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aCGH profiling of patient 15. a Partial karyotype showing 2 copies of ring chromosome 7. b The chromosome 7 aCGH plot shows a complex rearrangement with deletion, duplication, and amplification of the segments along the entire chromosome 7. The arrow indicates the genomic position of IKZF1 at 7p12.2.
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We present a comprehensive comparison of PAX5,IKZF1, and CDKN2A/B abnormalities in 21 B-cell precursor acute lymphoblastic leukemia (B-ALL) patients studied by aCGH and gene-specific FISH assays. In our cohort of B-ALL patients, alterations of IKZF1, PAX5, and CDKN2A/B were detected by aCGH analysis in 43, 52, and 57% of samples, respectively. Dele...
Citations
... PAX5 is another gene frequently altered, occurring in ~30% of Ph-Like B-ALL cases. IKZF1 and PAX5 alterations often occur together (35). ...
ABSTRACT Precursor B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy characterized by clonal proliferation of abnormal B-cell precursors in the bone marrow. Most of the B-ALL cases are diagnosed in children, although it can present at any age. Thanks to the tremendous advances in our understanding of its biology, identification of more and more prognostic and predictive biomarkers, and application of individualized risk-adjusted treatment, B-ALL has become the most curable malignancy in children, with a long-term survival rate close to 90% in newly diagnosed patients. However, the prognosis of B-ALL remains dismal in adults and children with relapse. Relapsed B-ALL continues to be the leading cause of cancer-related death in children and young adults. Risk stratification is currently based on age, white blood cell count, early therapeutic response, and chromosomal abnormalities such as ploidy and translocations. Recent advances in molecular diagnostic technologies have led to a rapid expansion of the list of molecular biomarkers associated with B-ALL, which show promise to improve the accuracy of risk prediction, and eventually achieve better risk-adapted treatment and clinical outcome. In this chapter, we provide an overview of the prognostic and predictive biomarkers in B-ALL, including some recently identified genomic alterations with significant prognostic impact.
... Another gene that is altered in approximately 30% of patients with Ph-like B-ALL is PAX5. IKZF1 and PAX5 alterations often occur together [82]. Among Ph-like B-ALL, CRLF2 rearrangements are equally common and consist of a translocation of the immunoglobulin heavy chain gene IGH to CRLF2 (IgH::CRLF2) or fusion due to an interstitial deletion of the PAR1 region centromeric to CRLF2 in chromosomes X and Y (P2RY8::CRLF2) [83]. ...
... Translocation t(1;19)(q23;p13.3), generating TCF3::PBX1 fusion, found in pre-B cell acute lymphoblastic leukemia, results in a chimeric protein that is directly associated with malignant transformation of hematopoietic cells and is observed in both adults and children with B-ALL at an overall frequency of 5-6% [82,130]. ...
Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies characterized by abnormal proliferation of immature lymphoid cells. It is the most commonly diagnosed childhood cancer with an almost 80% cure rate. Despite favorable survival rates in the pediatric population, a significant number of patients develop resistance to therapy, resulting in poor prognosis. ALL is a heterogeneous disease at the genetic level, but the intensive development of sequencing in the last decade has made it possible to broaden the study of genomic changes. New technologies allow us to detect molecular changes such as point mutations or to characterize epigenetic or proteomic profiles. This process made it possible to identify new subtypes of this disease characterized by constellations of genetic alterations, including chromosome changes, sequence mutations, and DNA copy number alterations. These genetic abnormalities are used as diagnostic, prognostic and predictive biomarkers that play an important role in earlier disease detection, more accurate risk stratification, and treatment. Identification of new ALL biomarkers, and thus a greater understanding of their molecular basis, will lead to better monitoring of the course of the disease. In this article, we provide an overview of the latest information on genomic alterations found in childhood ALL and discuss their impact on patients’ clinical outcomes.
