH motif (60 aa) allowing homo- or hetero-dimerization through the HLH domain and DNA binding through the basic part of dimerized protein.37

Class A bHLH: E2A, HEB
 

The class A bHLH, E2A and HEB, named the E proteins, are ubiquitously expressed as homo- or heterodimers. They bind DNA at specific E-Box sites in the enhancers of many T-cell specific regulatory genes like CD4 and pTalpha.38, 39 E2A and HEB are the bHLH transcription factors expressed in the thymus. E2A gene encodes two bHLH proteins, E12 and E47, by alternative splicing. A portion of E47 protein binds DNA as a complex with HEB.

The role of E proteins in thymocyte development is very complex.14 In mice, the absence of the E2A gene products leads to accumulation of double-negative thymocytes without TCRB gene rearrangement and to the development of aggressive T-cell lymphomas.40, 41 E2A proteins regulate V(D)J recombination, the expression of RAG and pTalpha genes required for the formation of pre-TCR.38, 42 E47/HEB heterodimers show proapoptotic activities.43 E2A proteins act as negative regulators of cell proliferation in thymic precursors.15, 44 They behave as gatekeepers at pre-TCR and alphabetaTCR checkpoints, both controlling further proliferation and differentiation.15 Specific inhibitors of E proteins, Id proteins, are playing opposing roles in regulating cell proliferation and oncogenic transformation.45

Class B bHLH: LYL1, TAL1, TAL2, bHLHB1
 

Class B bHLH proteins form heterodimers with class A bHLH and are expressed in a tissue-specific manner. LYL1, TAL1 and TAL2 are not expressed in the normal thymus46 but can be ectopically expressed in T-ALL.47 It has been proposed that by binding to E2A and HEB, they interfere with the normal activities of these proteins.

TAL1 (SCL, TCLS) maps on chromosome 1p32. Rearrangements of this locus are frequent in childhood T-ALL resulting in TAL1 activation either as a consequence of the t(1;14) (p32;q11)48 or more often due to a submicroscopic interstitial deletion generating the SIL-TAL1 fusion gene.49, 50 Other rare translocations targeting TAL1 have also been described.51 In addition, high expression levels of TAL1 in the absence of detectable TAL1 rearrangement are observed in about 40% of T-ALL.7, 52 These show maturation arrest at the late cortical stage and heterogeneous coexpression of the transcription factors LMO1/LMO2 and overexpression of the antiapoptotic gene BCL2A1.3

TAL1 is involved in embryonic and adult hematopoiesis53, 54 and in angiogenesis,55 but is not normally expressed in developing T-cells. However, it has been shown that TAL1 and its partners LMO1/2 are coexpressed in the most primitive thymocytes.56

The leukemogenic activity of TAL1 is not completely understood. Aberrant TAL1 expression may contribute to leukemia by interfering with differentiation and proliferation by inhibiting the transcriptional activity of E47/HEB.56, 57 In mice, thymic expression of TAL1 is associated with gene repression of several genes, some of which are being controlled by E47/HEB such as CD5, RAG1/2, TCRB. Such dominant-negative action of ectopically expressed TAL1 on E2A gene targets is supported by data showing that, in mice, enforced expression of TAL1 lacking the transactivation domain still leads to aggressive T-cell malignancies.58, 59 Also in agreement is the observation that HDAC inhibitors induce apoptosis of TAL1+tumors, supporting the hypothesis that TAL1 causes gene silencing.57

LYL1 is a partner gene of TCRB in the rare t(7;19)(q34;p13).60 LYL1 is also constitutively overexpressed in a subset of T-ALL, in the absence of chromosome rearrangements.3 LYL1 expression identifies T-ALL with an immature phenotype, expressing CD34 and sometimes myeloid markers.3 Its poor prognosis is possibly due to overexpression of antiapoptotic molecules, which is characteristic of early precursors.

