Frequency of numerical and structural changes among B-ALL patients of different cohorts
Acute leukemia is a broad term used to identify several malignancies of immature hematopoietic cells. Although, variable incidences have been reported between countries, ranging from 46 to 57 cases by million children, it is considered the most common childhood cancer worldwide . Acute lymphoblastic leukemia (ALL) is the most frequent subtype (75%-80% of cases; with the remaining 20-25% being of myeloid origin, AML). In ALL, B cell origin is the most frequently diagnosed (B cell ALL) representing 83%, and T cell ALL comprises 15% . The total of ALL cases represents 30-40% of all types of pediatric cancer.
One of the major achievements in cancer therapy has been the increased cure rates for ALL, from 10% in the 60s to 76-86% today, although these favorable numbers are mainly valid for developed countries[4,5]. The improvement in ALL cure rates can be in part attributed to the assessment of conventional prognostic factors and identification of molecular markers associated with a better response to therapy. Suitable risk stratification has permitted a more personalized treatment, selecting patients for receiving standard or intensified therapy, alone or in combination with drugs against ALL specific targets, and together with an enhanced supportive care have contributed to the increase in the event-free survival (EFS) rates. Conventional childhood ALL stratification is based on prognostic factors related to characteristics of the patient (age at diagnosis) and the disease itself white blood cell (WBC) count at diagnosis, immunophenotype of the leukemic cells, presence of known genetic fusions, numerical abnormalities or abnormal gene expression, and early response to therapy (evaluated by morphological methods or using a more accurate measurement such as minimal residual disease (MRD) analysis) [4–6].
From a genetic point of view, ALL is one of the best characterized malignancies. Numerical and structural chromosomal abnormalities have been described by cytogenetic methods, fluorescence
2. Signaling and transcription factors important in lymphopoiesis and leukemogenesis
Generation of lymphoid cells is a highly ordered multi-step process that in adult mammals starts in bone marrow with the differentiation of multipotent hematopoietic stem cells (HSC) (Figure 1A). HSCs start a differentiation pathway in which the capacity to form multiple lineages is gradually lost coinciding with a gain of lineage specific functions. Thus, HSCs yield multipotent progenitor cells (MPPs) still with myeloid and lymphoid potential, which eventually give rise to lymphoid-primed multipotent progenitor (LMPP) and early lymphoid progenitor (ELP) populations, with a progressive more restrictive lymphoid program. Similarly, ELPs generate early T lineage progenitors (ETP) and common lymphoid progenitors (CLP), and these populations, although still exhibit high plasticity, preferentially give rise
B and T cells are characterized by their potential to express receptors with a highly diverse repertoire of specificities: the B and T cell receptors (BCR and TCR). This diverse specificity is given by a recombination process termed VDJ recombination and it is the sequential assembly and testing of the BCR and TCR what defines the B/T development pathway. The first stages (pro and pre) are characterized by recombination of the antigen binding variable sequences (heavy and light chains for the BCR, and the β, α, γ or δ chains for the TCR) (Figure 1B). The subsequent stages require elimination of auto-reactive clones, and only clones selected against self-recognition become functional mature cells. Genetic and biochemical studies have shown that all forms of the BCR and TCR are required for progression through several defined developmental checkpoints [13,14]. This is an important concept, since it illustrates that different signaling and transcription programs are operating through all developmental stages, and therefore, if an aberrant program is established, development is unable to proceed. As we will see in the following sections, the leukemic gene fusions and other genetic abnormalities produce aberrant signaling pathways or abnormal transcriptional activities, leading to a developmental arrest in specific stages, events that seem to be required and characterize B and T cell ALL.
Early developmental stages are the ones generally found compromised in human pediatric B and T cell ALL. These stages in B cell ALL are early proB or pre-proB (before heavy-chain recombination), preB-I (after heavy-chain recombination), and preB-II (before light-chain rearrangement) (Figure 1B). These stages are also recognized by the expression of stage specific markers, a characteristic that has helped to classify the different types of pediatric ALL. B cells are recognized by the expression of CD19 and CD10, common B cell ALL by the expression of the BCR (IgM) either in cytoplasm (preB-I) or membrane (preB-II), and preB-I can also be differentiated from preB-II cells by expression of the enzyme terminal deoxynucleotidyl transferase (TdT) .
