Recurring regions of copy number alteration reported in ALL and involved genes with known or putative roles on leukemogenesis and cancer.
1. Introduction
Acute lymphoblastic leukemia (ALL) is mainly a disease of childhood that arises from recurrent genetic alterations that block precursor B- and T-cell differentiation and drive aberrant cell proliferation and survival [1]. Due to the advances in the cytogenetic and molecular characterization of the acute leukemias in the past two decades, genetic alterations can now be identified in more than 80% of cases of ALL [2]. These genetic lesions influence the prognosis and therapeutic approach used for treatment of ALLs [3]. This chapter describe genetic subtypes of ALL according to the hematological malignancies classification (WHO) 2008, risk groups, frequency of cytogenetic abnormalities, and their relationship with the prognosis of ALL, copy number alterations and somatic mutations in ALL.
2. Acute Lymphoblastic Leukemia (ALL) — Genetic subtypes
2.1. Definition and genetic subtypes according to the hematological malignancies classification (WHO) 2008
Acute lymphoblastic leukemia (ALL) is mainly a disease of childhood that arises from recurrent genetic alterations that block precursor B- and T-cell differentiation and drive aberrant cell proliferation and survival [1]. ALL is characterized by the accumulation of malignant, immature lymphoid cells in the bone marrow and, in most cases, also in peripheral blood. The disease is classified broadly as B- and T-lineage ALL [1].
ALL occurs with an incidence of approximately 1 to 1.5 per 100,000 persons. It has a bimodal distribution: an early peak at approximately age 4 to 5 years with an incidence as high as 4 to 5 per 100,000 persons, followed by a second gradual increase at about age 50 years with an incidence of up to 2 per 100,000 persons. ALL, the most common childhood malignancy, represents about 80% of all childhood leukemias; but only about 20% of adult leukemias [4]. The rate of success in the treatment of ALL has increased steadily since the 1960s. The five-year event-free survival rate is nearly 80 percent for children with ALL and approximately 40 percent for adults [5].
Diagnosis of ALL relies on an assessment of morphology, flow cytometry immunophenotyping, and identification of cytogenetic-molecular abnormalities [4]. Conventional and molecular genetics allow the identification of numerical and structural chromosomal abnormalities and the definition of prognostically relevant ALL subgroups with unique clinical features [6, 7]. However, acute lymphoblastic leukemia subtypes show different responses to therapy and prognosis, which are only partially discriminated by current diagnostic tools, may be further determined by genomic and gene expression profiling [4]. More accurate delineation of genetic alterations can also provide information important for prognosis. Minimal residual disease (MRD) detection and quantification have proven important in risk-group stratification for both pediatric and adult ALL [7].
It seems likely that one or several changes in the genome are required for a blast cell to evolve into a leukemic clone, and that all cases probably harbor some form of genetic alteration [7]. Due to the advances in the cytogenetic and molecular characterization of the acute leukemias in the past two decades, genetic alterations can now be identified in greater than 80% of cases of ALL [2]. Improvement in recognizing abnormalities in the blast cells will help in understanding the mechanisms that underlie leukemogenesis.
The cloning and characterization of recurrent chromosomal translocations has allowed the identification of genes critical for understanding of the pathogenesis and prognosis of ALL [5, 8, 9]. These genes are implicated in cell proliferation and/or survival, self-renewal, cell differentiation and, and cell cycle control [10, 11]. The main causes of gene deregulation are: (i) oncogene activation with ensuing ectopic or over-expression, which is mainly due to juxtaposition with T-cell receptor loci; (ii) gain of function mutations; (iii) tumor suppressor gene haploinsufficiency or inactivation, which is usually the result of deletion and/or loss of function mutation; and (iv) chromosomal translocations producing fusion proteins which are associated with specific subgroups of ALL [10].
Efforts to define the genetic lesions that underlie ALL have identified a number of different subtypes of ALL based on their lineage (T- versus B-cell), chromosome number, or the presence or absence of chromosomal translocations. Collectively, these genetic lesions account for approximately 75% of cases, and their presence significantly influences the therapeutic approach used for treatment [3].
B-lineage ALL (B-ALL) shows considerable genetic heterogeneity. Within the category ‘‘B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities’’, the 2008 World Health Organization classification of hematopoietic neoplasms recognizes seven recurrent genetic abnormalities including t(9;22) (q34;q11.2)
Burkitt lymphoma/mature B-ALL (BL) was included in the category of mature lymphatic neoplasms in the new WHO classification [12]. BL is characterized by translocation of
In B-ALL, malignant cells often have additional specific genetic abnormalities, which have a significant impact on the clinical course of the disease. In contrast, although the spectrum of chromosomal abnormalities in T-lineage ALL (T-ALL) has been further widened by the finding of new recurrent but cryptic alterations, no cytogenetically defined prognostic subgroups have been identified [16, 17].
T-ALL is mainly associated with the deregulated expression of normal transcription factor proteins. This is often the result of chromosomal rearrangements juxtaposing promoter and enhancer elements of T-cell receptor genes
Other type of rearrangement in T-ALL, mostly translocations, results in formation of ‘fusion genes’ that are associated with specific subgroups of T-ALL (
In addition, gain of function mutations (
2.2. Risk groups in ALL
During the past three decades, the prognosis of has been improved and the treatment achieved cure rates exceeding 80%. ALL in adults has followed the same trend with long-term survival of about 40%. One main factor behind this improvement is the development of risk-adapted therapy, that permit to stratify the patients in different clinical categories according to risk factors with prognostic influence and to define the intensity and duration of treatment [20].
The prognosis of patients with ALL is influenced by clinical, hematologic and genetic factors, including age, leukocyte count at diagnosis, percentage of blast in peripheral blood, immunophenotype, central nervous system (CNS) involvement, the presence or absence of mediastinal tumor, cytogenetic and molecular alterations and the presence of minimal residual disease (MRD) in different stages of treatment which is currently a defined risk of adapted therapy strategies [20-24].
With respect to age, children less than 24 months and adults more than 50 years old have a worse prognosis, while the better results are achieved for children between 1 and 10 years, followed by adolescents and young adults. The leukocytosis (>30X109L in B-ALL and >100X109L in T-ALL), the phenotype Pro-B ALL, and T-ALL, are related to a poor outcome and are used to stratify patients as high risk [23].
The study of these prognostic factors allows recognition of three subgroups with outcome clearly differentiated in children: standard risk (40% of cases - 90% survival), intermediate (45-50% - 70-80% survival) and high risk (10-15%-less than 50% survival) [23, 25], and two subgroups in adult, standard-risk (20-25% of cases, 60% survival) and high risk (75-80% - 30% survival) [23, 26].
3. Cytogenetic alterations in ALL
3.1. Cytogenetic alterations in B-cell precursor ALL (BCP-ALL)
A correlation between prognosis and the karyotype at diagnosis in ALL was firstly demonstrated by Secker-Walker (1978) [24]. Subsequently, during the third International Workshop on Chromosomes in Leukemia (IWCL, 1983), the first large series of newly diagnosed ALL were analyzed to establish cytogenetic and prognostic correlations. Sixty-six percent of the patients analyzed showed clonal aberrations, which were identified both high-risk and low-risk ALL patients [27]. Since then it has been considered that the cytogenetic alterations have prognostic value of first order in the ALL.