TAL2 and BHLH1 are upregulated in T-ALL as a consequence of recurrent but rare translocations: t(7;9)(q34;q32) which juxtaposes TAL2 and TCRB61 and t(14;21)(q11;q22) which juxtaposes BHLH1 and TCRA.62 Their homologies with TAL1 bHLH domain suggest a similar mechanism for leukemogenesis.

LIM domain only genes LMO1 and LMO2
 

The genes encoding the LIM domain only proteins LMO1 (RTBN1) and LMO2 (RTBN2) mapping on chromosome 11p15 and 11p13, respectively, are frequently rearranged in T-ALL.63 Most common are the t(11;14)(p15;q11) and t(11;14)(p13;q11) juxtaposing LMO1/LMO2 to the TCRA/D locus.64, 65 Translocations involving TCRB and LMO1 or LMO2 loci have also been reported.18

Abnormal expression of LMO1/2 has been found in 45% of T-ALL, even in the absence of typical chromosomal changes,3, 66 but often in association with deregulation of LYL1 (LMO2) or TAL1 (LMO1 and 2).

Aberrant activation of LMO2 via retroviral integration has been recently reported in two T-cell lymphoproliferative disorders in children participating in a gene therapy trial of X-linked Severe Combined Immunodeficiency.67 Activation of LMO1/2 occurs by promoter swap and/or by removing tissue-specific negative regulatory elements located 5' of promoter.68 LMO2 is essential for erythroid development in mice.69 In erythroid precursors, LMO2 physically associates with other nuclear factors (GATA-1, TAL1, LDB1 and E2A) to form pentameric complexes involved in the transcription of several genes.70 Such complexes have been described in one T-ALL cell line.71 Studies in mice show that LMO2 or TAL1 overexpression induces leukemia with a long latency.58, 72 Of interest, co-expression of LMO1 in the thymus of transgenic mice overexpressing TAL1 shortens the latency period before leukemia onset.58, 73 Along these lines, one case with T-cell lymphoproliferative disorder and retroviral activation of LMO2 mentioned above also displayed an acquired mutation in TAL1.67 The fact that null mice for TAL1 or for LMO2 develop the same phenotype and that in some leukemic patients, TAL1 or LYL1 and LMO2 are co-expressed argues in favor of common oncogenic pathways.3

Homeobox genes deregulation

Homeobox (HOX) genes are key regulators of embryonic development, involved in axial patterning, morphogenesis and cellular differentiation. All homeobox genes share a 61 amino acids motif, the homeodomain, a DNA binding domain, regulating transcription of target genes.74 There are two classes of homeobox genes.

Class I homeobox genes: HOXA–D
 

Class I HOX genes comprise 39 genes distributed in four HOX clusters (A–D) located on chromosomes 7p15, 17q21, 12q13 and 2q31 respectively. These regulatory genes share extensive homology with the HOM-C genes of Drosophila.75 In addition to embryonic development, some HOX genes of clusters A, B and C were shown to play a role in normal hematopoiesis, influencing stem cell renewal and lineage commitment.76

HOXA genes (A7, A9, A10, A11) are expressed during the early stages of human T-cell development.77 In KO mice, the absence of HOXA9 results in an early block of thymocyte differentiation with reduced expression of IL7 receptor.78 Conversely, overexpression of HOXA9 also results in defective T-cell development.79

HOXB3 is expressed in very immature progenitors and probably interferes with the choice of alphabeta versus italic gammadelta lineage in pro-T-cells.80 HOXC4 is expressed at all stages of T-cell development.77

In T-ALL, HOXA genes (especially HOXA10 and A11) can be upregulated as a consequence of an often cryptic inv(7) or t(7;7), which brings the TCRB enhancer within the HOXA locus.81 FISH analysis disclosed these rearrangements in up to 5% of T-ALL showing a mature phenotype (EGIL) with characteristic CD2 negative and CD4 single positive lymphoblasts. Expression-array of HOXA+ T-ALL indicates an arrest after lineage choice but before beta selection.4