... ALL is characterized by a high degree of heterogeneity in regards to severity, response to therapeutic schemes, as well as the overall survival rates, owing to the diverse genetic alterations that accumulate over time. These include both numerical and structural chromosomal rearrangements, gains and deletions of genomic regions (Copy Number Variations, CNVs) and, less commonly, single nucleotide alterations [2,3]. ...
... L10 55,XX,+X,+4, +6,dic(7;9)(p11;p11),+8, +10,+14,+18, +18,+21,+21 [3]/46,XX [17] BCR/ABL1 (-), MLL (-), ...
Coffin-Siris Syndrome 4 is an autosomal dominant congenital malformation syndrome caused by heterozygous mutations in the SMARCA4 gene with its main features being intellectual disability, developmental delay, behavioral abnormalities, and hypoplastic or absent fifth fingernails and fifth distal phalanges. Here, we report a young woman with developmental delay, moderate intellectual disability, and bilateral sensorineural hearing loss, referred for genetic testing. High-resolution chromosomal microarray analysis identified a 428-kb deletion in chromosome 19 which included the SMARCA4 gene. We conclude that haploinsufficiency of SMARCA4 may be a valid pathophysiological mechanism leading to milder Coffin-Siris syndrome phenotypes.
... IKZF1 and CDKN2A/B deletions are known to be associated with poor prognosis in pediatric and adult B-ALL populations [27][28][29] , mainly in the BCR-ABL1 B-ALL subpopulation. Our results suggest that, despite the low number of cases analyzed, CDKN2A/B deletions are markers of poor survival in B-other ALL, and the association between CDKN2A/B and IKZF1 deletions might also contribute to the dismal prognosis of BCR-ABL1-like. ...
BCR-ABL1-like B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains poorly characterized in adults. We sought to establish the frequency and outcome of adolescent and adult BCR-ABL1-like ALL using a novel RNA-Seq signature in a series of patients with BCP-ALL. To this end, we developed and tested an RNA-Seq custom panel of 42 genes related to a BCR-ABL1-like signature in a cohort of 100 patients with BCP-ALL and treated with risk-adapted ALL trials. Mutations related to BCR-ABL1-like ALL were studied in a panel of 33 genes by next-generation sequencing (NGS). Also, CRLF2 overexpression and IKZF1/CDKN2A/B deletions were analyzed. Twenty out of 79 patients (12–84 years) were classified as BCR-ABL1-like (25%) based on heatmap clustering, with significant overexpression of ENAM, IGJ, and CRLF2 (P ≤ 0.001). The BCR-ABL1-like subgroup accounted for 29% of 15–60-year-old patients, with the following molecular characteristics: CRLF2 overexpression (75% of cases), IKZF1 deletions (64%), CDKN2A/B deletions (57%), and JAK2 mutations (57%). Among patients with postinduction negative minimal residual disease, those with the BCR-ABL1-like ALL signature had a higher rate of relapse and lower complete response duration than non-BCR-ABL1-like patients (P = 0.007). Thus, we have identified a new molecular signature of BCR-ABL1-like ALL that correlates with adverse prognosis in adult patients with ALL.
... Mutations in PAX5 haplo-insufficient mice increase the penetrance and reduce the latency of development of B-ALL [49]. IKZF1 and PAX5 alterations frequently occur together [50,51]. While only IKZF1, and not PAX5 alterations, was independently associated with poor outcomes in one large study, defects in multiple B cell differentiation regulators (such as PAX5 in combination with others) were also associated with worse outcomes [21]. ...
Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk B-cell Acute Lymphoblastic Leukemia (B-ALL) characterized by a gene expression profile similar to Ph-positive B-ALL but lacking the BCR-ABL1 translocation. The molecular pathogenesis of Ph-like B-ALL is heterogenous and involves aberrant genomics, receptor overexpression, kinase fusions, and mutations leading to kinase signaling activation, leukemogenic cellular proliferation, and differentiation blockade. Testing for the Ph-like signature, once only a research technique, is now available to the clinical oncologist. The plethora of data pointing to poor outcomes for this ALL subset has triggered investigations into the role of targeted therapies, predominantly involving tyrosine kinase inhibitors that are showing promising results.
