Common Genetic Alterations and Clinical Significance B-ALL.
Abstract
Acute leukemia comprises of 31% of all cancers in children making it the most common childhood malignancy. Significant strides have been made in treatment, partly through risk stratification and intensified therapy. A number of subtypes remain at high risk for relapse and poor outcome, despite current therapies. Here we describe risk stratification and molecular diagnosis used to identify high risk leukemias and guide treatment. Specific cytogenetic alterations that contribute to high risk B and T cell acute lymphoblastic leukemia (ALL), as well as infant leukemia are discussed. Particular attention is given to genetic alterations in IKZF1, CRLF2, and JAK, that have been identified by whole genome sequencing and recently associated with Ph-like ALL. Ongoing studies of disease mechanisms and challenges in developing pre-clinical patient-derived xenograft models to evaluate therapies are discussed.
Keywords
- Acute lymphoblastic leukemia
- Pediatric Leukemia
- high risk leukemia
- Ikaros
- IKZF1
- CRLF2
1. Introduction
Acute leukemia comprises 31% of all cancers in children, making it the most common childhood malignancy. Acute lymphoblastic leukemia (ALL) makes up 80% of these cases and the remaining are leukemias of the myeloid lineage. Among the lymphoblastic leukemias, there are two immunophenotypic groups: B cell precursor ALL (B-ALL, 80% of all ALL) and T cell ALL (T-ALL, 20%). In the following sections, the further classification of each of these subtypes of leukemia, based on their molecular characteristics, is discussed. Also discussed are the clinical importance, prognosis, and new therapies available for each subtype.
2. Overview of classification of pediatric leukemia
2.1. Definition of standard and high risk leukemias
The National Cancer Institute (NCI) has classified acute lymphoblastic leukemia in children based on age at diagnosis, initial white blood count, and the presence of extra medullary disease.
Standard risk: initial WBC count less than 50,000/μL and age 1 to younger than 10 years
High risk: initial WBC count 50,000/μL or greater and/or age 10 years or older
The Children’s Oncology Group (COG) has classified acute leukemia into four risk groups using prognostic factors that are strongly predictive of outcome such as: 1) age; 2) initial white count; 3) gender; 4) presence of extra medullary disease at diagnosis (CNS or testicular disease); and 5) blast cytogenetic findings and ploidy, and 6) response to induction therapy [1, 2].
Based on these factors, the four risk groups for COG classification of newly diagnosed B-ALL for the AALL08B1 study are low risk, average risk, high risk, and very high risk. In T-ALL, high white count does not have a prognostic significance. The above classification applies to B cell phenotype cases. The presence of CNS or testicular disease, age <1 year, and trisomy 21 are considered high risk. The importance of tumor cell characteristics will be discussed in the following sections.
2.2. Molecular diagnosis and its importance
Immunophenotyping is used to classify leukemia into B-ALL and T-ALL [3, 4].
B-ALL: comprises 80% of ALL. B-ALL cells express cytoplasmic CD79a, CD19, HLA-DR. Surface CD10 (formerly known as common ALL antigen or CALLA) is seen in 90% of these cases. Subtypes are as follows:
Common Precursor B Cell ALL (75% of cases): These cells are CD10 positive and express no surface or cytoplasmic Ig. This group has the best prognosis.
Pro B ALL (5% of cases): Commonly seen in infants with MLL rearrangement. These cells are CD10 negative and express no surface or cytoplasmic Ig.
Pre B ALL (20% of cases): These cells express cytoplasmic Ig.
T-ALL: These cells express cytoplasmic CD3, with CD7 plus CD2 or CD5 on leukemic blasts. T-ALL is associated with older age, male gender, high initial white count, and mediastinal mass.
Cytogenetic alterations: The presence of recurrent numerical and structural chromosomal abnormalities in both ALL and AML are very common and are associated with prognostic significance. Hence, cytogenetic characteristics are now used for risk stratification of patients with ALL [5, 6].
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Risk stratification based on cytogenetic characteristics has revealed many subgroups of NCI standard and high risk groups that are now treated differently. Many treatment strategies using targeted therapies directed at specific genetic alterations in the tumor cells have opened up a new era of leukemia therapy. Figure 1 and Table 1 show cytogenetic abnormalities seen in ALL [6, 7].