Development of methods in cytogenetics has contributed to the understanding that ALL is not a homogeneous disease. Chromosome abnormalities have been detected by conventional G-banding in approximately 60–70% of all cases [7, 28]. Abnormal karyotypes have been reported in up to 80% of children and 70% of adults with ALL [29, 30]. There had been considerable developments in fluorescence in situ hybridization (FISH) for the detection of significant chromosomal abnormalities in leukemia in the 1990s [31]. The development of 24-color fluorescence in situ hybridization (FISH), interphase FISH with specific probes, and polymerase chain reaction (PCR) methods has improved the ability to find smaller changes and decreased the proportion of apparently normal karyotype to less than 20% in ALL [7].
In cases with B-ALL (excluding mature B-ALL), the most important subgroups for modal number are hypodiploidy, pseudodiploidy, and hyperdiploidy with a chromosome number greater than 50 [32]. The most structural rearrangements include translocations that generate fusion transcripts with oncogenic potential. The most important of the translocations are t(1;19)(q23;p13)(
3.1.1. Ploidy alterations
The presence of hypodiploidy (less than 45 chromosomes) is found in only 2% of ALL, and is associated with a very poor outcome [33]. The high hyperdiploidy (with more than 50 chromosomes) is the most common cytogenetic subgroup in childhood BCP-ALL, and associated to a long survival. Hyperdiploidy is more frequent in children (15%) than in adults (6%) [34].
The gain of chromosomes is nonrandom, the eight chromosomes that account for 80% of all gains are: +4(78%), +6 (85%), +10 (63%), +14 (84%), +17 (68%), +18 (76%), +21 (99%), and +X (89%) [24]. Trisomy 4, 10, and 17 are associated to favorable outcome in children [33]. Unlike hypodiploidy ALL patients, hyperdiploid ALL cases have an extremely good prognosis with event-free survival rates near 90% [21]. These patients seem to particularly benefit from high dose methotrexate [33].
Approximately 20% of hyperdiploid ALL have activating mutations in the receptor tyrosine kinase
3.1.2. E2A-PBX1 fusion t(1;19) (q23;p13)
The t(1;19) (q23;p13) represents 5% of children ALL, and 3% in adults ALL, this translocation is frequently associated with the pre-B immunophenotype, in approximately 25% of cases [5, 34, 35]. The t(1;19) (q23;p13) forms a fusion gene that encodes a chimeric transcription factor,
3.1.3. BCR-ABL fusion t(9;22) (q34;q11)
As a result of the t(9;22) (q34;q11)/Philadelphia chromosome (Ph+), the
3.1.4. 11q23-MLL rearrangements
Chromosomal rearrangements of the human
Some 104 different
3.1.5. ETV6-RUNX1 t(12;21) (p13;q22)
The t(12;21) (p13;q22) leads to a fusion
3.2. Cytogenetic alterations in Burkitt lymphoma/mature B-ALL (BL)
3.2.1. MYC/IG (t(8;14), t(2;8) and t(8;22))
The t(8;14)(q24;q32) and its variants t(2;8)(p11;q24) and t(8;22)(q24;q11) are associated with BL [13]. The t(8;14) is most common, found in 85%, whereas t(2;8) and t(8;22) are found in around 5 and 10%, respectively [24]. The crucial event in all three reciprocal translocations is the juxtaposing of
The abnormalities of
3.2.2. Secondary chromosome changes in BL
Several cytogenetic reports have correlated the presence of cytogenetic abnormalities with the outcome of patients with non-Hodgkin lymphomas, showing that secondary chromosome changes may influence the clinical phenotype of lymphoid tumors [43].
Most of the secondary chromosome changes are unbalanced rearrangements, leading to DNA gains or losses. These changes have been studied in Burkitt’s lymphoma-derived cell lines and primary tumors by cytogenetic techniques including karyotype analysis [44-48], fluorescence in situ hybridization (FISH) [49], multiplex FISH (M-FISH) [50], spectral karyotype analysis (SKY), comparative genomic hybridization (CGH)[43, 51-54], and microarray analysis [55].
Additional recurrent chromosomal abnormalities have involved chromosomes 1, 6, 7, 12, 13, 17, and 22. Gains of the long arm of chromosomes 1 (+1q) or 7 (+7q) or 12 (+12q), deletion (del) 17p13 and abnormalities of band 13q34 usually occur in adult BL, without or in the setting of an HIV infection [13, 44-46, 51, 56]. Some secondary abnormalities have been associated with tumor progression, such as abnormalities on 1q, + 7q and del(13q) which have been independently associated with a worse outcome [43-46, 49, 50].
3.3. Cytogenetic alterations in T-ALL
Conventional karyotyping identifies structural chromosomal aberrations in 50% of T-ALL. Numerical changes are rare, except for tetraploidy which is seen in approximately 5% of cases. The presence of chromosomal abnormalities is not associated to the prognosis [19]. Some nonrandom translocations that are specific to T-lineage malignancies have been identified. They involve genes coding for transcriptional regulators transcriptionally deregulated in malignancies [57].
Extensive characterization of specific chromosomal abnormalities for T-ALL led to the identification of several oncogenes whose expression was up-regulated under the influence of the transcriptional regulation elements of genes which are normally expressed during T-cell differentiation [58]. T-cell malignancies are often associated with unfavorable features compared with childhood precursor B-cell ALL. However, the use of more intensive treatments and risk adapted therapy has significantly improved the outcome of patients with T-ALL. Event-free survival rates of 60% to 70% are now reported in children [57].
3.3.1. Rearrangements involving TCR genes
3.3.1.1. Deregulation of homeobox genes
The homeobox (
3.3.1.1.1. TLX1 (HOX11) (t(10;14)(q24;q11) and its variant t(7;10)(q35;q24))
The translocation t(10;14)(q24;q11) and its variant t(7;10)(q35;q24) are a nonrandom alteration identified in T-ALL. Either of these is present in 5% of pediatric to 30% of adult T-ALL [1]. Both of them lead to the transcriptional activation of an homeobox gene,
There is some evidence that
3.3.1.1.2. TLX3 (HOX11L2) (t(5;14)(q35;q32))
The cryptic translocation, t(5;14)(q35;q32), is restricted to T-ALL, is present in approximately 20% of childhood T-ALL and 13% of adult cases. This translocation is associated with strong ectopic expression of another homeobox gene called
Although
3.3.1.1.3. HOXA@ cluster (inv(7)(p15q34))
Other rearrangement involving
In contrast to
3.3.1.2. Deregulation of TAL1-related genes
Although expression of
3.3.1.2.1. TAL1 (SCL,TCL5) ( t(1;14)(p32;q11), t(1;14)(p34;q11) and t(1;7)(p32;q34))
Alteration of the
As the translocation as interstitial deletion disrupt the coding potential of
The deletions aberrantly triggers activated
3.3.1.2.2. TAL2 (t(7;9)(q34;q32))
As a consequence of t(7;9) (q34;q32), the
3.3.1.2.3. LYL1 (t(7;19)(q34;p13))
In the t(7;19)(q35;p13), the
3.3.1.3. Deregulation of LIM-domain only genes LMO1 and LMO2
3.3.1.3.1. LMO1 (t(11;14)(p15;q11) and LMO2 (t(11;14)(p13;q11))
The genes encoding the LIM-domain only proteins
Generally the ectopic expression of
3.3.1.4. Deregulation of family of tyrosine kinases — LCK gene (t(1;7)(p34;q34))
The lymphocyte-specific protein tyrosine kinase (
3.3.1.5. Deregulation of MYB gene — Duplication and t(6;7)(q23;q34)
Finally, other rearrangements involving TCR genes affect genes like
3.3.2. Fusion genes rearrangements
3.3.2.1. PICALM-MLLT10 (CALM-AF10) — t(10;11)(p13;q14)
The
The precise mechanism for
3.3.2.2. MLL-fusions
Translocations implicating
3.3.2.3. ABL1-fusions
Translocations of
4. Copy number alterations in acute lymphoblastic leukemia
In spite of continually improving event-free (EFS) and overall survival (OS) for ALL, particularly in children, a number of patients on current therapies will relapse. Therefore it is important to know the group of patients with high risk of relapse [72, 73]. As the risk-stratification of ALL is partly based on genetic analysis, different genomic technologies designed to detect poor-risk additional genetic changes are being expanded substantially. Analyses of somatic DNA copy number variations in ALL aided by advances in microarray technology (array comparative genomic hybridization and high density single nucleotide polymorphism arrays) have allowed the identification of copy gains, deletions, and losses of heterozygosity at ever-increasing resolution [74].