... Childhood BCP-ALL with iAMP21 consistently has 3 or more copies of the RUNX1 gene (62). Deletion of IKZF1, CDKN2A, RB1, and PAX5 genes are considered as other genetic alterations related to iAMP21 (30). Translocations, mutations and polymorphisms are the most common DNA level prognostic biomarkers in chALL. ...
... The chromosomal translocation t(1;19)(q23;p13) is the most prevalent translocation in E2A gene and appears in ∼5-7% of childhood B-ALL cases. The resulting E2A-PBX1 is a chimeric fusion protein created by the amino-terminal transactivation domains of E2A and the DNA-binding homeodomain of PBX1 (30). Another E2A related translocation, t(17;19)(q22;p13), happens rarely among childhood B-ALL and includes the aminoterminal transactivation domains of E2A and the leucine zipper dimerization domain of HLF (31,64). ...
... Another E2A related translocation, t(17;19)(q22;p13), happens rarely among childhood B-ALL and includes the aminoterminal transactivation domains of E2A and the leucine zipper dimerization domain of HLF (31,64). In pediatric B-ALL, t(1;19) is related to a favorable outcome, while chromosomal translocation t (17;19) is associated with a poor prognosis (30,65). ...
Biomarkers are biological molecules found in body fluids or tissues, which can be considered as indications of a normal or abnormal process, or of a condition or disease. There are various types of biomarkers based on their application and molecular alterations. Treatment-sensitivity or drug resistance biomarkers include prognostic and predictive molecules with utmost importance in selecting appropriate treatment protocols and improving survival rates. Acute lymphoblastic leukemia (ALL) is the most prevalent hematological malignancy diagnosed in children with nearly 80% cure rate. Despite the favorable survival rates of childhood ALL (chALL), resistance to chemotherapeutic agents and, as a consequence, a dismal prognosis develops in a significant number of patients. Therefore, there are urgent needs to have robust, sensitive, and disease-specific molecular prognostic and predictive biomarkers, which could allow better risk classification and then better clinical results. In this article, we review the currently known drug resistance biomarkers, including somatic or germ line nucleic acids, epigenetic alterations, protein expressions and metabolic variations. Moreover, biomarkers with potential clinical applications are discussed.
... An extensive B-ALL FISH panel was negative, while a T-ALL FISH panel demonstrated two distinct abnormalities, including PICALM-MLLT10 fusion and a CDKN2A deletion (at 9p21). Deletions of CDKN2A can be observed in both B-cell and T-cell ALL/LBL [12][13][14][15] ; however, PICALM-MLLT10 fusion is a recurrent translocation observed in approximately 7-10% of T-ALL/LBL cases and is associated with a poor prognosis in adult patients with ETP ALL/LBL [16][17][18] . In addition, while PICALM-MLLT10 fusion can be detected in myeloid lineage neoplasms or T/myeloid leukemia [19] , only a single case of B-ALL/LBL has been reported with this translocation [6] . ...
T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is usually diagnosed based on the presence of immature lymphoid marker terminal deoxynucleotidyl transferase (TdT), and T-cell specific markers, specifically CD3, by immunohistochemistry (IHC) staining on bone marrow and/or extramedullary tissue. We present a novel, TdT and CD3 negative, aggressive early T-cell precursor LBL (ETP-LBL) initially misdiagnosed as a high grade B-cell lymphoma due to expression of CD79a and the erroneous detection of BCL2/IGH fusion. The patient was eventually evaluated using molecular diagnostic techniques, including fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) assays that demonstrated PICALM-MLLT10 fusion and a NOTCH1 mutation in the absence of BCL2/IGH fusion. The use of NGS, specifically mate-pair sequencing (MPseq), subsequently confirmed an in-frame PICALM-MLLT10 fusion. Our retrospective analysis showed that PICALM-MLLT10 fusion has no association with CD3/TdT negativity, as 6/49 T-ALL/LBL cases from Mayo Clinic database (01/1998-09/2018), including this case, were noted to have PICALM-MLLT10 fusion; however, none of the other cases were associated with CD3/TdT negativity. We emphasize the importance of a comprehensive hematopathologic evaluation including multiple molecular studies for the appropriate interrogation and classification of a difficult acute leukemia diagnosis, and to prevent potential diagnostic errors of clinical significance.
