functional experiments, NUDT15 was firstly reported to be
involved in metabolic pathway of mercaptopurine, and the risk
allele of the top GWASNUDT15 SNP can largely reduce the
enzyme activity of NUDT15 [109]. Interestingly, RAF of such
SNP is much higher in East Asians (~10%) than Caucasians
(~0.4%) and barely detected in Africans (0%), which perfectly
explain the paradox of higher myelosuppression rate vs. lower
TPMT*3C rate in East Asians than other ethnicities [107]. Actually,
array-based GWASs have been successfully used to detect multiple
germline markers for ADRs (e.g., cisplatin-induced ototoxicity
[110]) and were proved to be powerful tools in pharmacogenomics
studies.3.6 Translational
Practice
The array-based genetic investigation has been widely conducted as
potential new diagnostic tests in treatment approaches of
B-progenitor ALL [9]. For instance, 15%–30% of B-ALL cases
have alterations ofIKZF1and are associated with very poor out-
come in ALL, including an up to threefold increased risk of treat-
ment failure in ALL [63, 67], not only because such alterations are
enriched in BCR-ABL1 positive ALL [63, 67, 68]. Actually,IKZF1
alterations is independently associated with poor outcomes in mul-
tivariate analysis adjusting for established clinical prognostic factors
(e.g., age, WBC, cytogenetic subtypes) [111]. In contrast, multiple
studies have failed to observe any association betweenPAX5altera-
tions and outcome suggesting that these changes may only be
important in establishing the leukemic clone, rather than influen-
cing responsiveness to therapy [9]. Few associations between indi-
vidual genetic alterations and outcome in T-ALL have been
identified, except for ETP T-ALL, which have poor responsiveness
to initial therapy (as evidenced by high levels of minimal residual
disease) and very poor outcome. Detection of the ETP immuno-
phenotype is being used to identify these patients and intervene
with aggressive therapies, such as bone marrow transplantation.
For clinical applications, as a remarkable molecular prognostic
factor, all types ofIKZF1alterations must be able to detect in
clinical assays. However, no single assay is capable of detecting all
of these alterations. Alternative approaches include customized
arrays, genomic quantitative PCR [62], multiplex ligation-
dependent probe amplification [112], and sequence mutation
screening methods. Therefore, a simple and one-step assay is largely
required to detectIKZF1alteration in clinical level. In contrast,
CRLF2overexpression can be detected by flow cytometry, and
CRLF2 rearrangement may be detected by FISH, genomic PCR,
or reverse transcriptase PCR (RT PCR) [64]. JAK mutations may
be detected by a variety of well-established methods for sequence
mutation detection, such as Sanger sequencing. These approaches
are being investigated in large prospective clinical trials [44].Insights of Acute Lymphoblastic Leukemia with Development of Genomic... 399