&lt;b&gt;&lt;i&gt;IKZF1&lt;/i&gt;&lt;/b&gt; Gene Deletion in Pediatric Patients Diagnosed with Acute Lymphoblastic Leukemia in Mexico

Ayón‐Pérez, Miriam Fabiola; Pimentel-Gutiérrez, Helia J; Durán‐Avelar, Ma. de Jesús; Vibanco-Pérez, Norberto; Pérez-Peraza, Víctor M; Pérez-González, Oscar; Barrientos-Ríos, Rehotbevely; Santillán-Ávila, Christian F; Zambrano‐Zaragoza, José Francisco; Agraz‐Cibrián, Juan Manuel; Gutiérrez‐Franco, Jorge; Vázquez‐Reyes, Alejandro

doi:10.1159/000499641

Cited by 7 publications

(4 citation statements)

References 29 publications

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“…However, other studies observed differences in IKZF1 large segment deletion frequency: 12% in German patients, 20.6% in Mexico patients, 16% in Swedish patients, and 28.6% in American patients. IKZF1 SNV and small InDel mutation in our study was 2.5%, almost close to the proportion reported in the literature (<1%) ( Mullighan et al, 2008 ; Dorge et al, 2013 ; Ofverholm et al, 2013 ; Ayon-Perez et al, 2019 ; Stanulla et al, 2020 ).…”

Section: Discussionsupporting

confidence: 90%

“…Deficiencies from these sites, such as the entire gene (including exons 1–8), or focal gene (including exons 2 and/or 8), or untranscriptional regulatory regions (including exon 1), can lead to IKZF1 hypofunction ( Iacobucci & Mullighan, 2017 ). The deletion of exons 4–7, lacking the ability to bind DNA, was a negative domain and thus led to leukemia ( Mullighan et al, 2008 ; Iacobucci et al, 2009 ; Chiaretti et al, 2016 ), which was the most common deletion pattern of IKZF1 in our cohort (36%), consistent with results in Germany, Japan, Sweden and the US and different from results in Mexico, where the deletion of exon 1 (85%) occurred most frequently ( Ayon-Perez et al, 2019 ). Although SNV or small InDel mutations of IKZF1 were infrequent and present, their molecular consequences could be either haploid insufficiency or dominant negative effects, as with deletions.…”

Section: Discussionsupporting

confidence: 88%

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Clinical and Genetic Characteristics of IKZF1 Mutation in Chinese Children With B-Cell Acute Lymphoblastic Leukemia

Zhang

Liu³

et al. 2022

Front. Genet.

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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.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 88%

Clinical and Genetic Characteristics of IKZF1 Mutation in Chinese Children With B-Cell Acute Lymphoblastic Leukemia

Zhang

Liu³

et al. 2022

Front. Genet.

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“…Ayón-Perez et al. found that 20.6% (36 cases) ( 37 ), while Rosales-Rodríguez et al. ( 38 ) detected 27% (63 cases) both using MLPA.…”

Section: Discussionmentioning

confidence: 98%

IKZF1plus is a frequent biomarker of adverse prognosis in Mexican pediatric patients with B-acute lymphoblastic leukemia

Garcia-Solorio,

Núñez-Enriquez,

Jiménez-Olivares

et al. 2024

Front. Oncol.