... PAX5 somatic gene mutations are among the hallmarks of Bcell ALL. Genome wide analysis has shown that PAX5 mutations occur frequently in pediatric and adult B-cell ALL [135] . PAX5 gene harbors insertion, deletion, point mutations and translocation. ...
An alarming increase in acute lymphoblastic leukemia among children and males has drawn attention of investigators to delve into the genetic causes of ALL and to discover new therapeutic strategies with better prognosis. Although the survival rate in children is much higher than adults, but there's a need to find new potential molecular targets with better treatment outcome. Genomic profiling has made it possible to identify various genetic defects important for driving leukemogenesis. Study of the genetic lesions not only give a better understanding of genes function but also helps to target various signaling pathways involved in disease progression. The current review provides an overview of important genetic defects and dysregulation in their downstream signaling pathways in acute lymphoblastic leukemia.
... Whole chromosomal gain of the sex chromosomes has been shown to be common in adult pre-B ALL, and deletions of CDKN2A/B are highly characteristic of LBL/ALL in all age groups in hemizygous and homozygous forms (20). Inactivation of the tumor suppressor genes, CDKN2A/B, is associated with a poor outcome in all B-LBL patients (21). This is in line with the poor outcome in our case. ...
The aim of the present study was to describe a rare case of orbital precursor B-lymphoblastic lymphoma (B-LBL) in an adult. A 56-year-old male in complete remission of a gastric precursor B-LBL was referred to our orbital clinic due to rapid development of left-sided painless periorbital swelling, diplopia, and proptosis. Complete ophthalmoplegia was observed. Notably, magnetic resonance imaging showed swelling of the medial and inferior rectus muscles in the left orbit and biopsies were performed. Following histological diagnosis of precursor B-LBL, the patient was treated with radiotherapy (2Gy x 20) and chemotherapy according to the NOPHO ALL 2008 protocol.
... There is a commercially available FISH probe covering entire IKZF1 gene, which is designed for detection of gain or loss of the entire locus or translocations; however, intragenic IKZF1 deletion could not be detected correctly by the probe. 22 Thus, an ideal probe was designed, cloned, and combined with another BAC clone that annealed the 3 0 region of IKZF1. The probe set worked effectively for cell lines and clinical samples, and various types of deletions were detected. ...
Intragenic deletion of IKZF1 is a recurrent genomic alteration in acute lymphoblastic leukemia. The deletions are mediated by illegitimate variable(diversity)joining recombination via cryptic recombination signal sequences (RSSs). We developed a fluorescence in situ hybridization (FISH) probe set that can detect any type of IKZF1 deletion, including the commonly deleted exon 4 to 7 region. The probe set consists of a designed probe for the commonly deleted region (Cy3; red) and a bacterial artificial chromosomes clone probe for detecting the 3' flanking region (Spectrum Green). Intact IKZF1 showed a fusion signal, and the deleted allele showed loss of the red signal (0R1G1F). The FISH probes worked correctly for human leukemic cell lines and clinical samples. One case showed an atypical break-apart signal (1R1G1F). Inverse PCR of the case revealed rearrangement of the excised IKZF1 fragment into a legitimate RSS site at Ig κ on chromosome 2, suggesting a pathogenic role of this recombination-activating gene 1/2-mediated event. In this study, we established FISH probe detecting IKZF1 deletion in a quick, quantitative, and cost-effective manner, and the results provided a novel insight into B-cell receptor editing by rearrangement of a cryptic RSS-mediated genomic fragment in acute lymphoblastic leukemia pathology.