Several microarray platforms have been used for the analysis of DNA copy number abnormalities (CNAs) in ALL, such as array-based comparative genomic hybridization (array-CGH), bacterial artificial chromosome (array-BAC) array CGH and oligonucleotide array CGH (oaCGH), single nucleotide polymorphism array (aSNP) and single molecule sequencing [75]. These microarray platforms vary in resolution, technical performance, and the ability to detect DNA deletions, DNA gains, and copy neutral loss of heterozygosity. These techniques have improved the detection of novel genomic changes in ALL blast cells [76]. The aCGH also detects the majority of karyotypic findings other than balanced translocations, and may provide prognostic information in cases with uninformative cytogenetics [77, 78]. In addition, the use of these methods documented multiple regions of common genetic cryptic alterations. These analyses provide information about multiple submicroscopic recurring genetic alterations including target key cellular pathways. However, many aberrations are still undetected in most cases, and their associations with established cytogenetic subgroups remain unclear [28, 79].
4.1. CNA in BCP-ALL
Most of ALL (79-86%) showed alterations in the number of copies (CNA) by aCGH techniques. The CNA frequently involved chromosomes 1, 6, 8, 9, 12, 15, 17 and 21; and rarely chromosomes 2, 3, 14 and 19. The losses have been more frequent than gains [6, 7, 28, 35, 77, 78, 80-85].
In precursor B-cell ALLs, most of the abnormalities have been gains of 1q (multiple loci), 9q, 17q, amplification of chromosome 21 (predominantly tetrasomy 21), and loss of 1p and 12p. Other recurrent chromosomal rearrangements have been found in both B-and T ALLs, such as loss of 6q (heterogeneous in size), 9p (9p21.3), 11q, and 16q, as well as gain of 6q and 16p. Other recurrent findings have included dim (13q), dim (16q) and enh (17q) [6, 7, 28, 35, 77, 78, 80-85] (Figure 1).
Several observations suggest that the CNAs are biologically important. The identification of these recurrent chromosomal rearrangements in ALL has defined Minimal Critical Regions (MCR), which are target small regions of the genome, that are often small enough to pinpoint the few candidate genes that present in these chromosomal regions [75].
Many of these MCR contain genes with known roles in leukemogenesis of ALL. These lesions include deletions of lymphoid transcription factors and transcriptional coactivators (e.g.
|
|
|
|
|
|
|
|
loss | 1 | p33 | 0.039 | 47.728 | 47.767 |
|
[75, 85] |
loss | 1 | q44 | 1.74 | 245.113 | 246.853 |
|
[80, 110] |
loss | 2 | p21 | 0.287 | 43.425 | 43.712 |
|
[75, 85] |
loss | 3 | p22.3 | 0.306 | 35.364 | 35.670 |
|
[85, 110] |
loss | 3 | p14.2 | 0.254 | 60.089 | 60.343 |
|
[75, 83, 85, 110] |
loss | 3 | q13.2 | 0.148 | 112.055 | 112.203 |
|
[75, 85, 110] |
loss | 3 | q26.32 | Various |
|
[75, 83, 85, 110] | ||
loss | 4 | q25 | 0.049 | 109.035 | 109.084 |
|
[75, 85, 110] |
loss | 4 | q31.23 | 0.145 | 149.697 | 149.842 |
|
[75, 85, 110] |
loss | 5 | q31.3 | 0.087 | 142.780 | 142.867 |
|
[75, 85] |
loss | 5 | q33.3 | 0.553 | 157.946 | 158.499 |
|
[75, 80, 83, 85, 110] |
loss | 6 | p22.22 | 0.023 | 26.237 | 26.260 |
|
[75, 85, 110] |
loss | 6 | q21 | 0.088 | 109.240 | 109.328 |
|
[75, 85, 110] |
loss | 7 | 7p | Whole p-arm | Whole p-arm |
|
[35, 85] | |
loss | 7 | q21.2 | 0.209 | 92.255 | 92.464 |
|
[85, 110] |
loss | 7 | p12.2 | 0.048 | 50.419 | 50.467 |
|
[75, 83, 85] |
loss | 8 | q12.1 | 0.094 | 60.032 | 60.126 |
|
[75, 85, 110] |
loss | 9 | p21.3 | 0.237 | 21.894 | 22.131 |
|
[6, 35, 75, 80, 83, 85, 110] |
loss | 9 | p13.2 | 0.088 | 36.932 | 37.020 |
|
[75, 80, 83, 85, 110] |
loss | 10 | q23.31 | 0.062 | 89.676 | 89.738 |
|
[75, 85, 110] |
loss | 10 | q24.1 | 0.178 | 97.889 | 98.067 |
|
[75, 85, 110] |
loss | 10 | q25.1 | 0.078 | 111.782 | 111.860 |
|
[75, 85, 110] |
loss | 11 | p13 | 0.155 | 33.917 | 34.072 |
|
[75, 85] |
loss | 11 | p12 | 0.008 | 36.618 | 36.626 |
|
[75, 85, 110] |
loss | 11 | q22.3 | 0.034 | 36.600 | 36.634 |
|
[80, 110] |
loss | 11 | q23.3 | 0.274 | 118.369 | 118.643 |
|
[80, 85] |
loss | 12 | p12.1 | 4.5 | 19.309 | 23.809 |
|
[35, 110] |
loss | 12 | p13.2 | 0.086 | 11.813 | 11.899 |
|
[6, 35, 75, 80, 83, 85, 110] |
loss | 12 | q21.33 | 0.218 | 92.291 | 92.509 |
|
[75, 80, 85, 110] |
loss | 13 | q14.11 | 0.031 | 41.555 | 41.586 |
|
[75, 85, 110] |
loss | 13 | q14.2 | 0.149 | 49.016 | 49.165 |
|
[6, 75, 80, 83, 85, 110] |
loss | 13 | q14.2-3 | 0.889 | 50.573 | 51.462 |
|
[75, 85] |
loss | 15 | q12 | 0.038 | 26.036 | 26.074 |
|
[80, 110] |
loss | 15 | q14 | – | – | – |
|
[75, 110] |
loss | 15 | q15.1 | 0.792 | 41.258 | 42.050 |
|
[85, 110] |
loss | 17 | 17p | Whole p-arm | Whole p-arm |
|
[83] | |
loss | 17 | q11.2 | 0.169 | 29.066 | 29.235 |
|
[75, 83, 85, 110] |
loss | 17 | q21.1 | 0.045 | 37.931 | 37.976 |
|
[75, 85, 110] |
loss | 19 | p13.3 | 0.229 | 1.351 | 1.580 |
|
[75, 85, 110] |
loss | 20 | 20p12.1 | 0.035 | 10.422 | 10.457 |
|
[75, 85] |
loss | 20 | q11.22 | 1.426 | 32.304 | 33.730 |
|
[6, 110] |
loss | 21 | q22.12 | 0.004 | 36.428 | 36.432 |
|
[75, 85] |
loss | 21 | q22.2 | 0.023 | 39.784 | 39.807 |
|
[75, 85, 110] |
gain | 1 | q23.3-q44 | 81.326 | 164.759 | qtel |
|
[75, 85] |
Gain | 6 | q23.3 | 0.182 | 135.492 | 135.674 |
|
[75, 80, 85] |
Gain | 9 | 9q | Whole q-arm | Whole q-arm |
|
[83, 85] | |
Gain | 9 | q34.12-q34.3 | 7.676 | 133.657 | qtel |
|
[75, 85, 110] |
Gain | 10 | 10p | Whole p-arm | Whole p-arm |
|
[83, 85] | |
Gain | 21 | 21 | 46.8 | Whole chromosome | Whole chromosome |
|
[6, 83] |
Gain | 21 | 21q | Whole q-arm | Whole q-arm |
|
[35, 83] | |
Ampl | 21 | iAMP21** | 11.713 | – | – |
|
[6] |
Gain | 21 | q22.3 | 0.589 | 42.775 | 43.364 |
|
[80] |
Gain | 21 | q22.11-12 | 4.022 | 32.322 | 36.344 |
|
[80] |
Gain | 21 | q22.11-q22.12 | 2.303 | 33.974 | 36.277 |
|
[75, 85] |
Gain | 22 | q11.1-q11.23 | 21.888 | ptel | 23.563 |
|
[75, 85] |