T cells are recognized by the expression of CD3, CD5 and CD7. Early T cells lack expression of CD4 and CD8 (double negative or DN stages). Contrary to B cell ALL, T cell ALL clones often express markers of more advanced stages of development (for instance double positive stages). However, these clones also show a lack of expression or cytoplasmic TCRβ, indicating that transformation happened before rearrangement of this TCR component or just after, and thus arguing that transformation targeted ETP/DN1 or DN3´cells . The acquisition of markers of more mature cells is probably due to marker aberrant expression or leukemia-induced developmental progression in absence of the TCR signal. Although, postnatal B cell early maturation only happens in bone marrow, T cells mature in thymus. LMPP, ELP, CLP and ETP cells are all able to leave bone marrow in response to environmental signals and complete the T cell maturation program in thymus. Therefore, ETP/DN1 cells are normal residents of bone marrow, while double positive T cells are only found in thymus. T cell transformation of very early populations also agrees with the predominant presence of the T cell leukemic clone in bone marrow .
Limitation of lineage choice during development is regulated by a combination of signaling pathways and transcription factors. The main receptor controlling the proB stage is the IL-7R, which is composed of an α chain (IL-7Rα) and the common cytokine receptor G chain (GC) [16,17]. Deletion of IL-7Rα or GC leads to developmental arrest at the early proB stage [18–21]. IL-7 activates three major signaling pathways: 1) JAK–STAT, 2) phosphatidylinositol 3-kinase (PI3K)–Akt and 3) Ras-Raf-Erk . STAT5 (signal transducer and activator of transcription 5) is the predominant STAT protein activated by IL-7 [22,23] and STAT5 loss also arrest B cells at the early proB stage. Once the preBCR is expressed, it can take over many of the functions performed by the IL-7 receptor, since the preBCR also activates the PI3K-Akt and Ras-Raf-Erk pathways [24,25].
Downstream of IL-7 two transcription factors have been documented as the most important for cell entry into the B cell lineage: E2A/TCF3 (immunoglobulin enhancer binding factors E12/E47/transcription factor 3) and EBF1 (Early B cell Factor 1) [26–28]. On the other hand, PAX5 (Paired box 5) is the more important transcription factor for B cell commitment. Loss of E2A and EBF1 blocks entry into the B cell lineage, and loss of PAX5 redirects B cells into other lineages [28–30]. One of the main molecular functions of PAX5 (acting together with E2A, EBF1 and STAT5) is to allow VDJ recombination [31,32]. Ectopic expression of PAX5 and E2A allows VDJ recombination in non-B cells [45, 46]. Also, E2A, PAX5, IKZF1 and RUNX1, among other transcription factors, are responsible for expression of the VDJ recombinase (RAG) [33,34].
The most important cells that give rise to T cells are ELPs and CLPs. Although, both B and T cells are mainly originated from them, an important genetic difference between cells prone to the B lineage is the expression of EBF1 and PAX5, while for T cells is NOTCH1 signaling. NOTCH1 directs progenitors into the thymus and it is the master orchestrator of T cell lineage entry and development [35,36]. NOTCH contains multiple epidermal growth factor (EGF)-like repeats through which it binds its ligands DLL-1, -2, -4 (Delta-like ligand), and Jagged-1 and -2 expressed by bone marrow and thymus stromal cells. Upon ligand binding NOTCH1 initiates a series of proteolytic cleavage events, the first one catalyzed by the ADAM family of metalloproteinases and the second by the γ−secretase complex. This cleavage activates NOTCH1 removing the extracellular portion and translocating to the nucleus its intracellular region (ICN), where it becomes part of a large transcriptional activation complex together with CSL and histone acetylase p300. Also, ICN has a C-terminal PEST domain involved in regulation of NOTCH1 ubiquitylation and proteasome-mediated degradation, therefore controlling protein turnover [35–38].