The exact mechanism of activation of these HOX genes remains to be explored. Beyond the classical activation due to the juxtaposition of TCRB regulatory elements in the vicinity of the HOXA genes, it has also been suggested that the breakpoint in the HOXA gene cluster could disrupt the normal schedule of sequential up- and downregulation of these genes within the HOXA locus.81 Indeed, the expression of each HOX gene in blood progenitors follows stage and lineage-specific programs that are tightly regulated, and differentiation into mature blood cells is accompanied by a progressive downregulation of HOX gene expression.82

HOX genes are known targets of MLL and are upregulated in ALL cases with MLL translocations.83 Similarly, the CALM-AF10 translocation results in HOXA upregulation6 as will be discussed below. Altogether, expression studies (microarrays and/or RQPCR) have identified a subgroup of HOXA expressing T-ALL.4 Included in this group are the T-ALL with TCR-HOXA,81 MLL,83 CALM-AF106 translocations, and a few cases without these rearrangements, which suggests the presence of additional yet undisclosed mechanisms of HOXA activation.

Class II homeobox genes: TLX1, TLX3
 

Class II homeobox genes (also named non-HOX genes or divergent homeobox genes) are dispersed throughout the genome.84 They encode cofactors for HOX proteins and are not involved in homeotic transformations. Their pattern of expression is more restricted. They are implicated in organogenesis and in differentiation of specific cell types.

In T-ALL, the class II orphan homeobox HOX11 (TLX1) and HOX11L2 (TLX3) have been extensively studied.

TLX1/HOX11 is not normally expressed in developing T-cells and HOX11-/- mice are asplenic, suggesting a role in spleen development.85

The TLX1 homeobox gene has been identified as the gene located at the 10q24 breakpoint region of t(10;14)(q24;q11) and t(7;10)(q34;q24).86 As a result of the juxtaposition with promoter elements of TCRA and B, respectively, the full-length protein is expressed at a high level. In addition, loss of negative regulatory elements upstream of the promoter could also explain the ectopic transcription of TLX1.87 TLX1 is also frequently activated in T-ALL in the absence of an overt genetic rearrangement.3, 7, 88 Promoter demethylation has been suggested.89 TLX1 is expressed in up to 30% of T-ALL, more often in adults than in children. These leukemias show an early cortical phenotype and a more favorable outcome than all other classes of T-ALL.90 It has been suggested that downregulation of antiapoptotic genes at this stage of thymocyte development could explain their better prognosis.3 The oncogenic potential of TLX1 is well established but its transforming mechanisms remain unclear and are the subject of intense research. Forced expression of TLX1 in murine bone marrow gives rise to T-ALL-like malignancies after long latencies, which suggests that additional mutations are required for full blown leukemia.91, 92 Mechanisms requiring homeodomain-DNA interactions have been proposed.93 In addition, recent works suggest that TLX1 modulates G1/S transcriptional network of T-ALL by interacting with the catalytic subunits of the protein serine/threonine phosphatases PP2A and PP1.94, 95

TLX3/HOX11L2 expression in T-ALL is in most cases caused by the cryptic translocation (5;14)(q35;q32) juxtaposing TLX3 to the distal region of BCL11B,96 a gene universally expressed during T-cell differentiation. The t(5;14) is found in approximately 20% of childhood T-ALL and 13% of adult cases. Rare variants have been reported: a t(5;14) that involves NKX2-5, another homeobox gene instead of TLX3,97 a t(5;7)(q35;q21) involving TLX3 and CDK6,98 and a t(5;14)(q35;q11) juxtaposing TLX3 and TCRA/D genes.99 TLX3 is very similar to TLX1 and microarray studies indicate that TLX1+ and TLX3+ T-ALLs cluster together, suggesting common mechanisms of action.3, 4 TLX3 expressing T-ALLs show a less narrow phenotype than TLX1, either more immature or slightly more mature4 and they do not have the favorable outcome reported for TLX1+ cases.3, 100, 101 More studies, including also analysis of combined involvement of other T-cell oncogenes, are needed to clarify this point.102