The average number of CNAs per ALL case is usually low, suggesting that this disease is not characterized by inherent genomic instability. This has been shown in a large SNP arrays study performed on pediatric ALL cases (B-progenitor and T-lineage). It allowed to identify a relatively low number of CNAs in ALL -a mean of 6.5 lesions per case- indicating that gross genomic instability is not a feature of most ALL cases [75, 85], although it is higher that the number of genomic changes in myeloid malignancies. Furthermore, similar studies have found 4.2 lesions per case in the precursor B-cell childhood ALLs (3.1 losses and 1.1 gains), and 2.6 lesions per case in the T-ALLs (1.7 losses and 0.9 gains) [80].
In spite of the large number of novel alterations, most of them have been focal deletions (less than a megabase) that involve only one or a few genes in the minimal region of genetic alteration. Apart from high hyperdiploid ALL, gains of DNA have been specifically uncommon and a few of them were focal gains [75, 85].
The pattern and number of CNAs is similar in the genetic ALL subtypes. Notably, less than one deletion per case was observed in
High-resolution genomic profiling studies in childhood ALL also reveals recurrent genetic lesions, affecting genes with an established and critical role in leukemogenesis such as
4.2. CNA in T-ALL
Genome-wide profiling in T-ALL has been used to identify copy number alterations accompanying novel structural abnormalities, such as the
Using SNP, BAC, or oligo-array CGH platforms, focal deletions have also identified in T-ALL, leading to deregulated expression of
4.3. CNA in BL
High rates of CNAs have been reported in BL. CNAs have been observed in 65% [53] and 76% [43] of BL cases by conventional CGH. CNAs have been reported in 54% and 100% of BL patients by oaCGH and aSNP respectively [14, 55]. In addition, high-resolution molecular inversion probe (MIP) SNP assay have been reported 64% of CNAs in BL [94].
CGH and aCGH studies on cases of BL have shown that the increased number of gains and losses are significantly associated with shorter survival [43]. Gains are more frequent than losses in a range from 52% to 65% [14, 53, 94]. These studies have reported gains on chromosomes 1q, 7, 8q, 12, 13, 22 and Xq and losses in 6q, 13q, 14q, 17p, and Xp [14, 15, 43, 51, 53-55, 94, 95]. Some studies have also identified cases with gains on 2p [43, 55], 3q27.3 [14], 4p [43], 15q [51, 55], and 20p12-q13 [51].
It has been demonstrated that chromosomal gains or losses in the most frequently altered regions in BL, such as 1cen-q22, 1q31-q32, 7q22-qter, 8q24-qter, 13q31-q32, and 17p13-pter, influence changes in locus-specific gene expression levels of many genes that probably are associated with pathogenesis of BL. For example, the chromosomal region 1q showed increased gene expression levels in cases with gains, and correlates with the expression of germinal center-associated genes. By contrast, genetic losses in the chromosomal region 17p13 lead to a down regulation of genes located in this region, not only
4.4. CNA analysis of paired diagnostic and relapse ALL samples
Detailed comparative analysis of paired diagnostic and relapse ALL samples, using high resolution genomic profiling, have showed the next findings: i) frequent changes in DNA copy number abnormalities have been observed at relapse, ii) there are loss of copy number lesions present at diagnosis in ALL relapse samples, and acquisition of new additional (secondary) lesions in the relapse samples in nearly all analyzed patients, iii) deletions were more common than gains about newly acquired copy number abnormalities in the relapse samples. These data support the clonal evolution in ALL. The pattern of deletions on the antigen receptor loci was comparable between relapse and diagnosis, suggesting the emergence of a related leukemic clone, rather than the development of a distinct second leukemia. It should be noted that several cases were found in which the diagnosis and relapse samples carrying alternative lesions affecting the same gene(s), including
These findings indicate that relapse is frequently the result of the emergence of a leukemic clone that shows significant genetic differences from the diagnostic clone. Whether these represent rare clones at the time of diagnosis or are the emergence of new clones should be further investigated [96].
5. Somatic mutations in acute lymphoblastic leukemia
Genome-wide profiling of DNA copy number alterations (CNA) coupled with focused candidate gene resequencing has identified novel genetic alterations in key signaling pathways in the pathogenesis of both B-progenitor and T-ALL. These findings are associated with leukemogenesis, treatment outcome in ALL, and are being exploited in the development of new therapeutic approaches and in the identification of markers of poor prognosis [72, 98].
5.1. Gene mutations in BCP-ALL
Somatic mutations in several genes are present in BCP-ALL. These mutations have identified in genes which are involved in RAS signaling (48%), B-cell differentiation and development (18%), JAK/STAT signaling (11%), TP53/RB1 tumor suppressor (6%) and noncanonical pathways and in other/unknown genes (17%) [72]. The incidence of the most recurrently mutated genes in ALL is described in the Table 2.
|
|||
|
|
|
|
RAS signaling |
|
17% | [72] |
|
16% | ||
|
7% | ||
|
5% | ||
|
3% | ||
B-cell differentiation and development pathway |
|
15% | |
|
3% | ||
JAK/STAT signaling |
|
2% | |
|
9% | ||
TP53/RB1 pathway |
|
4% | |
|
1% | ||
|
1% | ||
Others |
|
2% | |
|
4% | ||
|
2% | ||
|
9% | ||
|
|||
|
|
|
|
Cell cycle defects |
|
96% | [18] |
|
4% | ||
Differentiation impairment |
|
39% | |
|
20% | ||
|
7% | ||
|
20% | ||
|
7% | ||
|
5-10% | ||
|
4% | ||
|
<1% | ||
Proliferation and survival |
|
8% | |
|
5% | ||
|
5% | ||
|
<1% | ||
|
<1% | ||
|
<1% | ||
|
<1% | ||
|
"/>78% | ||
Self-renewal capacity |
|
56% | |
|
"/>44% |
The frequency of alterations in the TP53/RB1, RAS, and JAK signaling pathways is much higher in High Risk B-Precursor Childhood Acute Lymphoblastic Leukemia (HR B-ALL) cohort than reported for unselected pediatric B-precursor ALL patients. In this subgroup of patients have been recently proposed new targeted therapeutics, such as the RAS/MAPK signaling pathway [98].
