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Franca et al. Cancer Drug Resist 2019;2:256-70 I http://dx.doi.org/10.20517/cdr.2019.004 Page 263

cardiac myofiber disarray and die within 2 weeks after birth, likely because of the accumulation of ITP
[51]
in the nucleotide pool found in erythrocytes . Some reports have associated ITPA variants to human
diseases, such as psychiatric disorders, encephalopathy, young-onset tuberculosis and infertility [49,52-54] . The
human ITPA gene carries several polymorphisms associated with a reduction of enzymatic activity among
which ITPA SNPs rs1127354 and rs7270101. SNP rs1127354 consists in the C94A transversion at the exon 2
level, leading to the amino acid substitution p.Pro32Thr. This substitution determines complete depletion of
[55]
ITPA activity in homozygous individuals and a reduction to about 25% in heterozygous individuals . The
frequency of this polymorphism is around 5%-7% in the Caucasian population, but varies greatly depending
[56]
on the ethnicity ranging from 2% in Hispanic populations up to 19% in Asians . rs7270101 instead is the
intronic transversion IVS2 +21A>C, that alters a very conserved adenine at the level of a splicing site, thus
leading to an aberrant mRNA. This variant has a less severe effect than the C94A alteration: indeed, patients
heterozygous for this SNP show an activity of about 60% compared to wild-type . Genetic variants in
[55]
ITPA are of major interest in pharmacogenetic research being associated with altered outcomes for patients
undergoing antimetabolite therapy, in particular antileukemic agents such as thiopurines and methotrexate
or antivirals such ribavirin or zidovudine [57,58] .

The occurrence of toxicities during the ALL maintenance therapy was previously associated with ITPA
variants: in the context of the SJCRH Total XIIIB protocol, Stocco et al. found that ALL patients
[59]
with a variant ITPA allele had a higher probability of developing severe febrile neutropenia. Increased
accumulation of MMPN nucleotides has been described both in patients’ blasts, during a mercaptopurine-
based window therapy, and erythrocytes, during maintenance therapy with MP doses adjusted for TPMT
genotype. Adam de Beaumais et al. found that wild-type TPMT/variant ITPA ALL patients treated with
[6]
the EORTC (European Organization for Research and Treatment of Cancer)-58951 protocol had higher
MMPN concentration in erythrocytes in comparison to wild-type TPMT/wild-type ITPA and that a MMPN
8
threshold above 5000 pmol/8 × 10 RBC was associated to an increased risk of hepatotoxicity. Controversial
[60]
results were reported in Asian populations: Kim et al. did not find a difference in the cumulative incidence
of grade III/IV febrile neutropenia according to ITPA genotypes in Korean ALL pediatric patients whereas
Malaysian patients with ITPA 94A allele seemed more prone to develop fever and liver toxicity in therapeutic
[61]
protocols not individualized for TPMT . An Italian pharmacogenetic multicentric study was performed
on 508 pediatric ALL patients treated with the AIEOP-BFM 2000 protocol: four children were homozygous
variant for rs1127354 (94 AA genotype) and had a significant 13-fold increase in the risk of developing severe
(grade III-IV) neurological toxicities during the 2 months induction phase, when compared with wild-
type subjects, and showed also an higher risk of developing severe gastrointestinal complications (8-fold
[62]
increase in risk) . However, in this study, MP were introduced only four weeks after the beginning of the
treatment, thus the incidence of these adverse effects could not be uniquely ascribable to thiopurines and the
contribution of other drugs, such methotrexate, could be considered.

PACSIN2
Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2) is a member of the PACSIN
[63]
protein family . PACSIN2 is an ubiquitously expressed protein of ~56 kDa and is localized in physical
proximity to membranes. Structurally, PACSIN2 contains a membrane-sculpting Bin-Amphiphysin-Rvs
(BAR) domain at N-terminal, a central region with a proline rich motif and a C-terminal Src homology
3 (SH3) domain [64-65] . The F-BAR domain regulates membrane curvatures and invaginations formation
involved in vesicle budding, endocytosis and caveole biogenesis [66-68] , whereas the SH3 domain mediates
the interaction with many membrane proteins. PACSIN2 is encoded by a 180kbp gene located in the long
arm of chromosome 22 which includes 15 exons. Human and murine PACSIN2 cDNA and protein show
significant homology with 79.8% and 93.6% identity, respectively. The PACSIN2 knock-out mouse presents
a decreased mean corpuscular volume, decreased mean corpuscular hemoglobin concentration, decreased
[69]
leukocyte cell number, increased heart weight and improved glucose tolerance . A recent genome wide