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TRAINING and EDUCATION
either gene result in increased DNA methyla-
tion and gene silencing.
But, as with the HMAs, IDH1 and IDH2
inhibitors likely have multiple effects beyond
just acting on cells’ epigenetic modifications.
These agents affect the epigenome but do not
directly target an epigenetic-modifying enzyme
“The chemical produced by the mutant IDH1
and IDH2 enzymes, 2 hydroxyglutarate, acts
as an oncometabolite,” Dr. Prebet explained,
“so the influence of these drugs on epigenetic
modifications is only part of the story.”
Multiple Mutations
Hematologic malignancies are characterized
by mutations in multiple epigenetic regula-
tors, with some that result in disruption of
chromatin throughout the genome. “What
we know – and what is easy to demonstrate
– is that the genes that encode many of these
epigenetic enzymes are mutated, but what has
been harder to demonstrate is what that does
to the chromatin,” said Lucy A. Godley, MD,
PhD, professor of hematology and oncology
at the University of Chicago who studies how
epigenetic alterations affect the development
of hematologic malignancies.
Two recent studies underscore the likely
importance of epigenetic-functioning genes
in the development of AML. Both teams of
researchers identified mutations in the blood
cells that increased individuals’ risks of de-
veloping AML a decade later. 3,4 These genetic
changes, according to both groups, are likely
the initial steps necessary for normal blood
cells to transform into AML cells.
In the first study, the authors found that
people diagnosed with AML a median of
9.6 years from baseline (range not reported)
were four times as likely as those who did
not develop AML to have at least one AML-
associated mutation. 3 All participants with
TP53 mutations (n=21/21) and IDH1 or IDH2
mutations (n=15/15) eventually developed
AML, suggesting that these two mutations
confer a high probability of developing subse-
quent AML. Mutations in the DNMT3A gene
and the TET2 gene also increased the odds of
developing AML.
“These and other studies give us a picture
of how the average person, by accumulating
certain mutations over time, particularly in
chromatin-modifying genes, could develop
leukemia,” said Dr. Godley. Still, she acknowl-
edged that the exact mechanisms through
which these mutations facilitate leukemia
development are a mystery. “We think the
mutations result in global chromatin structure
and organization changes, but we don’t know
the molecular details.”
Both activating and inactivating mutations
in the EZH2 methyltransferase enzyme, which
maintains gene silencing by adding mono-,
di-, or trimethylation of a specific amino acid
on histone H3, have been identified in several
hematologic malignancies. “EZH2-activating
mutations are rare in solid tumors, but quite
common in B-cell malignancies such as fol-
licular lymphoma (FL) and diffuse large B-cell
lymphoma (DLBCL),” Dr. Melnick said, noting
that another type of EZH2 mutation, those that
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inactivate the enzyme, have been identified in
patients with MDS and myelofibrosis. 5-7
Again, this discovery has led to the devel-
opment of an epigenetic-targeting treatment,
the EZH2 inhibitor tazemetostat, which is be-
ing studied as a monotherapy in ongoing phase
I and II trials of FL and DLBCL. However, on
April 23, 2018, the FDA placed the agent on
partial clinical hold and halted enrollment in
the clinical trials following a report that a pe-
diatric patient participating in a phase I study
developed a secondary lymphoma.
“EZH2 mutations are a promising target in
non-Hodgkin lymphoma, but this area is still
a work in progress,” Dr. Prebet acknowledged.
“Epigenetics is