5.1.1. Ras signaling
Deregulation of the
In BCP-ALL, a number of associations with other genetic changes are already known, such as the link between mutations of genes within the RAS signaling pathway and high hyperdiploidy [79, 99, 101]. These mutations have been found in ~60% of high hyperdiploid childhood cases ALL. They are invariably mutually exclusive, and additional cooperative genetic events in this subgroup of patients [99, 101, 102].
5.1.1.1. NRAS and KRAS
Mutations in
5.1.1.2. FLT3
Activating mutations in the receptor tyrosine kinase
Furthermore, small molecule tyrosine kinase inhibitors have activity against
5.1.1.3. PTPN11
5.1.1.4. BRAF
The
Mutations in
5.1.2. B-cell differentiation and development pathway
5.1.2.1. PAX5
By SNP arrays, monoallelic deletion of
By sequencing, inactivating mutations of
Inactivating point mutations in
Chromosomal translocations
In
5.1.2.2. IKZF1 (IKAROS)
5.1.3. JAK/STAT signaling
5.1.3.1. JAK
Activating mutations involving the pseudokinase and kinase domains of Janus kinases (primarily
These mutations are transforming in-vitro, and trigger constitutive
The presence of
Particularly, gain-function mutations in
5.1.3.2. Mutations in JAK regulators. CRLF2 and IL7R
Signaling from the TSLP receptor activates signal transducer and activator of transcription (
Furthermore, in high-risk ALL,
Moreover, somatic mutations of Interleukin-7 receptor (
5.1.4. TP53/RB1 pathway
Mutations of the tumor suppressor gene
The presence of
The clinical significance of exclusive deletions might be explained by
5.2. Gene mutations in T-ALL
T-ALL has been associated with four different classes of mutations: (i) Affecting the cell cycle (
5.2.1. CDKN2A/CDKN2B
In up to 90% of ALL cases, the
The haploinsufficiency or inactivation of these tumor suppressor genes are involved in the development of T-ALL, because they not only promote uncontrolled cell cycle entry, but also disable the p53-controlled cell cycle checkpoint and apoptosis machinery. Thus,
5.2.2. Tp53
The acquisition of mutations in
5.2.3. NOTCH1
Gain-of-function mutations in
The presence of subclonal duplications of the chromosomal region 9q34 are present in about 33% of pediatric T-ALL patients; the critical region encloses many genes including
5.2.4. FBXW7
F-box protein FBXW7 is an E3-ubiquitin ligase that regulates the half-life of other proteins including CyclinE, cMYC and cJUN [11]. Heterozygous
5.2.5. JAK1
Somatic activating
Gain-of-function mutations in
5.2.6. PTEN
The PTEN phosphatase has been identified as an important regulator of downstream (pre)TCR signaling. It directly opposes the activity of the phosphor-inosital-3 kinase (PI3K) functioning as a negative regulator of the oncogenic PI3K-AKT signaling [11, 133]. Inactivation of
Independent from activation following (pre)TCR stimulation,
5.2.7. RAS
In T-ALL, activating
5.2.8. WT1
5.2.9. Mutated genes in Early Thymic Progenitors (ETP)-ALL
A new T-ALL subgroup, which is defined by a specific gene expression profile and a characteristic immunophenotype (CD1a-, CD8-, CD5weak with expression of stem cell or myeloid markers), has been recently described in pediatric T-ALL patients with poor outcome. This subgroup likely originates from early thymic progenitors (ETP) and has been called ETP-ALL. Recently, it has been described the high presence of
Moreover a recent study of whole-genome sequencing in ETP-ALL cases, has identified activating mutations in genes regulating cytokine receptor and RAS signaling in 67% of cases (
In summary, the recent development of the genome wide analysis has provided new and critical knowledge of genetic changes in ALL. These new chromosomal imbalances and mutations could provide new insights for the management of the disease that is still associated with a dismal prognosis in the adult patients.
Acknowledgments
This work was partially supported by grants from the "Fondo de Investigaciones Sanitarias - FIS" (FIS 02/1041, FIS 09/01543 and FIS 12/0028), grant Paula Estevez 2010 of the "Fundación Sandra Ibarra de Solidaridad contra el Cáncer". "Fundación Samuel Solorzano Barruso", research project 106/A/06 SACYL and by the "Acción Transversal del Cáncer" project, through an agreement between the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation, and the University of Salamanca's Cancer Research Foundation (Spain) and the Research Network RTIIC (FIS). RMF is fully supported by an agreement of study commission remunerated (No. 223-2011) granted by the "Universidad Pedagógica y Tecnológica de Colombia - Colombia". MHS is supported by a grant from "Spanish Foundation of Hematology and Hemotherapy."
References
- 1.
Teitell, M.A. and P.P. Pandolfi, Molecular genetics of acute lymphoblastic leukemia. Annu Rev Pathol, 2009. 4: p. 175-98. - 2.
Bacher, U., A. Kohlmann, and T. Haferlach, Gene expression profiling for diagnosis and therapy in acute leukaemia and other haematologic malignancies. Cancer Treat Rev, 2010. 36(8): p. 637-46. - 3.
Downing, J.R. and C.G. Mullighan, Tumor-specific genetic lesions and their influence on therapy in pediatric acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program, 2006: p. 118-22, 508. - 4.
Jabbour, E.J., S. Faderl, and H.M. Kantarjian, Adult acute lymphoblastic leukemia. Mayo Clin Proc, 2005. 80(11): p. 1517-27. - 5.
Pui, C.H., M.V. Relling, and J.R. Downing, Acute lymphoblastic leukemia. N Engl J Med, 2004. 350(15): p. 1535-48. - 6.
Bungaro, S., et al., Integration of genomic and gene expression data of childhood ALL without known aberrations identifies subgroups with specific genetic hallmarks. Genes Chromosomes Cancer, 2009. 48(1): p. 22-38. - 7.
Usvasalo, A., et al., Acute lymphoblastic leukemias with normal karyotypes are not without genomic aberrations. Cancer Genet Cytogenet, 2009. 192(1): p. 10-7. - 8.
Rowley, J.D., The critical role of chromosome translocations in human leukemias. Annu Rev Genet, 1998. 32: p. 495-519. - 9.
Armstrong, S.A. and A.T. Look, Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol, 2005. 23(26): p. 6306-15. - 10.
Gorello, P., et al., Combined interphase fluorescence in situ hybridization elucidates the genetic heterogeneity of T-cell acute lymphoblastic leukemia in adults. Haematologica, 2010. 95(1): p. 79-86. - 11.
Van Vlierberghe, P., et al., Molecular-genetic insights in paediatric T-cell acute lymphoblastic leukaemia. Br J Haematol, 2008. 143(2): p. 153-68. - 12.
Swerdlow, S.H., et al., WHO classification of tumours of haematopoietic and lymphoid tissues . 4ª ed. 2008, IARC Lyon: World Health Organization. - 13.
Miles, R.R., S. Arnold, and M.S. Cairo, Risk factors and treatment of childhood and adolescent Burkitt lymphoma/leukaemia. Br J Haematol, 2012. 156(6): p. 730-43. - 14.