3. Infant leukemia and leukemia with MLL rearrangement
3.1. Overview of infant leukemia
Infant leukemia comprises only 1–2 % of childhood ALL. The cells often show an immature pro-B phenotype. They present with very high WBC count and large extra medullary disease burden which confer poor prognosis in this subset of children [8].
3.2. Biology of infant leukemia
Rearrangements of the
3.3. Risk stratification, current therapeutic approaches and outcome in infant leukemia
Infant ALL is considered high risk for many reasons. The factors that confer poor prognosis are age younger than 6 months, extreme hyperleukocytosis (>300,000 white blood cells/μL), CD10 negativity, and the presence of
Infant ALL is currently treated with intensive chemotherapy including high dose cytarabine – “AML-like” therapy. The prednisone poor responders are classified as high risk and require intensification of therapy. Hematopoietic stem cell transplantation for infants with ALL in first remission remains controversial [15, 16].
4. FLT3 mutations in ALL
4.1. Incidence of FLT3 alterations in ALL and its prognostic significance
Constitutive activation of FMS-like tyrosine kinase 3 (FLT3) plays an important role in the pathogenesis of hematopoietic malignancies.
4.2. FLT3 inhibitors in the treatment of leukemia with FLT3 alterations
Recent gene expression studies have shown that in
5. BCR-ABL positive leukemia
5.1. Incidence, current therapy, and outcome in BCR-ABL+ (Ph+) leukemia
Chimeric BCR–ABL1 protein is encoded by
Ph+ ALL comprises 3–4% of pediatric ALL, and about 25% of adult ALL cases. Prior to tyrosine kinase inhibitors, these patients had dismal outcomes despite the use of intensive chemotherapy and hematopoietic stem cell transplant in the first remission was the best available option [24].
5.2. Tyrosine kinase inhibitors in BCR-ABL+ (Ph+) leukemia and current challenges
Imatinib was the first generation of tyrosine kinase inhibitors that changed the face of treatment for Ph+ ALL and CML. The addition of Imatinib to intensive chemotherapy in childhood BCR-ABL1–positive ALL results in a 4-year event-free survival rate of 84%, more than double that of historical controls [25]. About 40% of the newly diagnosed Ph+ ALL patients carry point mutations within the kinase-binding domain of BCR-ABL that confers resistance to Imatinib.
Dasatinib and Nilotinib are second-generation tyrosine kinase inhibitors. Dasatinib is a multikinase inhibitor targeting several tyrosine kinases, including BCR-ABL and SRC kinases. It is 325 times more potent than Imatinib, binds to the active and inactive forms of BCR-ABL, and has excellent CNS penetration. These are effective in patients resistant to Imatinib, except those with the
Currently, allogeneic hematopoietic stem cell transplant (HSCT) is the standard of care in second remission for patients with Ph+ ALL. It has been observed that most of the patients treated with tyrosine kinase inhibitor (TKI)-based therapy will eventually relapse without HSCT. However, benefits of allogeneic HSCT in first remission, after intensive chemotherapy and TKI therapy, has to be considered based on donor availability, minimal residual disease (MRD) status, and clinical status of the patient [27]. Recent studies in both adults and children have failed to prove clear benefit of allogeneic HSCT in the first remission for this group of patients mainly because of the small sample size [23, 28, 29].
6. Ikaros -altered ALL
6.1. Overview of Ikaros
Ikaros is a DNA-binding zinc finger protein encoded by the
6.2. Clinical importance of Ikaros deletion
6.3. Regulation of Ikaros function in T cell leukemia
The role of Ikaros in normal T cell development is demonstrated by evidence that Ikaros regulates the expression of key genes in T cell differentiation. T cell differentiation is significantly impaired in Ikaros-deficient mice. Terminal deoxynucleotide transferase (
6.3.1. Regulation of Ikaros function
Casein kinase has been shown to phosphorylate Ikaros at multiple sites, and indeed, CK2 kinase is responsible for the majority of Ikaros phosphorylation. Studies by the Dovat group showed that a single phosphomimetic mutation at amino acid 13 or 294 caused the redistribution of Ikaros protein in the nucleus from pericentromeric localization to a diffuse nuclear staining pattern, while phosphoresistant mutations produced no changes in the subcellular localization of Ikaros. These data suggest that targeting of Ikaros to pericentromeric heterochromatin is regulated by its phosphorylation at specific amino acids [34, 38].
