occur in the early step of ALL leukemogenesis and mostly cooper-
ate with additional oncogenic events afterward. Meanwhile, altera-
tions in lymphoid development-related genes are unique hallmark
for leukemogenesis. For instance, genes regulating B-lymphoid
development were mutated in over 40% of B-ALL cases, most
involved PAX5 and IKZF1 genes [63, 66]. These alterations
often impact only a single copy of the gene and are predicted to
result in haploinsufficiency or dominant-negative for some focal
deletions.PAX5is the most common target of genetic alteration
in B-ALL and is involved and targeted by focal or broad deletions,
translocation, and core domain-located mutation [76]. While
IKZF1alterations include broad deletions of the gene that result
in haploinsufficiency, focal intragenic deletions result in expression
of aberrant dominant-negative IKAROS isoforms and sequence
mutations [63].IKZF1alterations are present in more than 80%
of BCR-ABL1-positive ALL cases in both adults and children
[63, 77] but uncommon in ALL subtypes with other genomic
alterations, such as TEL-AML1 ALL [62, 78]. Interestingly,
IKZF1 alterations are also enriched in BCR-ABL1-like ALLs,
which have been classified as high-risk class. Importantly, with the
genome-wide CNA investigation, novel rearrangements have been
identified involving the geneCRLF2, accounting for one third of
BCR-ABL1-like cases and more than 50% of ALL cases with Down
syndrome [64, 79]. These rearrangements are either a translocation
ofCRLF2into the immunoglobulin heavy-chain locus or a focal
deletion that results in a novel fusion P2RY8-CRLF2 [64, 79, 80],
resulting in overexpression of CRLF2 on the surface of leukemic
cells. Meanwhile, ~60% of patients with CRLF2 rearrangements
have concomitant gain-of-function mutations ofJAK1orJAK2
[64, 79, 81]. Genomic profiling has also been successfully investi-
gated to identify new alterations in T-ALL, identifying deletions
dysregulating LMO2 [82], amplification of MYB [83, 84], amplifi-
cation associated with the NUP214-ABL1 rearrangement [85],
and deletion and sequence mutation of PTEN [86] and WT1 [87].3.5 Inherited
Predispositions to ALL
SNP microarrays utilize oligonucleotide probes to detect
thousands of SNPs simultaneously and are widely used to conduct
genome-wide association studies (GWASs) to examine the associa-
tion of SNP genotype with disease susceptibility or other pheno-
types (e.g., interindividual drug response) [88]. Actually, several
independent GWASs have been conducted in Caucasians as well as
in diverse ethnicities to investigate the inherited predispositions to
ALL susceptibility by using Affymetrix or Illumina SNP microar-
rays, identifying multiple SNPs mainly at six genetic loci:ARID5B,
IKZF1, CEBPE, CDKN2A, PIP4K2A-BMI1, and GATA3
[59, 72, 89–93]. These associations have been validated in inde-
pendent cohorts and summarized with meta-analyses [94],Insights of Acute Lymphoblastic Leukemia with Development of Genomic... 397