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Page 314 Meyer et al. Cancer Drug Resist 2019;2:313-25 I http://dx.doi.org/10.20517/cdr.2019.11
[1]
of childhood ALL and T-cell ALL (T-ALL) accounting for the remaining 15% . Owing to the development
of high-throughput genome sequencing technologies, the genomic landscapes of pediatric B- and T-ALL
have been extensively characterized. This in turn has allowed for the classification of ALL into a number of
[2,3]
distinct molecular subtypes that are each associated with specific chromosomal alterations . Interestingly
however, these chromosomal lesions are thought to be insufficient to drive leukemogenesis. Analysis of
neonatal blood spots has revealed that many leukemia-associated chromosomal translocations occur during
fetal hematopoiesis, despite the fact that overt leukemia frequently does not arise until later in childhood.
Furthermore, the incidence of these alterations in neonatal samples is significantly higher than the overall
[4]
incidence of childhood ALL . These data suggest that additional cooperating events are necessary to
promote leukemic transformation.

In addition to germline and somatic mutations, epigenetic alterations are increasingly being recognized
as important contributors to oncogenesis in a wide variety of cancer types. These epigenetic alterations
have been shown to cooperate with genetic mutations to drive the aberrant gene expression profiles that
[5]
are characteristic of cancer cells . In ALL specifically, epigenetic alterations carry prognostic significance,
and changes in the epigenetic landscape during treatment are now thought to underlie the acquisition of
chemoresistance, ultimately leading to disease relapse. While survival rates for childhood ALL now approach
[1]
90% , cure rates following relapse remain poor. Given the prevalence of pediatric ALL, relapsed ALL
[6]
remains a leading cause of cancer-related mortality in children . As a result of these data, there is significant
interest in better understanding how changes in the epigenetic landscape contribute to leukemogenesis, how
this landscape evolves upon exposure to chemotherapy, and how epigenetic modulators might augment the
efficacy of standard chemotherapy to decrease the likelihood of disease relapse and improve outcomes for
children with ALL.

CYTOSINE METHYLATION
Cytosine methylation is a covalent epigenetic mark that plays a critical role in the regulation of gene
expression. Methyl groups are transferred to DNA via DNA methyltransferases and are removed via the
activity of demethylase enzymes [Figure 1A]. While cytosine methylation can occur throughout the genome,
this mark has been most extensively studied in the context of the clusters of CpG dinucleotides, known
as CpG islands (CGIs), that are found in a significant percentage of mammalian promoter sequences .
[7]
Methylation of these CGIs is generally associated with repression of gene expression. During normal
development, most of these CGIs remain unmethylated, thereby promoting an open chromatin state that
facilitates dynamic gene expression. In contrast, most of the CpG dinucleotides throughout the remainder of
[8]
the genome are heavily methylated in normal developing cells and in cells required for adult tissue renewal .

While these patterns of CpG methylation are tightly regulated during normal development, aberrant
CpG methylation is thought to contribute to oncogenesis via two major mechanisms. First, widespread
hypermethylation of promoter CGIs leads to transcriptional silencing of the associated genes. In this way,
promoter hypermethylation of tumor suppressor genes can cooperate with genetic inactivation of these
genes to result in complete loss of tumor suppressor activity . Conversely, global hypomethylation of CpGs
[7]
outside of promoter sequences is thought to increase genomic instability, thereby facilitating the acquisition
of chromosomal abnormalities . Both of these abnormalities are common in ALL, where they are thought
[7]
to contribute to differences in disease biology and response to therapy.

Aberrant methylation in ALL
Consistent with the aberrant methylation patterns observed in a wide variety of cancer types, promoter
hypermethylation is a key feature of ALL. Promoter-specific analyses of methylation patterns across
matched pairs of diagnostic and remission samples from children with B-ALL revealed widespread promoter
hypermethylation specifically in the disease samples that was absent in the remission samples and in non-