Polymorphism in<i>IKZF1</i>gene affects age at onset of childhood acute lymphoblastic leukemia

Górniak, Patryk; Pastorczak, Agata; Zalewska-Szewczyk, Beata; Lejman, Monika; Trelińska, Joanna; Chmielewska, Marta; Sokół-Jeżewska, Agnieszka; Kowalczyk, Jerzy; Szczepański, Tomasz; Matysiak, Michał; Kazanowska, Bernarda; Młynarski, Wojciech

doi:10.3109/10428194.2013.866661

Cited by 15 publications

(11 citation statements)

References 17 publications

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“…Although only the rs4132601 has been shown to decrease the mRNA expression of IKZF1 in lymphocytes and that it merely confers a moderately increased risk (odds ratios between 1·5 and 2·8) of adult and paediatric BCP ALL, this SNP may nevertheless be an important factor in familial ALL (Burmeister et al , ). Interestingly, Górniak et al () recently reported that the rs413260 is associated with age at diagnosis, with carriers of the GG genotype being significantly younger (median age 3·8 years) compared with those with the TG or TT variants (median age 5·6 years).…”

Section: Constitutional Changes Of Ikzf1 In Human Diseasementioning

confidence: 99%

“…There are, as of yet, no known germline SNPs in IKZF1 that correlate with the presence of somatic ∆ IKZF1 in the leukaemic cells (Górniak et al , ). However, the expression of the GATA3 gene, which codes for a transcription factor involved in the regulation of T‐cell development (Yagi et al , ), seems to correlate with ∆ IKZF1 , and, interestingly, Perez‐Andreu et al () reported that a SNP in GATA3 leading to decreased expression of this gene was significantly more common in ∆ IKZF1 ‐positive than in ∆ IKZF1 ‐negative BCP ALLs.…”

Section: Cooperative Changes In Bcp All With ∆Ikzf1mentioning

confidence: 99%

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Ikaros and leukaemia

Olsson

Johansson

2015

Br J Haematol

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SummaryThe IKZF1 gene at 7p12.2 codes for IKAROS (also termed IKZF1), an essential transcription factor in haematopoiesis involved primarily in lymphoid differentiation. Its importance is underlined by the fact that deregulation of IKAROS results in leukaemia in both mice and men. During recent years, constitutional as well as acquired genetic changes of IKZF1 have been associated with human disease. For example, certain germline single nucleotide polymorphisms in IKZF1 have been shown to increase the risk of some disorders and abnormal expression and somatic rearrangements, mutations and deletions of IKZF1 (DIKZF1) have been detected in a wide variety of human malignancies. Of immediate clinical importance is the fact that DIKZF1 occurs in 15% of paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL) and that the presence of DIKZF1 is associated with an increased risk of relapse and a poor outcome; in some studies such deletions have been shown to be an independent risk factor also when minimal residual disease data are taken into account. However, cooperative genetic changes, such as ERG deletions and CRLF2 rearrangements, may modify the prognostic impact of DIKZF1, for better or worse. This review summarizes our current knowledge of IKZF1 abnormalities in human disease, with an emphasis on BCP ALL.Keywords: IKZF1, deletion, mutation, leukaemia, prognosis.The zinc finger protein IKAROS (also termed IKZF1) is encoded by the IKZF1 gene, located in chromosome subband 7p12.2 (chr7:50,304,124-50,405,101; http://www.ensembl.org/index.html) and was first identified in 1992 as an important transcription factor for the maturation of T lymphocytes in mice (Georgopoulos et al, 1992); however, an isoform of this protein, LyF-1, had previously been reported as an essential player in the regulation of both T-and B-cell lineage specification (Lo et al, 1991).In the mid-and late-1990s, mutations of IKZF1 or abnormal expression of IKAROS were, for the first time, implicated in leukaemia and numerous subsequent studies have since addressed the pathogenetic and clinical impact of IKA-ROS and its various isoforms in human disease, revealing, for example, that germline single nucleotide polymorphisms (SNPs) in IKZF1 are associated with increased (or decreased) susceptibility to certain disorders, that a constitutional IKZF1 deletion (DIKZF1) may increase the risk of developing acute lymphoblastic leukaemia (ALL), that aberrant expression and hypermethylation of IKZF1 occurs in some solid tumours, that IKZF1 is rearranged due to translocations in a few haematological malignancies, that sequence mutations of IKZF1 (mutIKZF1) are present in both solid tumours and leukaemia, and that DIKZF1 is common in chronic myeloid leukaemia (CML) in lymphoid blast crisis and in adult and paediatric B-cell (BCP) ALL. These findings will be reviewed herein, with a focus on IKZF1 abnormalities in BCP ALL.

