[Association of IKZF1 gene polymorphism with acute lymphoblastic leukemia in Chinese children].
Ontology highlight
ABSTRACT:
SUBMITTER: Dong A
PROVIDER: S-EPMC7342116 | biostudies-literature | 2016 Sep
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BACKGROUND:Studies on gene polymorphism association are centered on childhood acute lymphoblastic leukemia (ALL), a common hematological malignancy in children younger than 16 years. Single-nucleotide polymorphisms (SNPs) in some genes, such as ARID5B and CDKN2B, are associated with the risk of childhood ALL. T-cell leukemia homeobox 1 (TLX1), a member of the HOX gene family, was identified based on its abnormal expression in T-lineage leukemia. This study aimed to determine whether TLX1 is associated with B-ALL and which SNP plays a significant role in ALL. METHODS:A total of 217 cases of ALL and 241 controls were included in this study. Six tag SNPs (rs75329544, rs946328, rs12415670, rs2075879, rs17113735, and rs1051723) were selected, and genotyping was carried out on Sequenom MassARRAY platform. RESULTS:Rs17113735 was possibly the risk locus associated with increased risk for ALL, whereas rs946328 was possibly associated with decreased risk for ALL. Moreover, rs17113735 was likely to be the risk locus for B-cell ALL (B-ALL), and rs2075879 was associated with decreased risk for B-ALL (P < .05). All SNPs in the two sample types (ALL and B-ALL samples) demonstrated linkage disequilibrium except between rs75329544 and rs2075879. Haplotype analysis showed no significant difference between the cases and controls in the two sample types. CONCLUSION:TLX1 gene polymorphisms are associated with ALL (rs17113735 and rs946328) and possibly play a significant role in B-ALL (rs17113735 and rs2075879). This work provides a reference for the diagnosis and therapy of this disease.
| S-EPMC7521250 | biostudies-literature
Project description:Acute lymphoblastic leukemia (ALL) is a malignancy associated with altered lymphoid precursor hyperplasia and accompanied with different genetic mutations. Few studies have been reported on the association between gene mutations and clinical features of IKZF1 mutation in children with B-cell ALL (B-ALL). We investigated clinical and genetic characteristics in 200 newly diagnosed pediatric B-ALL through multiplex ligation-dependent probe amplification (MLPA) and targeted next-generation sequencing (NGS) method. We found that IKZF1 mutations, including large segment deletions, small insertions or deletions (InDels) and single nucleotide variations (SNVs), were detected in 22 patients with a positive mutation rate of 11.0%. IKZF1 mutation was significantly associated with higher WBC count (19.38 × 109/L vs. 5.80 × 109/L, p = 0.002). Compared with IKZF1 wild-type cases, a higher frequency of IL7R gene mutation was discovered in IKZF1 mutant cases (9.1% vs. 0.0%, p = 0.012). Patients with IKZF1 mutation were less sensitive to glucocorticoid induction than patients without IKZF1 mutation (63.6% vs. 9.0%, p < 0.001). On the 15th day of induction, minimal residual disease (MRD) > 10-3 level were higher in IKZF1 mutant patients than wild-type patients (45.5% vs. 22.3%, p = 0.018). In conclusion, our study reveals the association between genetic mutations and clinical features in Chinese children with B-ALL, which might contribute to molecular classification, risk stratification and prognosis evaluation, and provide new ideas for targeted therapy in ALL.
| S-EPMC9000999 | biostudies-literature
Project description:BackgroundAcute lymphoblastic leukemia is the most prevailing pediatric hematologic malignancy, and various factors such as environmental exposures and genetic variation affect ALL susceptibility and patients outcome. According to genome-wide association studies, several single nucleotide polymorphisms (SNPs) in IKZF1 (rs4132601) and CDKN2A (rs3731249 and rs3731217) genes are associated with ALL susceptibility. Hereupon, this study aimed to discover the association between these SNPs and the risk of childhood ALL among a sample of the Iranian population.MethodsA total of fifty children with ALL were included in this case-control study, along with an additional fifty healthy children, matched for age and gender. High-resolution melting (HRM) analysis was employed to genotyping rs4132601, rs3731249, and rs3731217.ResultsIn the patient group, the CT genotype and T allele frequency of rs3731249 were significantly greater than controls (p = 0.01 and p = 0.005, respectively). Moreover, the positive association of CT and dominant model (CT + TT) genotypes and T allele at rs3731249 with the risk of ALL was confirmed (OR = 9.56, OR = 10.76 and OR = 11.00, respectively). There was no significant relation between rs4132601 (IKZF1), rs3731217 (CDKN2A), and childhood ALL.ConclusionThe present study indicates that CT genotype and T allele at rs3731249 (CDKN2A) can significantly increase the risk of ALL among children.