NOTCH1 expression is importantly regulated by E2A , and is essential for activation of genes necessary for T cell entry and early development. Indeed, NOTCH1 expression is turned off in late stages of T cell development, forced expression of NOTCH1 in multipotent progenitor cells direct them to the T cell lineage and controls the expression of several transcription factors important for T cell early development, e.g.
Some of the transcription factors drivers of T cell ALL are normally expressed in non-malignant thymocytes since they are essential regulators of T-cell ontogeny, while others are not expressed in normal ones, but they are rather ectopically expressed by transformed cells (Figure 2). This is contrary to B cells, in which most of the transcription factors associated with transformation fulfill an important regulatory function (Figure 2). This observation supports different mechanisms for the origin of B and T cell ALL. In agreement,
3. Criteria for ALL risk stratification
The clinical and laboratory criteria supporting risk stratification vary among institutions, with most groups considering as high risk the following characteristics: age ≥ 10 or <1 years at presentation, WBC ≥ 50,000/µl, presence of extramedullary disease, T cell immunophenotype, presence of adverse genetic abnormalities such as t(9;22) (
All the above-mentioned prognostic factors are used to classify patients into two risk groups, high and standard risk. For instance, it is known that increased WBC count confers poor prognosis for B cell ALL patients and in T cell ALL, a leukocyte count greater than 100,000/µl is associated with high risk of relapse in the central nervous system. Also, patients with hyperleukocytosis, greater than 400,000/µl, are at high risk of central nervous system hemorrhage and pulmonary and neurological events due to leukostasis. However, most of these risk criteria are better understood for B cell and they are not as clear for T cell ALL patients . Recently, evaluation of early response to therapy has been demonstrated being an important parameter for treatment efficacy and disease prognosis. Based on the latter criteria, it is possible to identify the group of patients that require augmented therapy to improve their outcome.
3.1. Prognostic significance of treatment response
The frequency of bone marrow or circulating lymphoblasts after one week of chemotherapy is associated with risk for relapse  and nowadays, this constitutes one of the most useful prognostic factors in childhood ALL. An efficient early response to treatment is determined by evaluating clearance rates of leukemic cells after the induction phase of treatment . This pharmacological response depends on numerous variables, including drug sensitivity /resistance of the leukemic cells, the dosage and the ability of individual patients to metabolize and eliminate anti-leukemic drugs [43,44].
The Berlin-Frankfurt Munster (BFM) group has traditionally employed the response to prednisone for 7 days and one dose of intrathecal methotrexate to stratify patients. Peripheral blood blast count of 1,000/µl after prednisone treatment is used as a threshold to assign patients into two groups, prednisone good responders (GR) and poor responders (PR). The ALL-BMF Group demonstrated in large series of infant patients treated with effective risk-based ALL therapy that prednisone response is a strong prognostic parameter for outcome; 75% of infants were good responders (GR) and achieved an EFS of 53% at 6 years using conventional therapy, whereas poor responder infants had an EFS of 15% . The Tokyo Cancer Children´s Leukemia Group also showed that B and T cell ALL patients with high blast counts at day 8, had a 4 years EFS of 74%; in contrast, patients without blasts presented an EFS of 89% for B and 95% for T cell ALL . Thus, it is well accepted that early response to prednisone treatment is a strong indicator of EFS . However, this assessment is limited by the low sensitivity (5-10% blasts) of microscopy-based methods of blast quantification . The morphological analysis of blasts by conventional methods easily underestimates the presence and frequency of residual cells. PCR or flow cytometry- based methods for detecting MRD are at least 100 times more sensitive.
