3% in children to 20% in adults and more than 50% in patients older
than 50 years old [6, 21, 25]. However, patients with t(1;19)
translocations (E2A-PBX1) have similar frequency among patients
with different ages, accounting for ~3–5%. The rest of the patients
with no obvious translocations are called as B-others. In T-cell
ALL, the presence of t(11;19) translocations (MLL-ENL fusion),
overexpression of HOX11 gene [22], and more than half of the
cases of T-cell ALL have activating mutations of the NOTCH1
gene [10, 26].
Importantly, the prognosis outcome of patients is strongly
associated with their molecular subtypes. For instance, the chromo-
some numbers in patients with aneuploidy are positively associated
with survival outcomes, that is, patients with hyperdiploidy (more
than 50 chromosomes per leukemia cell) exhibit a highly favorable
prognosis [10, 24], while patients with hypodiploidy (fewer than
45 chromosomes per leukemia cell) confer a poor outcome, espe-
cially in subgroups with rare low hypodiploidy (33–39 chromo-
somes) and getting even worse in near-haploidy (23–29
chromosomes). For translocations, patients with TEL-AML1
fusion have a very high survival rate and low risk of relapse, which
is in contrast to those with BCR-ABL1 and MLL-AF4. It is also
considered that the age influences the prognostic effect of these
genetic lesions. For instance, among patients with BCR-ABL1
fusion, the survival rate decreased in the order of children, adoles-
cents, and adults [21, 25, 27], while for patients with MLL-AF4
fusion, infants fare considerably worse than older children, and
adults have an especially poor outcome [21, 28]. Patients with
MLL-ENL fusion and HOX11 overexpression confer a good prog-
nosis [28–30].
With long time of investigation, ALL has been classified into
several different molecular subtypes (Fig.2), which is very useful to
determine the risk-adapted therapy.2.3 Inherited
Predispositions in ALL
Inherited genetic variants are considered to play important roles on
leukemogenesis due to the young age of ALL patients at diagnosis.
However, most of the ALL cases are sporadic with very rare familial
cases, suggesting common germline variants rather than rare muta-
tions may account for susceptibility of more ALL patients. There-
fore, association studies were conducted to identify the common
ALL-related SNPs by comparing the frequency of variants in unre-
lated ALL cases and controls. In the pre-genome-wide investiga-
tion era, there were several association studies that examined the
possible roles of genes in candidate pathways, and finally multiple
SNPs were identified to reach statistical significance inCYP1A1,
XRCC1[31], andHLA-DP[32],however, with no validation or
inconsistent significance in independent patient cohorts. There-
fore, a more powerful and accurate strategy is warranted to identify
the top ALL-related common and rare variants [18].Insights of Acute Lymphoblastic Leukemia with Development of Genomic... 391