MLL fusion genes
 

The MLL gene at chromosome band 11q23 has structural and functional homologies with the Drosophila Trithorax gene. It acts as a transcriptional regulator and represents a major component of the cellular memory system, which maintains the established transcription patterns. The MLL protein is required to maintain the transcription of specific members of the HOX gene family.103, 104, 105

MLL is known to rearrange with more than 50 partners in several translocations encoding chimeric proteins in which the N-terminal portion of MLL is fused to the C-terminal portion of the partner.106 Translocations involving MLL at chromosome band 11q23 are seen in both myeloid and lymphoid malignancies, frequently in infant acute leukemias and in secondary leukemia in patients treated with topoisomerase inhibitors. Gene expression profiling has shown that B-precursor ALL associated with MLL translocations is a distinct subtype of acute leukemia, readily distinguished from either AML or ALL.107, 108

MLL fusions are found in 4–8% of T-ALL.20, 83, 107 The preferential partner is ENL (MLLT1). Translocation (11;19) (q23;p13.3) encoding MLL-ENL is often found in young adolescents and carries a better prognosis than usually associated with MLL rearrangement.109, 110 Other partners (AF10, AF6, AF4, AFX1) are occasionally seen. Their prognostic impact is not known.

Expression-array analysis demonstrated increased expression of a subset of HOX genes (HOXA9, HOXA10, HOXC6) and of MEIS1 the HOX gene co-regulator, to be a central mechanism of leukemic transformation by MLL-oncoprotein in MLL+, T-ALL and MLL+B-ALL. On the other hand, the upregulation of myeloid genes and expression of FLT3 characteristic of MLL B-ALL is not found in MLL T-ALL.83

T-ALL with MLL fusion represents a distinct molecular subtype with a specific expression profile, characterized by differentiation arrest at an early stage of thymocyte development and with commitment to italic gammadelta lineage.3, 4

CALM-AF10 (PICALM-MLLT10) fusion
 

The t(10;11) (p13;q14) is recurrent in T-ALL,111 but is also found in leukemias of other lineage like AML. This translocation fuses CALM (Clathrin Assembly protein-like Lymphoid-Myeloid Leukemia gene, also called PICALM) to AF10 (also called MLLT10).112 Both CALM and AF10 are occasional MLL fusion partners.113 Both are ubiquitously expressed and AF10 functions as a transcription factor. In mice, retroviral expression of CALM-AF10 was reported to induce biphenotypic acute leukemia (Deshpande et al., Blood 2003; 102: 216a, abstract no. 758). CALM-AF10 fusion is detected in 9–10% of T-ALL and is restricted to mature cases expressing italic gammadeltaTCR and their precursor, immature italic gammadelta (IM italic gamma/delta) T-ALLs.19 The translocation is often cryptic and requires molecular detection either by FISH or RT-PCR.

Several different fusion transcripts have been described. Within T-ALL, AF10 content differs with the stage of maturation arrest: the more 5' breakpoints are associated to mature TCRitalic gammadelta cases and the more 3' breakpoints are associated to IM italic gamma/delta T-ALLs.19 These findings suggest a possible role for AF10 protein in TCRitalic gammadelta lineage commitment at the early stages of hematopoietic differentiation. The mechanism by which the fusion transcript is leukemogenic is not clear.

Expression arrays disclosed upregulation of the HOXA5, HOXA9 and HOXA10 genes and their cofactor MEIS1.4, 6 This strongly indicated common oncogenic pathways in CALM-AF10 and MLL-TALLs. Unique to CALM-AF10 is the overexpression of BMI1, a gene located at 10p12.3 in close vicinity of AF10. BMI1 is essential for self-renewal of normal and leukemic stem cells.114 BMI1 controls cell proliferation by inhibiting the CDKN2A locus115 and is thus an alternative to the deletion of the CDKN2A locus observed in 70% of T-ALL, but not present in CALM-AF10 T-ALL.