The common principle for all MRD assessments is that leukemogenic process results in molecular and cellular changes, which distinguish leukemic cells from their normal counterparts . In patients with ALL, MRD can be monitored by flow cytometry, PCR amplification of gene fusion transcripts, and PCR amplification of the B and T cell antigen receptors (BCR/TCR specific VDJ recombinants). Combining information about cell size, granularity and expression of surface and intracellular molecules, it is possible to identify by flow cytometry a phenotypic signature characteristic of leukemic cells. Flow cytometry-based identification of cell immunophenotypes allows the detection of one leukemic cell among 10,000 normal cells (0.01%) [47,48]; however, these assays require high expertise for quality results, previous knowledge of immunophenotypic profiles of normal and leukemic cells and experience to select the best markers useful for each patient . Other option to distinguish leukemic from normal cells is the PCR screening of gene fusion transcripts, produced by specific chromosomal translocations, among the most common of them are:
MRD studies revealed that many patients who achieve remission by traditional methods harbored residual disease predisposing them to relapse [46,48]. The most immediate application of MRD testing is the identification of patients who are candidates for treatment intensification, since levels of MRD are proportional to the risk of relapse . The most appropriate time for evaluation of MRD vary between different groups, for the ALL-BMF 95 protocol in Austria, MRD quantification by flow cytometry of bone marrow samples must be estimated on days 33 and 78 post-treatment. In the experience of St. Jude Children’s Research Hospital, the presence of 0.01% residual cells on days 19, 46, or subsequent time points during treatment, is strongly associated with a high risk of relapse [54,55]. The Children’s Oncology Group quantifies MRD in bone marrow on day 29 post-treatment, and ≥ 0.01% of MRD is associated with poor outcome . The Dana-Farber Cancer Institute ALL Consortium, considers MRD cut-off values of 0.1% for prediction of 5-year relapse hazard . Recently, the Italian cooperative group AIEOP identified 3 risk groups based on MRD values by flow cytometry of bone marrow samples on day 15 of treatment. Those risk groups are: standard (<0.01% MRD) with a 5-years cumulative incidence of relapse (CIR) of 7.5%, intermediate (0.01% - <10% MRD) with CIR of 17.5%, and high (>10% MRD) with CIR of 47.2% . MRD is also useful as an independent predictor of second relapse in patients with ALL who had a previous relapse and achieved a second remission [59,60]. Notably, the time of first relapse and MRD are the only 2 significant predictors of outcome in a multivariate analysis .
3.2. Genetic abnormalities in ALL as prognostic factors
From a genetic point of view, ALL is one of the best characterized malignancies. Numerical and structural chromosomal abnormalities have been described by cytogenetic methods, FISH, PCR, and more recently, by next generation sequencing. Chromosomal abnormalities are clonal markers of the ALL blast, since the cytogenetic and molecular analyses have revealed that approximately 75% of ALL-children present these genetic lesions . To date, more than 200 genes have been found participating, downstream of common ALL translocations. Interestingly, a handful of these genes are affected by more than one translocation, thus supporting specific mechanisms of leukemogenesis .
The genetic abnormalities found in ALL are basically of two types: 1) gains or losses of one or several chromosomes (numerical abnormalities) and 2) translocations generating gene fusions that encode proteins with novel functions (chimeric proteins), or that re-locate a gene close to a strong transcriptional promoter causing gene overexpression. These translocations are produced by double-strand breaks (DSB) in different chromosomes or different regions of one chromosome, that are then recombined through non-homologous end-joining mechanisms [9,61]. These events of illegitimate recombination result in juxtaposition of normally separated regions, relocating a gene or producing a chimeric fusion gene .
Several studies have demonstrated that the first genetic lesion in childhood ALL often occurs in uterus. Screening of many of the genetic lesions that characterize the ALL blast in blood samples from Guthrie cards supports their prenatal origin. These studies have shown the presence of the same gene fusion in blood samples collected at birth and in the leukemic blasts at diagnosis. Thus, an intrauterine origin of
The known ALL genetic abnormalities have been relevant for the identification of genes involved in cancer and therefore for the insights in the biology of the leukemogenic process. Importantly, these genetic abnormalities are a disease signature that has been an invaluable tool for the precise disease diagnosis, prognosis and stratification into risk groups, guiding patient management and treatment choice . The Third International Workshop on Chromosomes in Leukemia was the first major study demonstrating the independent prognostic significance of cytogenetic findings in ALL, providing data on clinical relevance of chromosomal recurrent aberrations, and elucidating its molecular basis and biologic consequences . Given their importance, it is the main goal of this chapter to describe in detail the most important genetic abnormalities in the stratification of ALL patients, highlighting aspects of their oncogenic mechanisms, incidence and prognosis.