6.3.2. CK2 mediated phosphorylation of Ikaros impairs Ikaros function
Recent studies have demonstrated that CK2-mediated phosphorylation of Ikaros controls essential functions of Ikaros including DNA-binding, subcellular localization, and chromatin remodeling, as well as the level of Ikaros protein in cells (via ubiquitination and degradation). Phosphorylation of Ikaros by CK2 kinase also regulates cell cycle progression and Ikaros function in T cell differentiation [39, 40]. Since the overexpression of CK2 kinase and the loss of Ikaros function have been strongly associated with leukemogenesis, it is proposed that increased CK2 kinase activity leads to impaired function and/or degradation of Ikaros, which results in malignant transformation and the development of leukemia.
6.4. Inhibition of CK2 as a potential therapeutic approach to treat high risk leukemia
Casein Kinase II inhibition has been an attractive therapeutic strategy in several malignancies. A specific CK2 inhibitor, CX-4945, orally bioavailable small molecule is in Phase I clinical trial for solid tumors. The role of CK2 inhibitor as an antileukemic drug in ALL needs to be explored.
7. Hypodiploid ALL
7.1. Subclassification and treatment outcome of hypodiploid ALL
Hypodiploid ALL comprises 1–2% of all B-ALL cases and confers poor prognosis. Hypodiploid ALL is a chromosome number abnormality in the leukemic cells that results in 45 chromosomes or less. Hypodiploid ALL has been subdivided in various ways. In general, Hypodiploid ALL may be subclassified into the following four groups:
near-haploid cases – 24–31 chromosomes
low-hypodiploid cases – 32–39 chromosomes
high-hypodiploid cases – 40–43 chromosomes
near-diploid cases – 44–45 chromosomes
Patients with 44 or 45 chromosomes have a much better outcome than patients with fewer than 44 chromosomes [41].
7.2. Genomic profiles of hypodiploid ALL
Recently, a large group of 124 pediatric patients with hypodiploid ALL were analyzed using microarray profiling of gene-expression and copy-number alteration, and next-generation sequencing. These analyses indicate that near-haploid and low-hypodiploid ALL are distinctive from each other and from other types of ALL. In near-haploid ALL, genetic alterations target RTK (receptor tyrosine kinase) signaling, Ras signaling, and the lymphoid transcription factor gene
RTK and Ras signaling alterations were present in more than two-thirds (70.6%) of near-haploid ALL cases, while they were much less common in low-hypodiploid (8.8%) and near-diploid ALL (31.8%). The RTK and Ras signaling alterations involve deletion, amplification, and/or sequence mutation of
The
The
8. Leukemias involving the E2A-PBX1 translocation
8.1. Introduction: Wild type E2A and PBX1
The
8.2. Structure and function of the E2A-PBX1 translocation
The chromosomal translocation between chromosomes 1 and 19 results in a fusion event between
The E2A-PBX1 fusion protein is capable of transforming various cell types. Enforced expression of E2A-PBX1 induces lethal lympho-proliferative diseases in transgenic mice and aggressive myeloproliferative diseases in a murine bone marrow transplantation model [50].
8.3. Target genes of E2A-PBX1
Many efforts have been made to find the mechanisms by which E2A-PBX1 mediates transformation of pre-B cells. One important way is try to find potential target genes or pathways that are regulated by E2A-PBX1. Using ChIP-chip assay, Diakos et al. found 108 direct E2A-PBX1 targets [51]; however, few targets have been studied in detail.
8.4. Clinical treatment and outcome for E2A-PBX1 ALL
For pediatric B-ALL patients with the E2A-PBX1 fusion protein, the prognosis has been controversial. It was initially associated with poor outcome when treated with antimetabolite-based therapy [54, 55], but the recent development of intensified chemotherapy has much improved the outcome of this subgroup. However, in a trial conducted by St. Jude Children’s Research Hospital, although patients with the t(1; 19) had an overall favorable outcome with intensified chemotherapy, this group had a significantly higher incidence of CNS relapse, suggesting intensive CNS-directed therapy is needed to further improve the outcome in this group of patients [56].