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Section: Constitutional Changes Of Ikzf1 In Human Diseasementioning

confidence: 99%

Section: Cooperative Changes In Bcp All With ∆Ikzf1mentioning

confidence: 99%

Ikaros and leukaemia

Olsson

Johansson

2015

Br J Haematol

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“…The animal model revealed that mice without IKAROS protein develop aggressive lymphoblastic leukemia [36, 37]. However, the role of the rs4132601 in the leukemogenesis is unclear; Górniak and colleagues hypothesized that the G allele decreases the stability and level of the mRNA expression; which delays progression through B-cell maturation and increases the risk of ALL [25, 38]. Lautner-Csorba and colleagues reported that the rs4132601 strongly increases the probability (0.97) of ALL and showed that the lower expression associated with the rs4132601 might contribute to the increased vulnerability to the disease [39].…”

Section: Discussionmentioning

confidence: 99%

IKZF1 genetic variants rs4132601 and rs11978267 and acute lymphoblastic leukemia risk in Tunisian children: a case-control study

et al. 2019

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Background Associations between IKZF1 gene variants and Acute Lymphoblastic Leukemia (ALL) was recently reported. We examined whether the common IKZF1 polymorphisms rs4132601 T/G and rs111978267 A/G are associated with ALL among a Tunisian pediatric cohort. Methods This case-control study involved 170 patients with ALL and 150 control subjects. SNP genotyping was performed by TaqMan® SNP Genotyping Assay. Results The minor allele G of IKZF1 gene polymorphism rs4132601 T/G was significantly higher in ALL cases than in control subjects (P = 0.029), with 1.54-fold increased risk of ALL. The association of rs4132601 with ALL was seen under co-dominant (P = 0.009), recessive (P = 0.006), and additive (P = 0.027) genetic models, of which the co-dominant (P = 0.027) and recessive (P = 0.027) association remained significant after adjusting for covariates, and False Discovery Rate correction. In contrast, no association was noted for rs111978267 variant. Two-locus (rs4132601-rs11978267) IKZF1 haplotype analysis demonstrated association of GA (P = 0.053), with increased ALL risk [OR (95% CI) = 1.58 (1.00–2.51)], which remained significant after controlling for key covariates [aP = 0.046; aOR (95% CI) = 1.61 (1.01–2.57)]. Conclusion We demonstrated the association of IKZF1 polymorphism rs4132601 T/G with increased risk of ALL among Tunisian pediatric cohort, with altered phenotypic changes among ALL patients.

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“…Thus, timely identification of these patient group and schedule of effective treatment may be especially important. Moreover, a recent study indicated there was an association between IKZF1 rs4132601 polymorphism and age at diagnosis of childhood ALL, with the patients older in carriers of GT and TT genotypes in comparison with carriers of GG genotype [33]. Also, the GT and TT genotypes were found to be risky for the development of ALL in patients aged >9 years [34].…”

Section: Discussionmentioning

confidence: 99%

Rs4846049 Polymorphism at the 3′-UTR of MTHFR Gene: Association with Susceptibility to Childhood Acute Lymphoblastic Leukemia

Zhang

2019

BioMed Research International

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Background Accumulating evidence has suggested the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were associated with susceptibility to childhood acute lymphoblastic leukemia (ALL). However, the known conclusions of currently known polymorphic loci (677 C > T and 1298 A > C) remain controversial. This study was to investigate new genetic biomarkers for ALL by analyzing the MTHFR polymorphisms at the 3′-untranslated region, which is a location bound by miRNAs. Methods Polymorphisms of rs4846049 (miR-555 binding) were assessed by PCR amplification and direct sequencing in 110 ALL patients and 105 healthy controls. The relative expression of MTHFR was detected by qRT-PCR. Results Overall, genotype distribution or allele carrier frequencies were not significantly different between patients with ALL and healthy controls (P > 0.05). Subgroup analysis results showed that T allele (OR = 0.134, 95% CI = 0.028–0.639; P=0.005) or genotypes with T allele (TT + GT) (OR = 0.133, 95% CI: 0.024–0.727; P=0.017) may be a protective factor for ALL susceptibility in patients with age >8 years. This conclusion was also true for the group only focusing on the precursor B-cell ALL patients. Furthermore, karyotype abnormality was more commonly observed in patients with the GG genotype (56.0%) compared to carriers of TT (0%) or GT (40.6%) genotypes, while c-myc break frequency was significantly higher in TT carriers (33%) than that of patients with GT (3.1%) or GG (0%) genotypes. PCR analysis showed patients carrying the GG genotype of rs4846049 exhibited the reduced mRNA expression of MTHFR. Conclusion MTHFR rs4846049 polymorphism may be associated with increased risk of childhood with ALL and MTHFR mRNA expression.

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Polymorphism inIKZF1gene affects age at onset of childhood acute lymphoblastic leukemia

Cited by 15 publications

References 17 publications

Ikaros and leukaemia

Ikaros and leukaemia

IKZF1 genetic variants rs4132601 and rs11978267 and acute lymphoblastic leukemia risk in Tunisian children: a case-control study

Rs4846049 Polymorphism at the 3′-UTR of MTHFR Gene: Association with Susceptibility to Childhood Acute Lymphoblastic Leukemia

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