4. Molecular and cytogenetic subgroups in pediatric B cell ALL
As it was previously mentioned, several genetic abnormalities are characteristic of ALL and have been relevant for the identification of genes involved in cancer and therefore have given insights into the biology of the leukemogenic process, plus they have been an invaluable tool for the precise disease diagnosis, prognosis and stratification into risk groups. Several of them will be discussed in the coming sections.
The Ph chromosome detected in CML varies from the one in ALL, with different
Ph positive childhood ALL is associated with older age at presentation, high leukocyte count, French-American-British (FAB) L2 morphology, and high incidence of central nervous system. Age at ALL presentation influences the prognosis of this genetic rearrangement; patients with ages ranging from one to nine years have a better prognosis than adolescents and young adults [70,74]. Thus, Ph positive is associated with a very high risk and poor prognosis. Although more than 95% of patients achieve an adequate response to induction therapy, these remissions are shallow and short-lived ; additionally, these patients frequently present high levels of MRD at the end of the induction therapy . Ph positive ALL incidence varies among different cohorts (Table 1), ranging between 2-3% for Western European countries (Germany, Italy, Austria, Britain, Switzerland) [76–78], 1-4% for American countries (USA and Mexico) [4,79] and 7-15% for Eastern countries (China, Taiwan, Malaysia-Singapore) .
Intensive research efforts were done to demonstrate the BCR-ABL1 transforming activity
||38||-||31||25||41||31||-||24||-||Excellent prognosis with anti-metabolite treatment|
||5||7||5||4||Improved prognosis with high-dose methotrexate treatment|
||3||2||2||2||1||4||5||17||7||Improved early treatment outcome with imatinib|
||25||22||21||25||13||9||7||19||13||Excellent prognosis with asparaginase|
According to studies in different populations (Table 1),
Clinical features of pre-B ALL positive for
Another translocation involving the
Myeloid/lymphoid or Mixed lineage leukemia gene (
MLL in its mature form consists of two non-covalently associated subunits, an N-terminal 320 kDa fragment (MLLN) and a C-terminal 180 kDa moiety (MLLC), which are both core components of the MLL complex and result from the cleavage of nascent MLL by an aspartic protease named taspase 1. The MLLN fragment is thought to bind DNA regulatory regions of clustered
As mentioned before, the frequency of
Several abnormalities secondary to
Several studies have supported that
The clonal origin of relapse has been investigated comparing CNA profiles from matched
More recently, it has been shown that genes associated with glucocorticoid mediated apoptosis could be deleted in
Hyperdiploidy with 51-65 chromosomes is also a frequent abnormality, 25-41% of ALL patients present this numerical aberration [10,83,85] and are generally associated with a favorable outcome (Table 1). This includes age 3-5 years and relative low WBC count at presentation, B cell precursor immunophenotype  and a 5-year EFS estimate of 85-95% when patients are treated with anti-metabolite based therapy [4,127]. Leukemic lymphoblasts in this subgroup have a high propensity to undergo apoptosis
High hyperdiploidy can be detected by cytogenetic analysis or flow cytometry. This latter technique measures the DNA content of the leukemic blasts in comparison to the normal cell pool and DNA content of 1.16 is considered as a prognostic indicator of favorable outcome. However, it is recommended to perform additional cytogenetic studies to detect specific chromosome gains, and discard the presence of additional genetic rearrangements, which could also influence disease outcome. About 50% of hyperdiploid cases present additional abnormalities as duplications of 1q or isochromosome 17q, this last abnormality confers adverse prognosis . High hyperdiploidy is often characterized cytogenetically by massive aneuploidy, originating a non-random gain of specific chromosomes, including some or all of +X, +4, +6, +10, +14, +17, +18, and +21; trisomies and tetrasomies of other chromosomes are also present in this group of patients .
In spite of the excellent prognosis associated to this genetic subtype, about 25% of the patients develop adverse events, indicating outcome differences and genetic subgroups between high hyperdiploid patients. For this reason, diverse studies have been performed trying to identify prognostic characteristics in these ALL patients. Based on cytogenetic studies and survival analyses, specific trisomies have been found associated to prognosis. Results from univariate analyses informed that gain of individual chromosomes 6, 4, 10 and 18 improves prognosis, in contrast, trisomy 5 confers worse prognosis [129–131]. Currently, the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) consider the presence of simultaneous trisomies of chromosomes 4, 10, and 17 as a favorable prognostic factor .
