AUTHOR=Garcia-Solorio Joaquin , Núñez-Enriquez Juan Carlos , Jiménez-Olivares Marco , Flores-Lujano Janet , Flores-Espino Fernanda , Molina-Garay Carolina , Cervera Alejandra , Casique-Aguirre Diana , Peñaloza-Gonzalez José Gabriel , Baños-Lara Ma. Del Rocío , García-Soto Ángel , Galván-Díaz César Alejandro , Olaya-Vargas Alberto , Aguilar Hilario Flores , Mata-Rocha Minerva , Garrido-Hernández Miguel Ángel , Solís-Poblano Juan Carlos , Luna-Silva Nuria Citlalli , Cano-Cuapio Lena Sarahi , Aristil-Chery Pierre Mitchel , Herrera-Quezada Fernando , Carrillo-Sanchez Karol , Muñoz-Rivas Anallely , Flores-Lagunes Luis Leonardo , Mendoza-Caamal Elvia Cristina , Villegas-Torres Beatriz Eugenia , González-Osnaya Vincent , Jiménez-Hernández Elva , Torres-Nava José Refugio , Martín-Trejo Jorge Alfonso , Gutiérrez-Rivera María de Lourdes , Espinosa-Elizondo Rosa Martha , Merino-Pasaye Laura Elizabeth , Pérez-Saldívar María Luisa , Jiménez-Morales Silvia , Curiel-Quesada Everardo , Rosas-Vargas Haydeé , Mejía-Arangure Juan Manuel , Alaez-Verson Carmen 

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

JOURNAL=Frontiers in Oncology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1337954

DOI=10.3389/fonc.2024.1337954

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Recurrent 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. <italic>IKZF1<sup>plus</sup></italic> is a complex biomarker associated with a poor prognosis. It is characterized by <italic>IKZF1</italic> deletion coexisting with <italic>PAX5</italic>, <italic>CDKN2A/2B</italic>, 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 <italic>IKZF1<sup>plus</sup></italic> profile and the mutational spectrum of <italic>IKZF1, PAX5, CDKN2A/2B</italic>, and <italic>ERG</italic> genes and evaluate their impact on overall survival (OS) in a group of patients with B-ALL.</p></sec><sec><title>Methods</title><p>A total of 206 pediatric patients with <italic>de novo</italic> 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.</p></sec><sec><title>Results</title><p>We identified the <italic>IKZF1<sup>plus</sup></italic> profile in 21.8% of patients, which was higher than that previously reported in other studies. A significantly older age (<italic>p=0.04</italic>), a trend toward high-risk stratification (<italic>p=0.06</italic>), and a decrease in 5-year Overall Survival (OS) (<italic>p=0.009</italic>) were observed, although heterogeneous treatment protocols in our cohort would have impacted OS. A mutation frequency higher than that reported was found for <italic>IKZF1</italic> (35.9%) and <italic>CDKN2A/2B</italic> (35.9%) but lower for <italic>PAX5</italic> (26.6%). <italic>IKZF1<sup>MUT</sup></italic> group was older at diagnosis (<italic>p=0.0002</italic>), and most of them were classified as high-risk (73.8%, <italic>p=0.02</italic>), while patients with <italic>CDKN2A/2B<sup>MUT</sup></italic> had a higher leukocyte count (<italic>p=0.01</italic>) and a tendency toward a higher percentage of blasts (98.6%, &gt;50% blasts, <italic>p=0.05</italic>) than the non-mutated patients. A decrease in OS was found in <italic>IKZF1<sup>MUT</sup></italic> and <italic>CDKN2A/2B<sup>MUT</sup></italic> patients, but the significance was lost after <italic>IKZF1<sup>plus</sup></italic> was removed.</p></sec><sec><title>Discussion</title><p>Our 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.</p></sec>