Scholtysik, R., et al., Detection of genomic aberrations in molecularly defined Burkitt's lymphoma by array-based, high resolution, single nucleotide polymorphism analysis. Haematologica, 2010. 95(12): p. 2047-55. - 15.
Boerma, E.G., et al., Translocations involving 8q24 in Burkitt lymphoma and other malignant lymphomas: a historical review of cytogenetics in the light of todays knowledge. Leukemia, 2009. 23(2): p. 225-34. - 16.
Chiaretti, S., et al., Gene expression profile of adult T-cell acute lymphocytic leukemia identifies distinct subsets of patients with different response to therapy and survival. Blood, 2004. 103(7): p. 2771-8. - 17.
Cauwelier, B., et al., Molecular cytogenetic study of 126 unselected T-ALL cases reveals high incidence of TCRbeta locus rearrangements and putative new T-cell oncogenes. Leukemia, 2006. 20(7): p. 1238-44. - 18.
De Keersmaecker, K., P. Marynen, and J. Cools, Genetic insights in the pathogenesis of T-cell acute lymphoblastic leukemia. Haematologica, 2005. 90(8): p. 1116-27. - 19.
Graux, C., et al., Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast. Leukemia, 2006. 20(9): p. 1496-510. - 20.
Usvasalo, A., et al., Prognostic classification of patients with acute lymphoblastic leukemia by using gene copy number profiles identified from array-based comparative genomic hybridization data. Leuk Res, 2010. 34(11): p. 1476-82. - 21.
Pui, C.H., et al., Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol, 2011. 29(5): p. 551-65. - 22.
Izraeli, S., Application of genomics for risk stratification of childhood acute lymphoblastic leukaemia: from bench to bedside? Br J Haematol, 2010. 151(2): p. 119-31. - 23.
Sancho, J.M.C., Avances en el diagnóstico y tratamiento, y significado pronóstico de la infiltración neuromeníngea en leucemias agudas y linfomas agresivos , inFacultad de Medicina. 2011, Universidad Autónoma de Barcelona. : Barcelona. p. 36. - 24.
Heim, S. and F. Mitelman, Cancer cytogenetics . Third ed. Acute Lymphoblastic Leukemia. 2009, New Jersey: John Wiley & Sons, Inc. Hoboken. - 25.
Pui, C.H., D. Campana, and W.E. Evans, Childhood acute lymphoblastic leukaemia--current status and future perspectives. Lancet Oncol, 2001. 2(10): p. 597-607. - 26.
Ribera, J.J.O.y.J.M., Leucemia Aguda Linfoblástica . 16 ed. Farreras-Rozman, Medicina Interna., ed. F.C.e. En C Rozman. 2009, Barcelona: Elsevier. - 27.
Mittelman, F., The Third International Workshop on Chromosomes in Leukemia. Lund, Sweden, July 21-25, 1980. Introduction. Cancer genetics and cytogenetics, 1981. 4(2): p. 96-98. - 28.
Kuchinskaya, E., et al., Array-CGH reveals hidden gene dose changes in children with acute lymphoblastic leukaemia and a normal or failed karyotype by G-banding. Br J Haematol, 2008. 140(5): p. 572-7. - 29.
Kim, J.E., et al., A rare case of acute lymphoblastic leukemia with t(12;17)(p13;q21). Korean J Lab Med, 2010. 30(3): p. 239-43. - 30.
Harrison, C.J. and L. Foroni, Cytogenetics and molecular genetics of acute lymphoblastic leukemia. Rev Clin Exp Hematol, 2002. 6(2): p. 91-113; discussion 200-2. - 31.
Harrison, C.J., et al., Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study. Br J Haematol, 2005. 129(4): p. 520-30. - 32.
De Braekeleer, E., et al., Cytogenetics in pre-B and B-cell acute lymphoblastic leukemia: a study of 208 patients diagnosed between 1981 and 2008. Cancer Genet Cytogenet, 2010. 200(1): p. 8-15. - 33.
Graux, C., Biology of acute lymphoblastic leukemia (ALL): clinical and therapeutic relevance. Transfus Apher Sci, 2011. 44(2): p. 183-9. - 34.
Downing, J.R. and K.M. Shannon, Acute leukemia: a pediatric perspective. Cancer Cell, 2002. 2(6): p. 437-45. - 35.
Steinemann, D., et al., Copy number alterations in childhood acute lymphoblastic leukemia and their association with minimal residual disease. Genes Chromosomes Cancer, 2008. 47(6): p. 471-80. - 36.
Schultz, K.R., et al., Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol, 2009. 27(31): p. 5175-81. - 37.
Meyer, C., et al., New insights to the MLL recombinome of acute leukemias. Leukemia, 2009. 23(8): p. 1490-9. - 38.
Meyer, C., et al., The MLL recombinome of acute leukemias. Leukemia, 2006. 20(5): p. 777-84. - 39.
Forestier, E., et al., Outcome of ETV6/RUNX1-positive childhood acute lymphoblastic leukaemia in the NOPHO-ALL-1992 protocol: frequent late relapses but good overall survival. Br J Haematol, 2008. 140(6): p. 665-72. - 40.
Golub, T.R., et al., Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc Natl Acad Sci U S A, 1995. 92(11): p. 4917-21. - 41.
Frick, M., B. Dorken, and G. Lenz, New insights into the biology of molecular subtypes of diffuse large B-cell lymphoma and Burkitt lymphoma. Best Pract Res Clin Haematol, 2012. 25(1): p. 3-12. - 42.
Hecht, J.L. and J.C. Aster, Molecular biology of Burkitt's lymphoma. J Clin Oncol, 2000. 18(21): p. 3707-21. - 43.
Garcia, J.L., et al., Abnormalities on 1q and 7q are associated with poor outcome in sporadic Burkitt's lymphoma. A cytogenetic and comparative genomic hybridization study. Leukemia, 2003. 17(10): p. 2016-24. - 44.
Lones, M.A., et al., Chromosome abnormalities may correlate with prognosis in Burkitt/Burkitt-like lymphomas of children and adolescents: a report from Children's Cancer Group Study CCG-E08. J Pediatr Hematol Oncol, 2004. 26(3): p. 169-78. - 45.
Poirel, H.A., et al., Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Leukemia, 2009. 23(2): p. 323-31. - 46.
Onciu, M., et al., Secondary chromosomal abnormalities predict outcome in pediatric and adult high-stage Burkitt lymphoma. Cancer, 2006. 107(5): p. 1084-92. - 47.
Xiao, H., et al., American Burkitt lymphoma stage II with 47,XY,+20,t(8;14)(q24;q32). Cancer Genet Cytogenet, 1990. 48(2): p. 275-7. - 48.
Lai, J.L., et al., Cytogenetic studies in 30 patients with Burkitt's lymphoma or L3 acute lymphoblastic leukemia with special reference to additional chromosome abnormalities. Ann Genet, 1989. 32(1): p. 26-32. - 49.
Nelson, M., et al., An increased frequency of 13q deletions detected by fluorescence in situ hybridization and its impact on survival in children and adolescents with Burkitt lymphoma: results from the Children's Oncology Group study CCG-5961. Br J Haematol, 2010. 148(4): p. 600-10. - 50.
de Souza, M.T., et al., Secondary abnormalities involving 1q or 13q and poor outcome in high stage Burkitt leukemia/lymphoma cases with 8q24 rearrangement at diagnosis. Int J Hematol, 2011. 93(2): p. 232-6. - 51.