Analysis by SNP array of high hyperdiploid patients have been performed and revealed that 80% presented CNAs, which are not detected by traditional cytogenetic methods. An association between duplication of 1q and +5 has often been observed, and also uniparental isodisomies of chromosomes 9 and 11, gains of chromosomes 17q and 21q, deletions and microdeletions of
ALL cases with 47-50 chromosomes have an intermediate prognosis , near-triploidy (69 to 81 chromosomes)  have a response to therapy similar to that of non-hyperdiploid, and ALL cases with near tetraploidy (82 to 94 chromosomes) have a high frequency of T cell immunophenotype (see T cell ALL section) and frequently harbors a cryptic ETV6-RUNX1 fusion . These tetraploid leukemias, although significantly less common, have a worse prognosis than the ones with 51-65 chromosomes. The genetic reason for this differential prognosis is presently unclear.
The hypodiploid ALL is defined as leukemic blasts with less that 46 chromosomes and it is present in 6-7% of patients with childhood ALL. Three different subgroups have been defined according to the number of chromosomes, which are also important for disease outcome: near-haploid ALL (less than 30 chromosomes), low hypodiploid ALL (33-39 chromosomes) and high hypodiploid ALL (42-45 chromosomes). Near-haploidy is observed approximately in 0.5% of ALL cases and it is most frequently associated with females, and together with low hypodiploidy is related with the worst prognosis. Also, children with near-haploidy tend to be younger than those with low hypodiploidy [134,136]. Most of the hypodiploid ALL patients belong to the high hypodiploid group.
The pattern of chromosome loss in near-haploidy is not random as there is preferential retention of two copies of chromosomes 6, 8, 10, 14, 18, 21, and the sex chromosomes. In rare cases, an apparent hyperdiploid genome is observed but the number of chromosomes results from doubling haploid or near-haploid chromosome content. In these cases, although there is an increased in the total number of chromosomes, this ALL is still characterized by losses of specific chromosomes. This ALL is frequently wrongly diagnosed without a careful cytogenetic and DNA content analysis , and an appropriate diagnosis is important as near-haploidy defines a rare type of ALL associated with short remission duration and poor prognosis. Therefore, a clear diagnosis of the total chromosome number is essential to stratify patients into the appropriate risk group.
5. Molecular and cytogenetic subgroups in pediatric T-cell ALL
T cell ALL is a neoplastic disorder characterized by malignant transformation of early thymocytes . It accounts for approximately 10-15% of pediatric ALL cases [2,37,137–139] and tends to present clinically with high circulating blast cell counts, mediastinal masses, and often central nervous system involvement [37,140]. Therefore, it is a high risk ALL with a relapse rate of about 30% within the first 2 years following diagnosis [15,139]. T cell ALL is caused by genetic alterations leading to a variety of changes that can affect cell cycle control, unlimited self-renewal capacity, impaired differentiation and loss of sensitivity to death signals . As previously described, T cell ALL shares some chromosome rearrangements with B cell ALL; however, about 50% of T-ALL patients have recurrent chromosomal translocations specific of this subtype. The most common chromosome abnormalities include rearrangements affecting the
||4-10||Homeodomain transcription factor
||3||bHLH transcription factor
||20||Homeodomain transcription factor
||17||bHLH transcription factor||Undefined||[15,37]|
5.1. Impaired differentiation caused by defects in transcription factors expression/function
5.1.1. Deregulation of
TLX1 and TLX3 Homeobox genes
Homeobox genes (
The cryptic chromosomal translocation t(5;14)(q35;q32) juxtaposes
5.1.2. Deregulation of
TAL1, a basic Helix-Loop-Helix (bHLH) gene
Two different models have explained the oncogenic potential and transformation mechanism of
It is documented that
A novel subgroup of early T cell precursor leukemia has been reported, characterized by simultaneous expression of T cell/ stem-cell/myeloid markers and very poor prognosis when treated with standard intensive chemotherapy. Interestingly, this subgroup includes a part of those patients with
5.2. Activation of the NOTCH1 signaling pathway
The first alteration described affecting
Glucocorticoids are normally used to treat T cell ALL patients and glucocorticoid resistance have been mapped to NOTCH1 aberrant expression. Recently, a combination therapy with glucocorticoids and GSIs in a mouse model of resistant to treatment T cell ALL show promising results, arguing that NOTCH1 inhibitors in combination with traditional anti-leukemic drugs might improve disease prognosis in patients with NOTCH1 mutations .