Prognosis is globally poor, particularly for the most immature subtype.19, 113

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Tyrosine kinase genes and other players in TCR signaling

Tyrosine kinases play a key role in (pre-)TCR signaling. They are critical in regulation of T-cell survival, proliferation and T-cell immune response.

In T-ALL, a number of these genes are activated either by gene fusion as a consequence of chromosomal rearrangements or by mutation. With the exception of cases with RAS mutations and ABL1 fusions, very few T-ALLs harbor constitutively activated kinases. The interest to identify these cases resides in the fact that numerous (specific) kinase inhibitors are currently developed and thus that targeted therapy may become a valuable option for these patients.

ABL1 fusions

ABL1 is a ubiquitously expressed cytoplasmic tyrosine kinase, encoded by a gene mapping on 9q34. It has recently been shown to play a role in TCR signaling.10, 11

The t(9;22)(q34;q11) encoding the BCR-ABL1 fusion kinase,116 characteristic of chronic myeloid leukemia, is found in 25% of precursor B-ALL and only rarely (1%) in T-ALL.1, 117

Specific for T-ALL is the NUP214-ABL1 fusion found in up to 6% of T-ALL.21 Interestingly, this fusion gene is found on amplified episomes, which are not visible cytogenetically, or exceptionally on hsr.102 Molecular detection by FISH or RT-PCR is required to diagnose such cases (Figure 2a). NUP214-ABL1 positive T-ALLs are characterized by ectopic expression of TLX1 or TLX3 and deletion of CDKN2A locus.21, 118

Other ABL1 fusion variants have rarely been reported. Like BCR-ABL1, ETV6-ABL1 resulting from t(9;12)(q34;p13)119 is found in CML, precursor B-ALL and exceptionally in T-ALL. In contrast, t(9;14)(q34;q32) encoding a EML1-ABL1 fusion protein has been described in a single T-ALL patient.120

All these fusions result in constitutive activation of ABL1 leading to activation of survival and proliferation pathways. Interestingly, imatinib, a specific inhibitor of ABL1 kinase seems to be effective in controlling the activity of these ABL1 fusion proteins in vitro, which opens therapeutic promises for these specific cases. An ETV6-ABL2 fusion transcript in combination with an ETV6 point mutation has been described in a T-cell acute lymphoblastic leukemia cell line.121

JAK2

JAK2 is an essential relay for transmitting signals from cytokine receptors to downstream signaling. In a pediatric T-ALL, a t(9;12)(p24;p13) encoding ETV6-JAK2 fusion gene was shown to result in constitutive tyrosine kinase activity.122 Subsequently, the transforming role of this fusion protein was demonstrated in mice transgenic for ETV6-JAK2, which developed leukemia.123

LCK

LCK, a member of the SRC family of tyrosine kinases, is specifically expressed in T-cells and is a key player in proximal (pre)-TCR signaling cascade, upstream to ABL1. In T-ALL it has been shown to be overexpressed in rare cases with t(1;7)(p34;q34), joining LCK to the TCRB locus.124, 125

FLT3

FLT3 is a receptor tyrosine kinase playing an important role in the development of hematopoietic stem cells. Activating mutations such as internal tandem duplication (ITD) in the juxtamembrane domain or point mutations in the activation loop of the kinase domain are most common in AML (30%), rare in precursor-B ALL and infrequent in T-ALL.126

In T-ALL, they seem to be restricted to cases with a very immature phenotype, expressing LYL1 and LMO2 and the KIT receptor.126, 127 Occasional expression of myeloid markers, supports the contention that FLT3+ T-ALL are leukemias with expansion of early progenitor cells.83

RAS

The RAS proteins play a critical role in transmitting survival signals from the cell membrane receptors to the intracellular transduction pathways. Mutations of RAS genes are common and have been described in various malignancies128 including acute leukemias.129 They lead to the constitutive activation of the RAS-MAPK signaling cascade.