9. Ph-like ALL
9.1. Description and prevalence of Ph-like ALL
Ph-like (BCR-ABL1-like) ALL defines a distinct subtype of high risk ALL that is characterized by a gene expression profile similar to that of Ph+ ALL but lacking the characteristic t(9;22) translocation. This subtype represents about 15–20% of all cases of ALL [57, 58]. The prevalence of Ph-like ALL increases with age: 10–13% of ALL in children and 21–27% of ALL in adolescents and young adults. Patients with Ph-like ALL have higher leukocyte counts at presentation and are more likely to have minimal residual disease at the end of induction chemotherapy. The survival rates of patients with Ph-like ALL is significantly lower when compared to non-Ph-like ALL among all age groups, adults faring worse than children [58]. Genes that are involved in B cell development, including
9.2. Translocations involving ABL1 in Ph-like B-ALL
The
The
9.3. Genetic alterations in Ph-like ALL that include EPOR and JAKs
A number of
Erythropoietin (EPO) is a hematopoietic growth factor for the erythroid lineage and regulates the production of red blood cells. The binding of EPO to its receptor EPOR leads to downstream activation of JAK2-STAT5, PI3 kinase, and MAP kinase pathways [70]. Rearrangements that involve EPOR have been found in ~4% of Ph-like ALL [58].
9.4. Ras pathway genetic alterations in Ph-like ALL
Ras pathway mutations have been described in pediatric ALL cases. In a report from the Children’s Oncology Group by Zhang et al., among 23 childhood B-ALL cases with a Ph-like gene expression profile, 9% had Ras pathway mutations. However, the proportion of Ras pathway mutated cases increased to 62% among ALL with focal
9.5. IKZF1 alterations in Ph-like ALL
Aberrations in the
9.6. Rearrangement of CRLF2 in Ph-like ALL
Overexpression of CRLF2 is responsible for more cases of Ph-like ALL than any other genetic alteration [58]. The
10. Biology of CRLF2 B-ALL – The most common form of Ph-like ALL
10.1. CRLF2–TSLP cytokine receptor component in CRLF2 B-ALL
CRLF2 is a type I cytokine receptor that, along with the IL7 receptor alpha (IL-7Rα), forms a heterodimeric receptor complex for the cytokine TSLP (thymic stromal lymphopoietin). In normal B-cell progenitors the expression of CRLF2 is undetectable by flow cytometry, although TSLP cytokine acts on these cells to induce proliferation [77]. In contrast, the high levels of CRLF2 on CRLF2 B-ALL cells can easily be detected by flow cytometry [68]. In CRLF2 B-ALL cells, TSLP has been shown to increase the phosphorylation of STAT5, AKT, and S6, indicating increased JAK-STAT and AKT/mTOR signaling [78]. Studies of TSLP effects in a range of cell types indicates that it can also indicate cell survival signals through the activation of several biological pathways including ERK, MAPK, PI3K/AKT/mTORC1, and NFκB, at least in some cell types [79]. The physiological significance of the signaling induced by TSLP in CRLF2 B-ALL cells remains to be determined [78].