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BackgroundRecurrent genetic alterations contributing to leukemogenesis have been identified in pediatric B-cell Acute Lymphoblastic Leukemia (B-ALL), and some are useful for refining classification, prognosis, and treatment selection. IKZF1plus is a complex biomarker associated with a poor prognosis. It is characterized by IKZF1 deletion coexisting with PAX5, CDKN2A/2B, or PAR1 region deletions. The mutational spectrum and clinical impact of these alterations have scarcely been explored in Mexican pediatric patients with B-ALL. Here, we report the frequency of the IKZF1plus profile and the mutational spectrum of IKZF1, PAX5, CDKN2A/2B, and ERG genes and evaluate their impact on overall survival (OS) in a group of patients with B-ALL.MethodsA total of 206 pediatric patients with de novo B-ALL were included. DNA was obtained from bone marrow samples at diagnosis before treatment initiation. A custom-designed next-generation sequencing panel was used for mutational analysis. Kaplan-Meier analysis was used for OS estimation.ResultsWe identified the IKZF1plus profile in 21.8% of patients, which was higher than that previously reported in other studies. A significantly older age (p=0.04), a trend toward high-risk stratification (p=0.06), and a decrease in 5-year Overall Survival (OS) (p=0.009) were observed, although heterogeneous treatment protocols in our cohort would have impacted OS. A mutation frequency higher than that reported was found for IKZF1 (35.9%) and CDKN2A/2B (35.9%) but lower for PAX5 (26.6%). IKZF1MUT group was older at diagnosis (p=0.0002), and most of them were classified as high-risk (73.8%, p=0.02), while patients with CDKN2A/2BMUT had a higher leukocyte count (p=0.01) and a tendency toward a higher percentage of blasts (98.6%, >50% blasts, p=0.05) than the non-mutated patients. A decrease in OS was found in IKZF1MUT and CDKN2A/2BMUT patients, but the significance was lost after IKZF1plus was removed.DiscussionOur findings demonstrated that Mexican patients with B-ALL have a higher prevalence of genetic markers associated with poor outcomes. Incorporating genomic methodologies into the diagnostic process, a significant unmet need in low- and mid-income countries, will allow a comprehensive identification of relevant alterations, improving disease classification, treatment selection, and the general outcome.

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“…It is this phenomenon that sparks the possibility that aberration in any IKZF gene may contribute to leukemogenesis by perturbing the transcriptional networks of IKZF genes normal functions including lymphoid maturation, tumor suppression, cell-cycle regulation, kinase signaling and chromatin modification ( 108 ). Early reports associated germline IKZF1 deletions with poorer treatment responses and unfavorable outcomes ( 114 – 116 ), while more recent studies found the converse to be true, with beneficial responses to induction therapy ( 117 ).…”

Section: Gene-specific Mechanisms Of Oncogenicitymentioning

confidence: 99%

Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

Zerella,

Homan,

Arts

et al. 2023

Front. Oncol.

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Transcription factors (TFs) play a critical role as key mediators of a multitude of developmental pathways, with highly regulated and tightly organized networks crucial for determining both the timing and pattern of tissue development. TFs can act as master regulators of both primitive and definitive hematopoiesis, tightly controlling the behavior of hematopoietic stem and progenitor cells (HSPCs). These networks control the functional regulation of HSPCs including self-renewal, proliferation, and differentiation dynamics, which are essential to normal hematopoiesis. Defining the key players and dynamics of these hematopoietic transcriptional networks is essential to understanding both normal hematopoiesis and how genetic aberrations in TFs and their networks can predispose to hematopoietic disease including bone marrow failure (BMF) and hematological malignancy (HM). Despite their multifaceted and complex involvement in hematological development, advances in genetic screening along with elegant multi-omics and model system studies are shedding light on how hematopoietic TFs interact and network to achieve normal cell fates and their role in disease etiology. This review focuses on TFs which predispose to BMF and HM, identifies potential novel candidate predisposing TF genes, and examines putative biological mechanisms leading to these phenotypes. A better understanding of the genetics and molecular biology of hematopoietic TFs, as well as identifying novel genes and genetic variants predisposing to BMF and HM, will accelerate the development of preventative strategies, improve clinical management and counseling, and help define targeted treatments for these diseases.

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<b><i>IKZF1</i></b> Gene Deletion in Pediatric Patients Diagnosed with Acute Lymphoblastic Leukemia in Mexico

Cited by 7 publications

References 29 publications

Clinical and Genetic Characteristics of IKZF1 Mutation in Chinese Children With B-Cell Acute Lymphoblastic Leukemia

Clinical and Genetic Characteristics of IKZF1 Mutation in Chinese Children With B-Cell Acute Lymphoblastic Leukemia

IKZF1plus is a frequent biomarker of adverse prognosis in Mexican pediatric patients with B-acute lymphoblastic leukemia

Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

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