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

Abstract

Background: 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. IKZF1^plus 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 IKZF1^plus 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.

Methods: A 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.

Results: We identified the IKZF1^plus 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%). IKZF1^MUT 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/2B^MUT 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 IKZF1^MUT and CDKN2A/2B^MUT patients, but the significance was lost after IKZF1^plus was removed.

Discussion: 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.

Keywords: CDKN2A/2B gene mutation; IKZF1 gene mutation; IKZF1plus; PAR1 deletions; PAX5 gene mutation; overall survival; pediatric B-ALL.

Figure 1

Overall survival curves at five years of IKZF1^plus were estimated with the Kaplan–Meier method. (A) Decreased OS in patients with IKZF1^plus (blue) versus NO-IKZF1^plus (yellow). (B) Overall survival curves stratified according to IKZF1^plus status and risk classification at diagnosis. The lowest OS was observed in the high-risk IKZF1^plus positive group. Standard-risk NO-IKZF1^plus patients (navy blue), high-risk NO-IKZF1^plus patients (light blue), high-risk IKZF1^plus (gray), standard-risk IKZF1^plus (yellow).

Figure 2

Frequency and type of mutations identified for IKZF1, CDKN2A/2B, PAX5, and ERG genes. For IKZF1, CNAs concomitant (red) with SV (green) were identified in some patients ( Supplementary Table 4 ); these patients were counted only in the CNA_del group in this figure. The PAR1 region was not included because only deletions can be detected by MLPA.

Figure 3

Schematic representation of the mutational profile identified in the IKZF1, PAX5, CDKN2A, CDKN2B, and ERG genes. Coding exons and the corresponding protein domain are shown for each gene. Red lines indicate the deleted region, and the percentage (right side) represents the proportion of cases with deletions. The remaining percentage corresponds to deleted regions with lower frequencies (not represented in the Figure). The complete deletion information is available in Supplementary Table 4 . (A) IKZF1; NM_006060, (B) PAX5; NM_016734.2, the yellow line represents regions with PAX5^igAMP , (C) CDKN2A; NM_000077, (D) CDKN2B; NM_004936, (E) ERG; NM_004449. Chromosome figures were taken from NCBI Bookshelf ID: NBK22266.