Activating mutations of N-RAS have been detected in 10% of a series of pediatric T-ALL.130 Other studies indicate that RAS is highly activated in 50% of T-ALL131 suggesting a key role for RAS activation in T-ALL pathogenesis. This also supports therapeutic approach using farnesyltransferase inhibitors.132

PI3-Kinase and PTEN

PI3K is another key element of TCR signaling that is negatively controlled by the tumor suppressor gene PTEN. Recent work showed that inactivation of PTEN resulted in uncontrolled proliferation of T-cells.133, 134 These and other experiments135 point to the PI3K/AkT pathway as a potential target for therapeutic intervention.

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Cell cycle defect: p16/p14 deletion at 9p21

Cell cycle progression is tightly regulated with various checkpoint controls in order to maintain genomic integrity of the cell and to obtain an adequate balance between cell proliferation and differentiation.

The INK4/ARF locus on chromosome 9p21 contains genes coding for three proteins, p16INK4A, p14ARF and p15INK4B involved in the cell cycle regulation.136, 137 P16INK4A and p14ARF are encoded by the same genomic region. Both transcripts have identical exons 2 and 3 but differ in their promoters and exon 1 (exons 1alpha and 1beta, respectively). Alternative splicing of exon 1 gives rise to alternative reading frames and therefore to unrelated proteins.

p16 and p15 are inhibitors of CyclinD-CDK protein complexes and maintain the cells in a quiescent stage. Inhibition of CDK inhibitors leads to uncontrolled cell cycle activity.138 p14ARF also controls cell cycle entry through interaction with p53 pathway. Indeed, p14 associates with MDM2 (a negative regulator of p53), resulting in upregulation of p53 and subsequent CDKN1A (p21) activation. p21 is a CDK inhibitor causing cell cycle arrest in G1/G2 in order to allow DNA repair or apoptosis in case of major DNA damage.139

Cryptic deletion (detectable by FISH) of the INK4/ARF locus on 9p21 is the most frequent anomaly detected in T-ALL.24, 140 Homozygous/hemizygous deletions are seen in 65/15% of cases, respectively. These deletions target the CDKN2A (p16/p14) and in part also CDKN2B (p15) genes. In addition, mutation or methylation of promoters of these genes is present in a substantial number of cases. Inactivation at transcriptional and post-transcriptional level have also been reported.141, 142

Globally, functional inactivation occurs in nearly all childhood T-ALL143 and in the vast majority of adult T-ALL. The majority of TAL1+ and HOX11+ T-ALL presents with homozygous deletion of p16. This indicates that inactivation of these tumor suppressor genes is directly implicated in T-cell leukemogenesis. The respective contribution of p16 and p14 inactivation still remains unclear. It also identifies the Rb1 and p53 pathways as potential targets for therapy.

Prognostic significance of INK4/ARF locus deletion in acute leukemia is inconsistent but seems to be unfavorable in childhood T-ALL as shown in one study in which p16 homozygously deleted T-ALL patients had a significantly lower 5-year disease-free survival.144

Cyclin D2 (CCND2)

Recently, three cases of T-ALL have been reported with marked overexpression of CCND2, as a consequence of translocation of CCND2 locus at 12p13 to regulator elements of the TCRB or TCRA/D locus.145 CCND2 is normally expressed in immature thymocytes and immature T-ALL. Ectopic high expression in these three cases was associated with TAL+, TLX1+ or TLX3+ molecular subtypes, NOTCH1 mutation and CDKN2A deletion, indicating a role for CCND2 in multistep leukemogenesis of T-ALL.