Zunino, A., et al., Chromosomal aberrations evaluated by CGH, FISH and GTG-banding in a case of AIDS-related Burkitt's lymphoma. Haematologica, 2000. 85(3): p. 250-5. - 52.
Zimonjic, D.B., C. Keck-Waggoner, and N.C. Popescu, Novel genomic imbalances and chromosome translocations involving c-myc gene in Burkitt's lymphoma. Leukemia, 2001. 15(10): p. 1582-8. - 53.
Salaverria, I., et al., Chromosomal alterations detected by comparative genomic hybridization in subgroups of gene expression-defined Burkitt's lymphoma. Haematologica, 2008. 93(9): p. 1327-34. - 54.
Barth, T.F., et al., Homogeneous immunophenotype and paucity of secondary genomic aberrations are distinctive features of endemic but not of sporadic Burkitt's lymphoma and diffuse large B-cell lymphoma with MYC rearrangement. J Pathol, 2004. 203(4): p. 940-5. - 55.
Toujani, S., et al., High resolution genome-wide analysis of chromosomal alterations in Burkitt's lymphoma. PLoS One, 2009. 4(9): p. e7089. - 56.
Berger, R. and A. Bernheim, Cytogenetics of Burkitt's lymphoma-leukaemia: a review. IARC Sci Publ, 1985(60): p. 65-80. - 57.
Cave, H., et al., Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951. Blood, 2004. 103(2): p. 442-50. - 58.
Ballerini, P., et al., HOX11L2 expression defines a clinical subtype of pediatric T-ALL associated with poor prognosis. Blood, 2002. 100(3): p. 991-7. - 59.
Hawley, R.G., et al., Transforming function of the HOX11/TCL3 homeobox gene. Cancer Res, 1997. 57(2): p. 337-45. - 60.
Keller, G., et al., Overexpression of HOX11 leads to the immortalization of embryonic precursors with both primitive and definitive hematopoietic potential. Blood, 1998. 92(3): p. 877-87. - 61.
Bernard, O.A., et al., A new recurrent and specific cryptic translocation, t(5;14)(q35;q32), is associated with expression of the Hox11L2 gene in T acute lymphoblastic leukemia. Leukemia, 2001. 15(10): p. 1495-504. - 62.
Wadman, I., et al., Specific in vivo association between the bHLH and LIM proteins implicated in human T cell leukemia. EMBO J, 1994. 13(20): p. 4831-9. - 63.
Xia, Y., et al., TAL2, a helix-loop-helix gene activated by the (7;9)(q34;q32) translocation in human T-cell leukemia. Proc Natl Acad Sci U S A, 1991. 88(24): p. 11416-20. - 64.
Xia, Y., et al., Products of the TAL2 oncogene in leukemic T cells: bHLH phosphoproteins with DNA-binding activity. Oncogene, 1994. 9(5): p. 1437-46. - 65.
Zhong, Y., et al., Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice. Oncogene, 2007. 26(48): p. 6937-47. - 66.
Harrison, C.J., Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia. Br J Haematol, 2009. 144(2): p. 147-56. - 67.
Palacios, E.H. and A. Weiss, Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene, 2004. 23(48): p. 7990-8000. - 68.
Clappier, E., et al., The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Blood, 2007. 110(4): p. 1251-61. - 69.
Dik, W.A., et al., CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes. Leukemia, 2005. 19(11): p. 1948-57. - 70.
Krivtsov, A.V. and S.A. Armstrong, MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer, 2007. 7(11): p. 823-33. - 71.
Lacronique, V., et al., A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science, 1997. 278(5341): p. 1309-12. - 72.
Harrison, C.J., Key pathways as therapeutic targets. Blood, 2011. 118(11): p. 2935-6. - 73.
Harrison, C.J., et al., Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia. Br J Haematol, 2004. 125(5): p. 552-9. - 74.
Macconaill, L.E. and L.A. Garraway, Clinical implications of the cancer genome. J Clin Oncol, 2010. 28(35): p. 5219-28. - 75.
Mullighan, C.G. and J.R. Downing, Global genomic characterization of acute lymphoblastic leukemia. Semin Hematol, 2009. 46(1): p. 3-15. - 76.
Mullighan, C.G., Genomic analysis of acute leukemia. Int J Lab Hematol, 2009. 31(4): p. 384-97. - 77.
Rabin, K.R., et al., Clinical utility of array comparative genomic hybridization for detection of chromosomal abnormalities in pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer, 2008. 51(2): p. 171-7. - 78.
Yasar, D., et al., Array comparative genomic hybridization analysis of adult acute leukemia patients. Cancer Genet Cytogenet, 2010. 197(2): p. 122-9. - 79.
Harrison, C., New genetics and diagnosis of childhood B-cell precursor acute lymphoblastic leukemia. Pediatr Rep, 2011. 3 Suppl 2: p. e4. - 80.
Kuiper, R.P., et al., High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. Leukemia, 2007. 21(6): p. 1258-66. - 81.
Strefford, J.C., et al., Genome complexity in acute lymphoblastic leukemia is revealed by array-based comparative genomic hybridization. Oncogene, 2007. 26(29): p. 4306-18. - 82.
Paulsson, K., et al., Microdeletions are a general feature of adult and adolescent acute lymphoblastic leukemia: Unexpected similarities with pediatric disease. Proc Natl Acad Sci U S A, 2008. 105(18): p. 6708-13. - 83.
Okamoto, R., et al., Genomic profiling of adult acute lymphoblastic leukemia by single nucleotide polymorphism oligonucleotide microarray and comparison to pediatric acute lymphoblastic leukemia. Haematologica, 2010. 95(9): p. 1481-8. - 84.
Dawson, A.J., et al., Array comparative genomic hybridization and cytogenetic analysis in pediatric acute leukemias. Curr Oncol, 2011. 18(5): p. e210-7. - 85.
Mullighan, C.G., et al., Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature, 2007. 446(7137): p. 758-64. - 86.
Mullighan, C.G., Genomic profiling of B-progenitor acute lymphoblastic leukemia. Best Pract Res Clin Haematol, 2011. 24(4): p. 489-503. - 87.
Greaves, M.F. and J. Wiemels, Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer, 2003. 3(9): p. 639-49. - 88.
Graux, C., et al., Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet, 2004. 36(10): p. 1084-9. - 89.
Van Vlierberghe, P., et al., The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. Blood, 2008. 111(9): p. 4668-80. - 90.
Van Vlierberghe, P., et al., The cryptic chromosomal deletion del(11)(p12p13) as a new activation mechanism of LMO2 in pediatric T-cell acute lymphoblastic leukemia. Blood, 2006. 108(10): p. 3520-9. - 91.
Palomero, T., et al., Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med, 2007. 13(10): p. 1203-10. - 92.
O'Neil, J., et al., FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med, 2007. 204(8): p. 1813-24. - 93.
Lahortiga, I., et al., Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia. Nat Genet, 2007. 39(5): p. 593-5. - 94.
Schiffman, J.D., et al., Genome wide copy number analysis of paediatric Burkitt lymphoma using formalin-fixed tissues reveals a subset with gain of chromosome 13q and corresponding miRNA over expression. Br J Haematol, 2011. 155(4): p. 477-86. - 95.
Capello, D., et al., Genome wide DNA-profiling of HIV-related B-cell lymphomas. Br J Haematol, 2010. 148(2): p. 245-55. - 96.
Mullighan, C.G., et al., High-Resolution SNP Array Profiling of Relapsed Acute Leukemia Identifies Genomic Abnormalities Distinct from Those Present at Diagnosis. ASH Annual Meeting Abstracts, 2007. 110(11): p. 234-. - 97.
