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Page 320 Meyer et al. Cancer Drug Resist 22019;2:313-25 I http://dx.doi.org/10.20517/cdr.2019.11

trial investigating panobinostat in children with refractory hematologic malignancies has been completed
[47]
(NCT01321346) . The Children’s Oncology Group also conducted a phase I trial of the HDAC inhibitor
[48]
vorinostat in children with refractory leukemia (NCT00217412) . Clinical trials involving DNMT inhibitors
and HDAC inhibitors for the treatment of pediatric ALL are summarized in Table 1.

Bromodomain inhibitors
In addition to enzymes that facilitate the transfer of epigenetic marks and those that remove them, a third
[21]
class of epigenetic regulators includes proteins that read and interpret these marks . One class of reader
proteins, the bromodomain-containing proteins, specifically recognizes acetylated lysine residues within
histones and functions to recruit and interact with transcriptional co-regulators to modulate target gene
[49]
expression [Figure 1C]. Bromodomain inhibitors have demonstrated efficacy in a large number of solid
[50]
tumor types and bromodomain-containing proteins are well-validated therapeutic targets in myeloid
[51]
[52]
malignancies , where bromodomain inhibitors have been evaluated in early phase clinical trials .
The role of bromodomain inhibitors in lymphoid malignancies is less well-understood, but preclinical
data suggest their potential utility. For example, in a mouse model of MLL-AF4 rearranged infant
ALL, bromodomain inhibition decreased leukemic cell engraftment in vivo and increased sensitivity
to glucocorticoid therapy. These effects were even more pronounced upon combined treatment with a
[53]
bromodomain inhibitor and an HDAC inhibitor , further highlighting the importance of the aberrant
epigenetic landscape for disease progression and response to therapy. Similarly, in a panel of primary ALL
samples, JQ1, an inhibitor of the BRD4 bromodomain-containing protein, demonstrated significant in
[49]
vitro cytotoxicity. One key transcriptional target of BRD4 is MYC . This induction of cytotoxicity was
accompanied by a reduction in c-Myc protein stability. Both in vitro and in a xenograft model of ALL, JQ1
[54]
synergized with the glucocorticoid dexamethasone , suggesting a role for these compounds to augment
chemosensitivity.

One high-risk subset of B-ALL frequently harbors chromosomal alterations involving the CRLF2 gene,
the protein product of which heterodimerizes with the interleukin-7 receptor (IL7R) to activate the JAK/
[55]
STAT signal transduction pathway . In these cells, JQ1 was found to downregulate both MYC expression
and IL7R expression, thereby attenuating JAK/STAT signaling output. In a patient-derived xenograft model
[56]
of CRLF2-rearranged ALL, JQ1 significantly prolonged survival . Furthermore, JQ1 has been shown to
inhibit STAT5 activity, thereby exploiting a key dependency of both CRLF2-rearranged B-ALLs and of many
T-ALLs. In a study of T-ALL specifically, JQ1-mediated inhibition of STAT5 transcriptional output resulted
[57]
in decreased leukemia cell survival .

CONCLUSION
Survival rates for children diagnosed with ALL have improved dramatically, but patients who relapse
continue to face a dismal prognosis. While efforts to understand the genomic landscape of ALL have allowed
for considerable advances in risk stratification and have informed the development of novel therapeutic
strategies, increasing evidence points to an important role for the epigenome as a mediator of disease relapse
and chemoresistance. Notably, key epigenetic regulators are frequently mutated in ALL, with selection
for these mutations at the time of relapse, and genome-wide approaches to interrogate the epigenetic
landscape have revealed relapse-specific patterns of epigenetic aberrations that tightly correlate with gene
expression. Further studies are needed to better understand the causal relationship between these epigenetic
abnormalities and leukemogenesis and how these abnormalities contribute to differences in chemotherapy
sensitivity. Many preclinical and early phase clinical studies have focused on reversing this altered epigenetic
state in the context of relapsed/refractory disease, with the goal of restoring chemosensitivity and inducing
remissions. While many of these studies have provided compelling proof of concept for this approach, the