| S-EPMC9354342 | biostudies-literature
Project description:BackgroundDespite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined.MethodsWe studied a cohort of 221 children with high-risk B-cell-progenitor ALL with the use of single-nucleotide-polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1-positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell-progenitor ALL.ResultsMore than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell-lineage genes, and it was similar to the signature of BCR-ABL1-positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion.ConclusionsGenetic alteration of IKZF1 is associated with a very poor outcome in B-cell-progenitor ALL.
| S-EPMC2674612 | biostudies-literature
Project description:PurposeAlthough MYBL2 had been validated to participate in multiple cancers including leukemia, the role of MYBL2 polymorphisms in acute lymphoblastic leukemia (ALL) was still not clear. In this study, we aimed to evaluate the association between MYBL2 single nucleotide polymorphisms (SNPs) and ALL risk in children.MethodsA total of 687 pediatric ALL cases and 971 cancer-free controls from two hospitals in South China were recruited. A case-control study by genotyping three SNPs in the MYBL2 gene (rs285162 C>T, rs285207 A>C, and rs2070235 A>G) was conducted. The associations were assessed by odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Subgroup and stratification analyses were conducted to explore the association of rs285207 with ALL risk in terms of age, sex, immunophenotype, risk level, and other clinical characteristics. The false-positive report probability (FPRP) analysis was performed to verify each significant finding. Functional analysis in silico was used to evaluate the probability that rs285207 might influence the regulation of MYBL2 .ResultsOur study demonstrated that rs285207 was related to a decreased ALL risk (adjusted OR = 0.78; 95% CI = 0.63-0.97, P = 0.022) in the dominant model. The associations of rs285207 with ALL risk appeared stronger in patients with pre B ALL (adjusted OR=0.56; 95% CI=0.38-0.84, P=0.004), with normal diploid (adjusted OR=0.73; 95% CI=0.57-0.95, P=0.017), with low risk (adjusted OR=0.68; 95% CI=0.49-0.94, P=0.021), with lower WBC (adjusted OR=0.62; 95% CI=0.43-0.87, P=0.007) or lower platelet level (adjusted OR=0.76; 95% CI=0.59-0.96, P=0.023). With FPRP analysis, the significant association between the rs285207 polymorphism and decreased ALL risk was still noteworthy (FPRP=0.128). Functional analysis showed that IKZF1 bound to DNA motif overlapping rs285207 and had a higher preference for the risk allele A. As for rs285162 C>T and rs2070235 A>G, no significant was found between them and ALL risk.ConclusionIn this study, we revealed that rs285207 polymorphism decreased the ALL risk in children, and rs285207 might alter the binding to IKZF1, which indicated that the MYBL2 gene polymorphism might be a potential biomarker of childhood ALL.
| S-EPMC8456030 | biostudies-literature
Project description:ImportanceAlterations in the IKZF1 gene drive B-cell acute lymphoblastic leukemia (B-ALL) but are not routinely used to stratify patients by risk because of inconsistent associations with outcomes. We describe a novel deletion in 22q11.22 that was consistently associated with very poor outcomes in patients with B-ALL with IKZF1 alterations.ObjectiveTo determine whether focal deletions within the λ variable chain region in chromosome 22q11.22 were associated with patients with B-ALL with IKZF1 alterations with the highest risk of relapse and/or death.Design, setting, and participantsThis cohort study included 1310 primarily high-risk pediatric patients with B-ALL who were taken from 6 independent clinical cohorts, consisting of 3 multicenter cohorts (AALL0232 [2004-2011], P9906 [2000-2003], and patients with Down syndrome who were pooled from national and international studies) and 3 single-institution cohorts (University of Utah [Salt Lake City], Children's Hospital of Philadelphia [Philadelphia, Pennsylvania], and St. Jude Children's Hospital [Memphis, Tennessee]). Data analysis began in 2011 using patients from the older studies first, and data analysis concluded in 2021.ExposuresFocal 22q11.22 deletions.Main outcomes and measuresEvent-free and overall survival was investigated. The hypothesis that 22q11.22 deletions stratified the prognostic effect of IKZF1 alterations was formulated while investigating nearby deletions in VPREB1 in 2 initial cohorts (n = 270). Four additional cohorts were then obtained to further study this association (n = 1040).ResultsThis study of 1310 patients with B-ALL (717 male [56.1%] and 562 female patients [43.9%]) found that focal 22q11.22 deletions are frequent (518 of 1310 [39.5%]) in B-ALL and inconsistent with physiologic V(D)J recombination. A total of 299 of 1310 patients with B-ALL had IKZF1 alterations. Among patients with IKZF1 alterations, more than half shared concomitant focal 22q11.22 deletions (159 of 299 [53.0%]). Patients with combined IKZF1 alterations and 22q11.22 deletions had worse outcomes compared with patients with IKZF1 alterations and wild-type 22q11.22 alleles in every cohort examined (combined cohorts: 5-year event-free survival rates, 43.3% vs 68.5%; hazard ratio [HR], 2.18; 95% CI, 1.54-3.07; P < .001; 5-year overall survival rates, 66.9% vs 83.9%; HR, 2.05; 95% CI, 1.32-3.21; P = .001). While 22q11.22 deletions were not prognostic in patients with wild-type IKZF1 , concomitant 22q11.22 deletions in patients with IKZF1 alterations stratified outcomes across additional risk groups, including patients who met the IKZF1plus criteria, and maintained independent significance in multivariate analysis for event-free survival (HR, 2.05; 95% CI, 1.27-3.29; P = .003) and overall survival (HR, 1.83; 95% CI, 1.01-3.34; P = .05).Conclusions and relevanceThis cohort study suggests that 22q11.22 deletions identify patients with B-ALL and IKZF1 alterations who have very poor outcomes and may offer a new genetic biomarker to further refine B-ALL risk stratification and treatment strategies.