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Multistep leukemogenesis and therapeutic perspective

From the above description and as seen in Table 2, it emerges clearly that multiple hits are cooperating in the generation of T-ALL, in agreement with the paradigm of multistep oncogenesis first developed for colon tumors by Vogelstein and Kinzler.146

  1. Defects in cell cycle control are a universal phenomenon in T-ALL, mostly due to loss of the INK4 locus (p16/p14).143 Since p16/14 inhibit Rb1 and p53, these pathways may provide interesting targets for therapy. Disruption of cell cycle control can also be operated by transcription factor modulation. For example, CALM-AF10 T-ALLs overexpress BMI1 that control cellular proliferation by suppressing p16.6 Also, enforced TAL1 expression negatively regulates p16 gene through interfering with the E boxes sequences of the p16 promoter.147 Conversely, E2A proteins positively regulate several CDK inhibitors' promoters and negatively affect cell growth, consistent with their tumor suppressor properties.44 HOX11 has been shown to act on the cell cycle by interacting with the protein serine/threonine phosphatases PP2A and PP1.94
  2. The very high incidence of NOTCH1 mutations, detected in all molecular subtypes of T-ALL strongly suggests that mutations occur in very immature progenitors, conferring them increased self-renewal capacity27 and resulting in accumulation of progenitor cells susceptible to undergo additional molecular hits. Of interest, italic gamma-secretase activity is essential for NOTCH1 cleavage and subsequent signaling, also in the case of mutated forms.148 Inhibitors of italic gamma-secretase, already available in the framework of treatment of Alzheimer's disease, could thus have important therapeutic applications, but the exact consequences of italic gamma-secretase inhibitor treatment still need to be determined.
  3. Aberrant expression of transcription factors is a universal finding in T-ALL. Overexpression of oncogenes is often the consequence of chromosomal translocations, but is also found in the absence of specific cytogenetic alterations and constitutes the basis of the molecular classification established after analysis of microarray gene expression profiles.3, 4 These gene expression signatures correspond to different stages of differentiation arrest resulting from deregulated transcription factors activity. bHLH proteins (TAL1, LYL1, TAL2) are oncogenic through inhibition of the E2A proteins regulatory activity. LMO1 and LMO2 overexpression is frequently found in TAL1+ or LYL1+ T-ALL3 and contributes to transforming activity of TAL1.58, 73 TLX1 (HOX11) and TLX3 (HOX11L2) are not normally expressed in thymocytes, but are aberrantly expressed in a substantial number of cases, classically with an early cortical phenotype.3
     Several HOX genes play a role in thymocyte development but their expression is transient. Recently, a subgroup of T-ALL has been identified with sustained aberrant expression of members of the HOXA family (A5, A10, A11).4 HOXA genes are targets of MLL and of CALM-AF10 fusion genes and are overexpressed in immature T-ALL carrying these translocations.6, 83 In addition, HOXA genes can be upregulated by virtue of translocation in TCRB locus, as seen in cases with inv(7) or t(7;7) in more mature cases81 (Table 2).
     Specific inhibitors of transcription factors are not yet available but more general approaches are investigated like the use of histone deacetylase (HDAC) inhibitors, proteasome inhibitors and short interfering RNAs.109
  4. Expression of constitutively activated tyrosine kinases, for example, LCK, FLT3 and ABL1 interfere with pre-TCR and TCR signaling and give proliferative and survival advantage to the cells. They have been identified in only about 10–20% of T-ALL.149 Their major interest is in the recent development of specific kinase inhibitors which have already been shown to constitute effective targeted therapies for other hematological malignancies. These are specific inhibitors of ABL1 and SRC kinases, FLT3 inhibitors and Farnesyl transferase inhibitors among others. Their application in T-ALL is likely to be restricted to cases with tyrosine kinase activation, although it can be expected that additional kinase activating events remain to be identified.

In summary, future targeted therapy will have to address the multiple molecular hits characteristic for the various subtypes of T-ALL and therefore a precise diagnosis of these genetic changes and gene expression signatures will be required to improve treatment adequacy and outcome.

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Acknowledgements

This text presents research results of the Belgian programme on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Science Policy Programming. The scientific responsibility is assumed by the authors. JC is a postdoctoral researcher, and PV is a clinical investigator of the 'Fonds voor Wetenschappelijk Onderzoek Vlaanderen'.