Kuiper, R.P., et al., Detection of Genomic Lesions in Childhood Precursor-B Cell ALL in Diagnosis and Relapse Samples Using High Resolution Genomic Profiling. ASH Annual Meeting Abstracts, 2007. 110(11): p. 995-. - 98.
Zhang, J., et al., Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood, 2011. 118(11): p. 3080-7. - 99.
Case, M., et al., Mutation of genes affecting the RAS pathway is common in childhood acute lymphoblastic leukemia. Cancer Res, 2008. 68(16): p. 6803-9. - 100.
Tartaglia, M., et al., Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood, 2004. 104(2): p. 307-13. - 101.
Paulsson, K., et al., Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia. Genes Chromosomes Cancer, 2008. 47(1): p. 26-33. - 102.
Wiemels, J.L., et al., RAS mutation is associated with hyperdiploidy and parental characteristics in pediatric acute lymphoblastic leukemia. Leukemia, 2005. 19(3): p. 415-419. - 103.
Perentesis, J.P., et al., RAS oncogene mutations and outcome of therapy for childhood acute lymphoblastic leukemia. Leukemia, 2004. 18(4): p. 685-92. - 104.
Armstrong, S.A., et al., FLT3 mutations in childhood acute lymphoblastic leukemia. Blood, 2004. 103(9): p. 3544-6. - 105.
Lee, J.W., et al., BRAF mutations in acute leukemias. Leukemia, 2003. 18(1): p. 170-172. - 106.
Gustafsson, B., et al., Mutations in the BRAF and N-ras genes in childhood acute lymphoblastic leukaemia. Leukemia, 2005. 19(2): p. 310-2. - 107.
Iacobucci, I., et al., Cytogenetic and molecular predictors of outcome in acute lymphocytic leukemia: recent developments. Curr Hematol Malig Rep. 7(2): p. 133-43. - 108.
Roberts, K.G. and C.G. Mullighan, How new advances in genetic analysis are influencing the understanding and treatment of childhood acute leukemia. Curr Opin Pediatr, 2011. 23(1): p. 34-40. - 109.
Iacobucci, I., et al., The PAX5 gene is frequently rearranged in BCR-ABL1-positive acute lymphoblastic leukemia but is not associated with outcome. A report on behalf of the GIMEMA Acute Leukemia Working Party. Haematologica, 2010. 95(10): p. 1683-90. - 110.
Mullighan, C.G., et al., Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med, 2009. 360(5): p. 470-80. - 111.
Zhou, Y., et al., Advances in the molecular pathobiology of B-lymphoblastic leukemia. Hum Pathol, 2012. 43(9): p. 1347-62. - 112.
Payne, K.J. and S. Dovat, Ikaros and tumor suppression in acute lymphoblastic leukemia. Crit Rev Oncog, 2011. 16(1-2): p. 3-12. - 113.
Mullighan, C.G., et al., JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A, 2009. 106(23): p. 9414-8. - 114.
Bercovich, D., et al., Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet, 2008. 372(9648): p. 1484-92. - 115.
Mullighan, C.G., JAK2--a new player in acute lymphoblastic leukaemia. Lancet, 2008. 372(9648): p. 1448-50. - 116.
Mullighan, C.G., et al., Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet, 2009. 41(11): p. 1243-6. - 117.
Harvey, R.C., et al., Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood, 2010. 115(26): p. 5312-21. - 118.
Rochman, Y., et al., Thymic stromal lymphopoietin-mediated STAT5 phosphorylation via kinases JAK1 and JAK2 reveals a key difference from IL-7-induced signaling. Proc Natl Acad Sci U S A, 2010. 107(45): p. 19455-60. - 119.
Buettner, R., L.B. Mora, and R. Jove, Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res, 2002. 8(4): p. 945-54. - 120.
Shochat, C., et al., Gain-of-function mutations in interleukin-7 receptor-alpha (IL7R) in childhood acute lymphoblastic leukemias. J Exp Med, 2011. 208(5): p. 901-8. - 121.
Hof, J., et al., Mutations and deletions of the TP53 gene predict nonresponse to treatment and poor outcome in first relapse of childhood acute lymphoblastic leukemia. J Clin Oncol, 2011. 29(23): p. 3185-93. - 122.
Diccianni, M.B., et al., Clinical significance of p53 mutations in relapsed T-cell acute lymphoblastic leukemia. Blood, 1994. 84(9): p. 3105-12. - 123.
Kawamura, M., et al., Alterations of the p53, p21, p16, p15 and RAS genes in childhood T-cell acute lymphoblastic leukemia. Leuk Res, 1999. 23(2): p. 115-26. - 124.
Cayuela, J.M., et al., Multiple tumor-suppressor gene 1 inactivation is the most frequent genetic alteration in T-cell acute lymphoblastic leukemia. Blood, 1996. 87(6): p. 2180-6. - 125.
Cheng, J. and M. Haas, Frequent mutations in the p53 tumor suppressor gene in human leukemia T-cell lines. Mol Cell Biol, 1990. 10(10): p. 5502-9. - 126.
Weng, A.P., et al., Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science, 2004. 306(5694): p. 269-71. - 127.
Breit, S., et al., Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood, 2006. 108(4): p. 1151-7. - 128.
Sambandam, A., et al., Notch signaling controls the generation and differentiation of early T lineage progenitors. Nat Immunol, 2005. 6(7): p. 663-70. - 129.
van Vlierberghe, P., et al., A new recurrent 9q34 duplication in pediatric T-cell acute lymphoblastic leukemia. Leukemia, 2006. 20(7): p. 1245-53. - 130.
Malyukova, A., et al., The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling. Cancer Res, 2007. 67(12): p. 5611-6. - 131.
Vainchenker, W. and S.N. Constantinescu, JAK/STAT signaling in hematological malignancies. Oncogene, 2012. - 132.
Flex, E., et al., Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med, 2008. 205(4): p. 751-8. - 133.
Gutierrez, A., et al., High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood, 2009. 114(3): p. 647-50. - 134.
Yokota, S., et al., Mutational analysis of the N-ras gene in acute lymphoblastic leukemia: a study of 125 Japanese pediatric cases. Int J Hematol, 1998. 67(4): p. 379-87. - 135.
von Lintig, F.C., et al., Ras activation in normal white blood cells and childhood acute lymphoblastic leukemia. Clin Cancer Res, 2000. 6(5): p. 1804-10. - 136.
Tosello, V., et al., WT1 mutations in T-ALL. Blood, 2009. 114(5): p. 1038-45. - 137.
Renneville, A., et al., Wilms' Tumor 1 (WT1) Gene Mutations in Pediatric T-Acute Lymphoblastic Leukemia. ASH Annual Meeting Abstracts, 2009. 114(22): p. 3075-. - 138.
Neumann, M., et al., High Rate of FLT3 Mutations In Adult ETP-ALL. ASH Annual Meeting Abstracts, 2010. 116(21): p. 1031-. - 139.
Paietta, E., et al., Activating FLT3 mutations in CD117/KIT(+) T-cell acute lymphoblastic leukemias. Blood, 2004. 104(2): p. 558-60. - 140.
Van Vlierberghe, P., et al., Activating FLT3 mutations in CD4+/CD8- pediatric T-cell acute lymphoblastic leukemias. Blood, 2005. 106(13): p. 4414-5. - 141.
Zhang, J., et al., The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature, 2012. 481(7380): p. 157-63.