| S-EPMC8377604 | biostudies-literature
Project description:Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high-risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here, we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations result in acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Retinoid receptor agonists reversed this phenotype, partly by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest, and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing an additional therapeutic option in IKZF1-mutated ALL.
| S-EPMC4573904 | biostudies-literature
Project description:Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL.
| S-EPMC5953820 | biostudies-literature
Project description:The gene fusions BCR-ABL1, TCF3-PBX1, and ETV6-RUNX1 are recurrent in B-cell acute lymphoblastic leukemia (B-ALL) and are found with low frequency in coexistence with CRLF2 (cytokine receptor-like factor 2) rearrangements and overexpression. There is limited information regarding the CRLF2 abnormalities and dominant-negative IKZF1 isoforms associated with surrogate markers of Jak2, ABL, and Ras signaling pathways. To assess this, we evaluated 24 Mexican children with B-ALL positive for recurrent gene fusions at diagnosis. We found CRLF2 rearrangements and/or overexpression, dominant-negative IKZF1 isoforms, and surrogate phosphorylated markers of signaling pathways coexisting with recurrent gene fusions. All the BCR-ABL1 patients expressed CRLF2 and were positive for pCrkl (ABL); most of them were also positive for pStat5 (Jak2/Stat5) and negative for pErk (Ras). TCF3-PBX1 patients with CRLF2 abnormalities were positive for pStat5, most of them were also positive for pCrkl, and two patients were also positive for pErk. One patient with ETV6-RUNX1 and intracellular CRLF2 protein expressed pCrkl. In some cases, the activated signaling pathways were reverted in vitro by specific inhibitors. We further analyzed a TCF3-PBX1 patient at relapse, identifying a clone with the recurrent gene fusion, P2RY8-CRLF2, rearrangement, and phosphorylation of the three surrogate markers that we studied. These results agree with the previous reports regarding resistance to treatment observed in patients with recurrent gene fusions and coexisting CRLF2 gene abnormalities. A marker phosphorylation signature was identified in BCR-ABL1 and TCF3-PBX1 patients. To obtain useful information for the assessment of treatment in B-ALL patients with recurrent gene fusions, we suggest that they should be evaluated at diagnosis for CRLF2 gene abnormalities and dominant-negative IKZF1 isoforms, in addition to the analyses of activation and inhibition of signaling pathways.
| S-EPMC8185361 | biostudies-literature
Project description:Transcription factor IKZF1 (IKAROS) acts as a critical regulator of lymphoid differentiation and is frequently deleted or mutated in B-cell precursor acute lymphoblastic leukemia. IKZF1 gene defects are associated with inferior treatment outcome in both childhood and adult B-cell precursor acute lymphoblastic leukemia and occur in more than 70% of BCR-ABL1-positive and BCR-ABL1-like cases of acute lymphoblastic leukemia. Over the past few years, much has been learned about the tumor suppressive function of IKZF1 during leukemia development and the molecular pathways that relate to its impact on treatment outcome. In this review, we provide a concise overview on the role of IKZF1 during normal lymphopoiesis and the pathways that contribute to leukemia pathogenesis as a consequence of altered IKZF1 function. Furthermore, we discuss different mechanisms by which IKZF1 alterations impose therapy resistance on leukemic cells, including enhanced cell adhesion and modulation of glucocorticoid response.
| S-EPMC5865415 | biostudies-literature