10.2. Role of JAK mutations in CRLF2 B-ALL
Overexpression of
To understand the contributions of CRLF2 and JAK2 to leukemogenesis, several groups have conducted studies using
10.3. Inherited background variability and susceptibility to CRLF2 B-ALL
Aside from these acquired genetic variations that contribute to leukemogenesis, other studies using Genome Wide Association techniques are employed to determine whether inherited (germline) genetic variations increase susceptibility to the development of high-risk Ph-like ALL. In a major study, 75 Ph-like ALL patients were compared to 6,661 non-ALL controls and two Single Nucleotide Polymorphisms (SNPs) within the
10.4. CRLF2 B-ALL and health disparities
CRLF2 B-ALL is five times more prevalent in patients of Hispanic/Latino origin and after initial treatment they experience a higher rate of relapse. This high prevalence of CRLF2 B-ALL in Hispanics is further supported by studies that have been conducted in regions where there is a high proportion of Hispanics. For example, the highest incidence of childhood ALL is in Hispanics compared to other ethnic groups in California [88]. In a study of pediatric B-ALL patients, 18 of 51 (35.3%) Hispanic/Latino patients harbored
10.5. Challenges of preclinical models of CRLF2 B-ALL
Current strategies to treat Ph-like ALL and more specifically CRLF2 B-ALL include: 1) stratification of patients using prognostic and clinical factors (age, gender, race, white blood cell count, CNS involvement, testicular involvement, steroid pretreatment and MRD, cell morphology, immunotyping and genetic alterations); and 2) administer treatment regimen based on risk group. Since 91% of the Ph-like ALL subset of patients (including CRLF2 B-ALL) is characterized by activated kinase signaling, tyrosine kinase inhibitors are currently recommended as part of the treatment regimen for these patients [58]. Recent studies were aimed at evaluating the effects of tyrosine kinase inhibitors, more specially JAK inhibitors and PI3K/mTOR inhibitors on CRLF2 B-ALL cells in vitro and in vivo [78, 93, 94]. Results from these studies have shown that
Human-mouse xenograft models are ideal in vivo models for studying disease mechanisms and for evaluating therapies for leukemia, particularly in context of inherited genetic variability. NOD/SCID mice have been shown to be receptive to the engraftment of human leukemia cells [95]. The development of additional mouse strains, such as the NOD/Scid/IL- 2Rγ null (NSG) strain have significantly increased the ability of human ALL cells to engraft [96]. These animal models are effective because mouse cytokines act on the human leukemia cells by providing the necessary growth signals required to facilitate proliferation and maintenance of leukemia cells [97]. However, while most mouse cytokines can activate receptors on human cells, some mouse cytokines are species-specific, e.g., IL-3, GM-CSF, and TSLP [97]. This poses a challenge in effectively recapitulating the systemic or BM microenvironment present in patients. It is important to conduct studies as far as possible with the full complement of cytokines present under physiological conditions in order to truly identify disease mechanisms and evaluate therapies.
10.6. Novel pre-clinical xenograft models that provide human cytokines
The lack of cross species cytokine activity has been partially addressed for studies of myeloid leukemia by the recent development of so-called “cytokine mice” [98]. These immune-deficient mice express human IL-3, SCF, and GMCSF, three cytokines that play important roles in the production of myeloid lineage cells and show no or poor cross species activity. Xenografts from cytokine mice showed enhanced AML engraftment [98]. Alternative strategies have been used to produce mice that express human IL-15 and FLT3 and other cytokines, which have resulted in enhanced production of functional human natural killer cells, dendritic cells, monocytes/macrophages, and erythrocytes [97]. However, human TSLP has not been included as part of the complement of cytokines used in these studies.
Current xenografts that evaluate therapeutic candidates for CRLF2 B-ALL do not include human TSLP [94], which is required to provide the human CRLF2-mediated signals that were demonstrated by previous groups in vitro [78]. There is a need to develop new preclinical animal models that include TSLP and other species-specific cytokines in order to accurately evaluate disease mechanisms. A model that includes TSLP and allows for modulating the levels of TSLP will be of great value to the study of CRLF2 B-ALL. The rationale for this is that CRLF2, the receptor for the endogenous ligand TSLP, is overexpressed on CRLF2 B-ALL cells and has contributed to increased pathway signaling in these cells. Additionally, the role of TSLP in the initiation and maintenance of CRLF2 B-ALL is unknown. Current studies in our laboratories are aimed at developing a human TSLP+ xenograft model that provides human TSLP to activate CRLF2-mediated signals in human CRLF2 B-ALL cells transplanted into xenograft mice. This model will be used to study disease mechanisms and identify therapies to effectively treat CRLF2 B-ALL.
11. Conclusion
In summary, great strides have been made in effectively treating pediatric leukemia. Risk stratification based on clinical features combined with intensified therapies has contributed to this outcome. Increasingly, more precise molecular phenotyping available from whole genome analyses make it possible to identify and study specific subtypes of high risk leukemias. Mechanistic studies that identify druggable targets in aberrant pathways are likely to fuel rapid advances in the future. This progress will depend on the development of relevant preclinical models for studying disease mechanisms and for evaluating candidate therapies.
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