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Meyer et al. Cancer Drug Resist 2019;2:313-25 I http://dx.doi.org/10.20517/cdr.2019.11 Page 317
[15]
Given the prognostic significance of aberrant methylation, Hogan et al. sought to determine whether
there are relapse-specific changes in methylation patterns across the genome. Using matched diagnostic and
relapsed samples from patients with B-ALL, the authors demonstrated an increase in promoter methylation
at the time of disease relapse. Integrating these data with an analysis of gene expression and copy number
changes also revealed a correlation between aberrant methylation and gene expression changes. Taken
together, these data demonstrate that aberrant genome-wide methylation may contribute to poor outcomes,
in part by mediating poor responses to chemotherapy that ultimately result in disease relapse.

Similar to these studies in B-ALL, genome-wide methylation profiling has been found to carry prognostic
significance in T-ALL. As in B-ALL, the methylome of T-ALL cells differs significantly from that of normal
[16]
thymocyte controls, with notable CGI hypermethylation in T-ALL . Using hierarchical clustering of
the most highly differentially methylated CpG sites across a cohort of T-ALL samples, T-ALLs could be
subdivided into those with a CGI methylator phenotype (CIMP+) and those without (CIMP-). CIMP- T-ALLs
[17]
were associated with significantly worse event-free survival (EFS) and overall survival . Furthermore,
this methylation-based classifier could enhance the value of existing prognostic factors. Specifically, the
presence of minimal residual disease (MRD) following the first month of therapy is an important prognostic
[18]
[19]
indicator in T-ALL . Borssén et al. performed methylome profiling of diagnostic samples from patients
who were MRD+ on day 29 of therapy and found that the CIMP- phenotype identified MRD+ patients
with significantly worse long-term outcomes relative to MRD+ patients with the CIMP+ phenotype,
demonstrating the potential for methylome analysis to add value to existing prognostic indicators. To
[20]
understand the molecular basis for these CIMP subgroups, Haider et al. very recently performed a
comprehensive analysis of primary pediatric T-ALLs. This analysis revealed distinct gene expression patterns
involving driver oncogenes in T-ALL, with a strong correlation between TAL1 overexpression and the
CIMP- phenotype. In contrast, the homeobox genes were more commonly overexpressed in CIMP+ T-ALLs.
In addition, CIMP+ T-ALLs had shorter telomeres, suggestive of a longer replicative history. Taken together,
the authors reason that CIMP- and CIMP+ T-ALLs follow distinct routes to leukemogenesis, leading to
differences in methylation patterns.

COVALENT HISTONE MODIFICATIONS
Another major class of cancer-associated epigenetic alterations involves aberrant covalent modifications of
histones. While these aberrations are less well-studied than DNA methylation, increasing evidence supports
their important role in leukemogenesis. Histone octamers, known as nucleosomes, are comprised of the core
histone proteins H2A, H2B, H3, and H4. The tails of these histone proteins undergo diverse covalent post-
translational modifications, including acetylation and methylation, that collectively play an important role in
[21]
the regulation of gene expression .
Histone acetylation is mediated by histone acetyltransferases (HATs), while deacetylation is mediated by
histone deacetylases (HDACs). The acetylation of histone lysine residues is generally associated with an open
chromatin state, promoting active gene transcription [Figure 1B]. In cancer, hyperacetylation involving
proto-oncogenes or hypoacetylation involving tumor suppressor genes can contribute to the aberrant
[21]
gene expression patterns required for oncogenesis . Histone lysine and arginine methylation is similarly
regulated by the activity of DNMTs and demethylases. The functional consequences of these methylation
[22]
events are diverse, as different marks may increase or decrease the expression of associated genes .

Histone acetylation
CREBBP is a HAT that plays an important role in normal hematopoietic cell function and that is
[23]
recurrently mutated in ALL, resulting in loss of HAT activity. A study of diagnostic and relapsed samples
from pediatric patients with ALL revealed loss-of-function CREBBP mutations in 18.3% of relapsed ALL
samples. In many cases, these mutations could be detected in the corresponding diagnostic sample, and