Abstract
Acute lymphoblastic leukemia (ALL) is the most frequent malignant disease in the pediatric population, accounting for about 25% of childhood cancers. Drastic therapeutic improvements have been made for pediatric ALL since the early 1960s, marking the most successful treatment paradigm in pediatric oncology. The clinical success derived from refined risk-adapted therapy based on presenting features, cytogenetics and minimal residual disease, prevention of central nervous system relapse, and improvement of supportive care measures. With contemporary therapies, survival of children with ALL now exceeds 90%. However, ALL represents one of leading causes of cancer-related death, as 15%-20% of patients continue to relapse and outcomes post-relapse remain poor. Since the early 2000s, large-scale genomic studies of ALL, greatly facilitated by the advent of next generation sequencing (NGS), have enabled the development of a novel taxonomy for ALL in the molecular era. The access to NGS technologies identifies novel ALL subsets characterized by “driver” oncogenic alterations, previously cryptic on conventional karyotyping methods. With genomic characterization, the group of formerly unclassified B-lineage ALL reduces from 25% to a marginal 5% of ALL. The revised molecular classification of ALL confers prognostic significance and describes the predilection of unfavorable ALL subtypes with increasing age, partially elucidating the worst outcome of adolescents and young adults with ALL. Large-scale genomic analysis also reveals inherited alterations predisposing to ALL occurrence or to different drugs’ sensitivities. Most importantly, the genomic portrait of ALL uncovers novel therapeutic vulnerabilities, paving the way towards precision medicine opportunities in ALL.
Highlights
In the last 60 years, substantial progress has been made in the management of pediatric acute lymphoblastic leukemia (ALL) that translated into meaningful survival improvement
These novel alterations can be divided into three different categories: (1) sequence mutations affecting transcription factors (e.g., PAX5 P80R, IKZF1 N159Y); (2) recurrent rearrangement of a single gene with multiple partners (e.g., ZNF384, MEF2D and NUTM1-rearranged ALL); (3) a range of different alterations involving multiples genes within the same molecular group [e.g., PAX5 alterations, DUX4/ERG subtype, ETV6-RUNX1-like ALL, or Philadelphia chromosome-like (Ph-like) ALL][8,9,10,11]
We aim to provide an overview of the most recent advances in ALL genomics, and to highlight the prognostic impact and therapeutic opportunities derived from this modern classification
Summary
In the last 60 years, substantial progress has been made in the management of pediatric acute lymphoblastic leukemia (ALL) that translated into meaningful survival improvement. The advent of high-throughput genomic approaches has marked a new paradigm in ALL characterization, revealing a diverse spectrum of subtype-defining alterations that were missed due to their cryptic nature or undetectable by orthogonal methods These novel alterations can be divided into three different categories: (1) sequence mutations affecting transcription factors (e.g., PAX5 P80R, IKZF1 N159Y); (2) recurrent rearrangement of a single gene with multiple partners (e.g., ZNF384, MEF2D and NUTM1-rearranged ALL); (3) a range of different alterations involving multiples genes within the same molecular group [e.g., PAX5 alterations, DUX4/ERG subtype, ETV6-RUNX1-like ALL, or Philadelphia chromosome-like (Ph-like) ALL][8,9,10,11]. Next-generation sequencing (NGS) platforms and large-scale genome-wide studies, especially microarray for copy number alterations (CNAs) and whole-transcriptome analysis, display a high ability to classify new molecular subgroups based on their gene expression profiles (GEP). Their prognostic and therapeutic significance will require further validation in large, prospective and uniformly-treated patient cohorts
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