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

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          Abstract

          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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          Most cited references37

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          The Ikaros gene is required for the development of all lymphoid lineages.

          The Ikaros gene encodes a family of early hematopoietic- and lymphocyte-restricted transcription factors. Mice homozygous for a germline mutation in the Ikaros DNA-binding domain lack not only T and B lymphocytes and natural killer cells but also their earliest defined progenitors. In contrast, the erythroid and myeloid lineages were intact in these mutant mice. We propose that Ikaros promotes differentiation of pluripotential hematopoietic stem cell(s) into the lymphocyte pathways. In the absence of a functional Ikaros gene, these stem cells are exclusively diverted into the erythroid and myeloid lineages.
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            The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity.

            The Ikaros family of proteins - comprising Ikaros, Aiolos, Helios, Eos and Pegasus - are zinc finger transcription factors. These proteins participate in a complex network of interactions with gene regulatory elements, other family members and a raft of other transcriptional regulators to control gene expression including via chromatin remodelling. In this way, Ikaros family members regulate important cell-fate decisions during hematopoiesis, particularly in the development of the adaptive immune system. Mutation of several family members results in hematological malignancies,especially those of a lymphoid nature. This review describes the key roles of Ikaros proteins in development and disease, their mechanisms of action and gene targets, as well as explaining their evolutionary origins and role in the emergence of adaptive immunity. Copyright © 2011 Elsevier Ltd. All rights reserved.
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              Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90.

              The multicenter trial ALL-REZ BFM (ie, Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Münster) 90 was designed to improve prognosis for children with relapsed acute lymphoblastic leukemia (ALL) by time-to-relapse- and site-of-relapse-adapted stratification and by introduction of novel chemotherapy elements and to evaluate new prognostic parameters in a large, population-based cohort. Five hundred twenty-five patients stratified into risk groups A (early bone marrow [BM] relapses), B (late BM relapses), and C (isolated extramedullary relapses) received alternating short-course intensive polychemotherapy (in blocks R1, R2, or R3) and cranial/craniospinal irradiation followed by maintenance therapy. Block R3 (high-dose cytarabine and etoposide) was introduced to improve the outcome compared with historical controls. Patients with early BM or T-ALL relapse (poor prognosis group [PPG]) were eligible for experimental regimens. One hundred seventeen patients received stem-cell transplantation (SCT). The probabilities (and standard deviations) of event-free survival (pEFS) and overall survival (pOS) at 10 years were 0.30 +/- .02 and 0.36 +/- .02, respectively. Significant differences existed between strategic groups (pEFS(A) = .17 +/- .03; pEFS(B) = .43 +/- .04; pEFS(C) = .54 +/- .06; pEFS(PPG) = .15 +/- .03; log-rank P < .001). Patients of high-risk groups A plus PPG did better with SCT than with chemotherapy (pEFS = .33 +/- .05 v 0.20 +/- .05; P = .005). The pEFS was similar to trials ALL-REZ BFM 85/87 (.36 +/- .03. v 0.37 +/- .03; P = .419; PPG excluded). Time point, site of relapse, immunophenotype, and SCT were significant predictors of pEFS in multivariate analyses. More than one third of patients in this large, population-based trial were cured. Neither R3 nor adaptation of chemotherapy intensity was capable of improving pEFS or of overcoming prognostic factors. In high-risk patients, remission induction regimens must be improved, and allogeneic SCT should be recommended in patients achieving second complete remission.
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                Author and article information

                Contributors
                + 216 98 24 61 53 , touhamimahjoub@gmail.com
                Journal
                BMC Med Genet
                BMC Med. Genet
                BMC Medical Genetics
                BioMed Central (London )
                1471-2350
                11 October 2019
                11 October 2019
                2019
                : 20
                : 159
                Affiliations
                [1 ]ISNI 0000 0004 0593 5040, GRID grid.411838.7, Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, , University of Monastir, ; Monastir, Tunisia
                [2 ]ISNI 0000 0001 2114 4570, GRID grid.7900.e, Hematology Department ; Faculty of Medicine Ibn Jazzar, , University of Sousse, ; Sousse, Tunisia
                [3 ]ISNI 0000000122959819, GRID grid.12574.35, Faculty of Sciences, , El-Manar University, ; Tunis, Tunisia
                [4 ]GRID grid.428191.7, School of Medicine, , Nazarbayev University, ; Nur-Sultan, Astana, Kazakhstan
                Author information
                http://orcid.org/0000-0002-0205-2731
                Article
                900
                10.1186/s12881-019-0900-1
                6788013
                31604453
                fd356082-72a2-425c-a73b-b773802d7fc2
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 26 April 2019
                : 30 September 2019
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Genetics
                acute lymphoblastic leukemia,gene polymorphism,ikzf1, rs4132601, rs111978267
                Genetics
                acute lymphoblastic leukemia, gene polymorphism, ikzf1, rs4132601, rs111978267

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