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Page 381 Santiago et al. J Transl Genet Genom 2021;5:380-95 https://dx.doi.org/10.20517/jtgg.2021.16

in ALL.

Keywords: Acute lymphoblastic leukemia, childhood leukemia, genomics, precision medicine, targeted therapies

INTRODUCTION
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. With modern therapies, more than
90% of children with ALL now become long-term survivors . The key factor for this success was the
[1]
refinement of multi-agent chemotherapy regimens’ delivery via enrollment of thousands of children with
ALL onto prospective randomized clinical trials. Results of these clinical trials define the current standard of
care and highlight the importance of central nervous system-directed therapy and risk-adapted therapy
based on patient’s presenting characteristics, leukemia biology and early response as measured by minimal
[2,3]
residual disease (MRD) . Clinical characteristics encompassing from age and leukocyte count at diagnosis,
leukemia immunophenotype to extramedullary disease involvement, have been first pinpointed as
prognostic factors and universally integrated for risk stratification and treatment assignment for childhood
9
ALL. For instance, age ≥ 10 years at diagnosis and presenting leukocyte count ≥ 50 × 10 /L [the National
Cancer Institute (NCI)-Rome criteria], as well as extramedullary disease and T-cell phenotype classify the
[4]
patients in the high-risk (HR) group due to lower survival . Sentinel genetic alterations, characterized by
chromosomal aneuploidies or rearrangements via conventional cytogenetics, represent an essential
component of risk stratification. Some alterations are associated with favorable prognosis, such as high
hyperdiploidy (51-65 chromosomes) and ETV6-RUNX1; while other cytogenetic abnormalities including
low hypodiploidy (< 40 chromosomes) or near-haploidy, intrachromosomal amplification of chromosome
+
21 (iAMP21), BCR-ABL1 or Philadelphia chromosome (Ph ), KMT2A (formerly known as MLL)
rearrangement (KMT2Ar) and TCF3-HLF confer a worse prognosis . Risk-group stratification based on
[5-7]
the patient’s clinical and molecular characteristics for tailored therapy intensification has contributed to the
dramatic improvement of pediatric ALL’s prognosis over the last 50 years . However, up to 25% of B-
[8]
lineage ALL (B-ALL) remain unclassified by conventional cytogenetics and is referred to as B-Others . The
[9]
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] [8-11] . 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). This approach has
unraveled new oncogenic drivers of leukemogenesis. Many of them have been shown to have prognostic
and/or therapeutic implications . The frequency of each molecular subgroup varies with age; thus partially
[2,9]
elucidates the age-related differential outcome in ALL . In this review, we aim to provide an overview of
[10]
the most recent advances in ALL genomics, and to highlight the prognostic impact and therapeutic
opportunities derived from this modern classification. It must be specified that some of these novel entities
discussed herein should be considered as provisional. Their prognostic and therapeutic significance will
require further validation in large, prospective and uniformly-treated patient cohorts.