6. New prognostic markers detected by genomic variation assays and gene expression evaluation in childhood ALL
The previously described genetic abnormalities in ALL influence the aggressive behavior of leukemic cells and the response to treatment in an important manner. Unfortunately, those abnormalities are not 100% predictive of disease outcome. More recently, genome wide analysis has identified genes associated with risk to relapse in patients with primary gene fusions and hyperdiploidy. These studies have also found novel gene abnormalities probably leading to altered signaling pathways and gene expression patterns in the leukemic blast. Nowadays, many novel cryptic translocations, mutations, deletions, and abnormal expression profiles are considered useful outcome markers in children with ALL and several of these more common markers will be further detailed in this section.
The Caspase-8-Associated Protein 2 gene, also known as FLICE associated Huge Protein (
The clinical significance of
Biologic basis of the variation of
The usefulness of
Ikaros plays an essential role in development and differentiation of lymphoid and myeloid lineages. It acts as a tumor suppressor and as a regulator of gene expression through a chromatin remodeling function. In normal cells, long Ik-1 and Ik-2 isoforms are more expressed than the predominantly dominant-negative isoforms, Ik-3, Ik-4, Ik-5 and Ik-6 [162,163]. During alternative splicing Ikaros is susceptible to loss the amino-terminal DNA-binding domain, leading to increased expression of specific isoforms, in particular Ik-6, which is strongly associated with B and T cell ALL [164–166].
On the other hand, SNP array analysis of B cell ALL children has revealed deletions of complete
“Short” and “long” isoforms can be expressed in leukemic cells from both B and T cell ALL patients, however, the frequency and expression levels seem to vary between specific immunophenotype and genetic subgroups [169,170]. For instance, Ph positive B cell ALL patients tend to have higher levels of Ik-6 in contrast to Ik-1 and Ik-2 . Interestingly, one study found that
Regarding prognosis, there is a strong correlation between mutations, deletions in
Recently, it has been shown that the mutation R683, within the JAK2 pseudokinase domain, is present in approximately 3-4% of childhood ALL patients . About 10% of high risk B cell ALL patients are R683+, however, the incidence is increased in patients with Down syndrome (18-28%) [179–181]. The incidence of
Approximately 40% of children with B cell ALL have
About 5-7% of Caucasian non-selected B cell ALL patients present
Rearrangements and overexpression of
A strong interaction among
According to these observations, it has been speculated that
Progress in risk adapted treatment of childhood ALL can currently cure up to 80% of patients. Prognostic factors including patient and disease characteristics as well as response to treatment, play a key role in stratification. Through exhaustive genetic characterization of ALL, gene fusions, point mutations, deletions and gross losses or gains of genetic material have been associated to prognosis. Recently, gene expression and comparative genomic hybridization microarrays have identified new potential genetic markers for predicting outcome. These markers have been evaluated in order to recognize patients prone to relapse, even when they present low risk characteristics by conventional parameters of risk stratification. Based on those studies, gene signatures, mutations and signaling pathways no previously associated to ALL have been identified. Detected abnormalities are involved in diverse cellular processes, as cell cycle progression, cell death, and regulation of gene expression. These activities directly influence how the leukemic blast responds to treatment, and have an important role in the relapse process. Novel genetic alterations that have been associated with poor outcome in ALL patients are rearrangements/mutations that trigger
To CONACyT FONSEC SSA/IMSS/ISSSTE//44402. (PPV) and CONACyT PhD grant 165427 (RJV).
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