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Page 385 Santiago et al. J Transl Genet Genom 2021;5:380-95 https://dx.doi.org/10.20517/jtgg.2021.16

However, with contemporary intensive risk-adapted treatment, the 5-year event-free survival (EFS) of T-
[8]
ALL exceeds 85%, thus approximating that of HR B-ALL . Unlike for B-ALL, the incorporation of
molecular classification in T-ALL trials is hindered by the heterogeneity of genetic alterations found in T-
ALL [8,37] . Immunophenotyping classification was first used to identify the HR subgroup of early T-cell
precursor (ETP) ALL which is characterized by lack of CD1a and CD8, dim CD5, and the expression of
aberrant stem-cell or myeloid markers [38,39] . About 12% of pediatric T-ALL is categorized as ETP leukemia
and 17% in the highly similar group of near-ETP leukemia (identical phenotype but with an elevated CD5
expression). Compared to non-ETP leukemias, these two subgroups are more likely to be resistant to
chemotherapy with high frequency of induction failure and MRD positivity [38,40] . However, when stratified
by MRD response, the outcome is similar between the different phenotypes and confirms that the
[41]
prognostic impact of MRD prevails over the immunophenotype . More recently, high-throughput genome
sequencing of a large T-ALL cohort identified 106 putative gene alterations and partitioned into eight
distinct molecular subgroups [Figure 2]. The prognostic impact of the sentinel genetic alterations in T-ALL
remains uncertain and did not outperform MRD-based risk classification [41,42] . T-ALL molecular profiling is
characterized by a large number of biologically relevant genomic alterations with 10 to 20 lesions in each
individual leukemia . Some anomalies are highly prevalent and occur in the vast majority of T-ALL. For
[43]
example, activating NOTCH1 mutations and CDKN2A/CDKN2B deletions are present in more that 50%
and in up to 70% of T-ALL, respectively [42,44,45] . Alterations encountered in T-ALL can be subdivided into
different signaling pathways: transcriptional regulation, NOTCH1 signaling, cell cycle control, kinase
activation, epigenetic regulation, RNA processing, ribosomal function and ubiquitination [10,42,43] . Alterations
in transcription factor regulation are nearly universal in T-ALL. T-cell receptor rearrangements, placing
oncogenic transcription factor genes under the control of strong T-cell specific enhancers, define major T-
ALL subtypes with remarkable transcription factor activation: TLX1, LYL1, LMO2/LYL2, TLX3 and
NKX2-1. Deregulation in the transcription factors HOXA, LMO1/LMO2 and TAL1 categorizes three other
subclasses [42,45] . Signaling pathway activation was observed in 65% of pediatric T-ALL affecting PI3K-AKT
(28%), JAK-STAT (25%) and RAS (14%). PI3K-AKT pathway mutations predominate in the TAL1 subtype,
while JAK-STAT and RAS pathway mutations are more common in TLX1, TLX3 and HOXA subgroups.
Interestingly, some genetic alterations are shared between B- and T-ALL, including KMT2A rearrangements
(10%-15% of T-ALL), ABL1 rearrangements, alterations in cell cycle genes (CDKN2A/B) and epigenetic
regulators (CREBBP) . The molecular classification partially correlates with the immunophenotypic
[42]
subgroups. ETP leukemia is found to be enriched in LMO2/LYL2; near ETP leukemia in TAL1 and TLX3-
dysregulated subgroups; whereas non-ETP leukemia is associated with TAL1 and TLX1 deregulation [39,42] .
ETP ALL harbors recurrent activating mutations in JAK-STAT and RAS-MAPK signaling pathways; some
of these mutations are also observed in acute myeloid leukemia. The gene expression profile of ETP ALL, as
well as its immunophenotype and mutational landscape, share similarities with stem-cell and myeloid
precursors, suggesting that ETP cells of origin may derive from a multipotent stem cell [39,42,46,47] .

Relapsed ALL
Relapses occur in 10% to 20% of pediatric ALL following first-line therapy and remain one of the leading
causes of cancer-related mortality in childhood [10,48] . The genomic landscape of relapsed ALL has been
explored by large-scale genome-wide studies involving matched diagnostic-relapsed leukemia samples. The
mutational burden at relapse is increased compared to that at diagnosis, with frequent acquisition of genetic
alterations that were absent at initial presentation [49,50] . The mutations present at diagnosis and relapse
involve several similar pathways: RAS signaling (NRAS, KRAS, PTPN11, FLT3), JAK-STAT pathway (ILR7),
NOTCH1 signaling (NOTCH1, FBXW7), transcription factors of lymphoid development (IKZF1, ETV6,
PAX5), cell cycle control (CDKN2A/B, TP53) and epigenetic modulators (KMD6A) [49,51] . Some of the
mutations retain from diagnosis to relapse, others are volatile and can either be lost or gained at relapse.
Volatile dynamics are more likely to be observed with FLT3, JAK2 and RAS pathway mutations, while