4.3 Genetic
Characteristics and
the Related NGS-Based
Genomic Technologies
Extensive efforts have been made to comprehensively understand
the genetic basis of leukemogenesis and treatment outcomes
through microarray-based profiling of gene expression as well as
DNA copy number alterations before 2010. Afterward, next-
generation sequencing (NGS) was firstly used to detect ALL in
2009 for sequence alterations and rearrangements to avoid the
disadvantages of microarrays [9, 153]. In the past 7–8 years of
studies to identify inherited and somatic genetic alterations in
ALL including sequencing of gene panels, WES, RNA-seq, and
WGS, hundreds of novel alterations and their interactions have
been revealed to achieve multiple ALL genomic landscapes
[69, 154–160]. Aims to obtain the insights of genomic profiling
of ALL are mainly:- Identification of novel subtypes of ALL.
- Characterization of the interactions of genetic alterations in each
ALL subtype. - Identification of the genetic basis of clonal heterogeneity and
the corresponding effects on treatment outcomes. - Definition of the role of inherited genetic variants in ALL sus-
ceptibility and drug response. - Most importantly translation of these findings to improve diag-
nostic, prognostic, and targeted treatment approaches [11].
Although multiple molecular subtypes have been described in
terms of the recurring gross chromosomal changes and chromo-
somal rearrangements, which are hallmarks of ALL, including mul-
tiple subtypes described above, the mechanism involved in their
role on leukemogenesis and treatment outcomes is poorly under-
stood. Firstly, some special subtypes with distinct clinical character-
istics have been submitted to whole genome profiling with WES,
RNA-seq, or even WGS. As an example, ETP T-ALL, a subtype of
T-ALL which has poor treatment outcomes, was submitted to be
comprehensively sequenced [159]. Genome profiling has shown
that ETP-ALL is a genetically heterogeneous disease, not only with
distinct gene expression profile but also lacking common chromo-
somal rearrangement [159]; however, recurrent gene mutations are
commonly observed in several pathways, including regulators of
hematopoietic development, RAS and cytokine receptor signaling
pathways, etc. [159], which are different with other T-ALL (e.g.,
tumor suppressor pathways including NOTCH [26], FBXW7
[161], and poorly understoodPHF6 in children [153, 162]).
Importantly, target therapy strategies (i.e., JAK inhibition and/or
chromatin-modifying agents) may be more effective for ETP-ALL
due to its involvement in JAK–STATand PRC2 pathways, and both
strategies have been proved to be effective in preclinical
models [163].Insights of Acute Lymphoblastic Leukemia with Development of Genomic... 403