Landscape of driver mutations and their clinical impacts in pediatric B-cell precursor acute lymphoblastic leukemia

Abstract

Recent genetic studies using high-throughput sequencing have disclosed genetic alterations in B-cell precursor acute lymphoblastic leukemia (B-ALL). However, their effects on clinical outcomes have not been fully investigated. To address this, we comprehensively examined genetic alterations and their prognostic impact in a large series of pediatric B-ALL cases. We performed targeted capture sequencing in a total of 1003 pediatric patients with B-ALL from 2 Japanese cohorts. Transcriptome sequencing (n = 116) and/or array-based gene expression analysis (n = 120) were also performed in 203 (84%) of 243 patients who were not categorized into any disease subgroup by panel sequencing or routine reverse transcription polymerase chain reaction analysis for major fusions in B-ALL. Our panel sequencing identified novel recurrent mutations in 2 genes (CCND3 and CIC), and both had positive correlations with ETV6-RUNX1 and hypodiploid ALL, respectively. In addition, positive correlations were also newly reported between TCF3-PBX1 ALL with PHF6 mutations. In multivariate Cox proportional hazards regression models for overall survival, TP53 mutation/deletion, hypodiploid, and MEF2D fusions were selected in both cohorts. For TP53 mutations, the negative effect on overall survival was confirmed in an independent external cohort (n = 466). TP53 mutation was frequently found in IGH-DUX4 (5 of 57 [9%]) ALL, with 4 cases having 17p LOH and negatively affecting overall survival therein, whereas TP53 mutation was not associated with poor outcomes among NCI (National Cancer Institute) standard risk (SR) patients. A conventional treatment approach might be enough, and further treatment intensification might not be necessary, for patients with TP53 mutations if they are categorized into NCI SR.

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

“…MEF2D (myocyte enhancer factor 2D) rearrangements occur in ~4% of childhood and 10% adult B-ALL cases. This subtype shows a distinct immunophenotype with low/absent expression of CD10, and positivity for CD38 and cytoplasmic µ chain, and distinct expression profiles [7,[85][86][87][88]. MEF2D is the 5 partner in all described fusions, whereas B-cell CLL/lymphoma (BCL) 9 and heterogeneous nuclear ribonucleoprotein U-like 1 (HNRNPUL1) are the two most recurrent 3 partners.…”

“…NUTM1 (nuclear protein in testis midline carcinoma family 1) rearrangements (<2% of childhood B-ALL and mostly infant without KMT2A-rearrangements) [7,13,88,[98][99][100] are characterized by fusion of NUTM1 to different partners, including transcription factors and epigenetic regulators (e.g., ACIN1, AFF1, ATAD5, BRD9, CHD4, CUX1, IKZF1, RUNX1, SLC12A6, and ZNF618), that drive aberrant NUTM1 expression [7,13]. In all fusions, the NUT domain is retained, and this is hypothesized to lead to global changes in chromatin acetylation [101] and to sensitivity to histone deacetylase inhibitors or bromodomain inhibitors in case of fusions with BRD9.…”

Near-Haploidy and Low-Hypodiploidy in B-Cell Acute Lymphoblastic Leukemia: When Less Is Too Much

“…The different RAS signaling alterations have been shown to be mutually exclusive, suggesting that, in contrast to the convergent evolution for RAS mutations observed in infants with MLL-rearranged B-ALL [ 52 ], a single alteration in the pathway is sufficient to maintain constitutive RAS-pathway activation. Focal deletions or point mutations in NF1 gene are the most recurrent genetic alterations of near-haploid B-ALL (≥44% of patients) [ 23 , 30 , 53 ]. NF1 encodes a RAS–GTPase-activating protein that negatively regulates Ras signaling.…”

“…A recent study by the Japan Association Childhood Leukemia Study Group (JACLS) reported a high frequency of mutations in CIC in both low-hypodiploid and near-haploid B-ALL, present in 5 of 9 patients [ 53 ]. CIC is a member of the high mobility group (HMG)-box superfamily of transcriptional repressors and is recurrently mutated in oligodendrogliomas and in round cell sarcomas.…”

“…CIC is a member of the high mobility group (HMG)-box superfamily of transcriptional repressors and is recurrently mutated in oligodendrogliomas and in round cell sarcomas. However, the germline status of CIC in B-ALL with hypodiploidy of <40 chromosomes is unknown and raises the question of whether it could be more prevalent in Asian ancestors than in non-Asian populations [ 53 ].…”