classifications such as risk group determination. Most of the anti-
leukemic drugs are developed from the 1950s through the 1980s.
The survival rates for ALL have increased steadily by optimally
using these drugs since the 1960s due to the stringent application
of prognostic factors for risk-adapted therapy. Therefore, multiple
diagnostic factors can also be considered as prognostic factors,
including age at diagnosis, WBC count, and ethnicity [10]. For
instance, patients with age of 1–9 years old and WBC<50,000
cells per cubic millimeter have a favorable treatment outcomes,
while Africans have lower survival rate than Caucasians [10]. Impor-
tantly, minimal residual disease (MRD) and central nervous system
(CNS) affection status are two strong non-genomic prognostic
factors [10]. MRD indicates the small numbers of leukemic cells
that remain in patients in remission after treatment and ranks as one
of the major causes of relapse in ALL. Flow cytometry examination
and real-time PCR have widely been used for MRD estimation
[6, 10].
2.2 Genetic
Characteristics and
Clinical Relevance of
the Molecular
Subtypes
In addition to the non-genomic signatures of ALL, genomic char-
acteristics have been widely observed, suggesting recurring gross
chromosomal changes are a hallmark of ALL [19]. Indeed, the
subsequent studies indicated that primary genetic abnormalities
of leukemia cells have important prognostic significance [6, 21,
22 ]. Before the genome-wide investigation, approximately 75% of
childhood ALL cases have been observed to harbor a recurring
chromosomal alteration detectable by karyotyping, fluorescence
in situ hybridization (FISH), or other low-throughput molecular
techniques, such as reverse transcription PCR and Sanger sequenc-
ing [23], and most of these alterations (including aneuploidy and
translocations) tend to be mutually exclusive in B-ALL. Leukemia
cells with aneuploidy were firstly identified through chromosome
counting by using microscope, with which the patients can be
separated into hyperdiploidy, hypodiploidy, and normal. Afterward,
with the observation of abnormal chromosome length as well as the
karyotyping, multiple types of translocations were characterized.
Interestingly, the most frequent translocation, t(12;21)
(TEL-AML1 fusion, also named as ETV6-RUNX1), was not
observed at first since the length change is not obvious. After
advanced techniques (e.g., FISH) were investigated, such fusion
has been revealed in a large proportion of ALL patients.
Frequencies of different types of genomic alterations may vary
among age groups. For instance, patients with hyperdiploidy and
TEL-AML1 fusion are the most common subtypes, accounting for
~25% and ~22%, respectively, in pediatric patients, but only 10% in
total for adult patients [24], patients with t(4;11) translocation
(MLL-AF4 fusion) account for approximately 50% in infants, 2%
in children, and 5%–6% in adults, while patients with t(9;22) trans-
location (BCR-ABL1 fusion) increase in frequency with age, from
390 Heng Xu and Yang Shu