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Demystifying the Lab
ASH Clinical News takes a look at the complex scientific techniques that
hematologists/oncologists hear about every day, with practical information
for the practicing clinician.
DEMYSTIFYING
Epigenetics in Hematology
In the early 20th century, German researcher
Theodor Boveri described the basic tenets of
tumor biology: Cells can turn cancerous when
they lose the programming that controls their
division and death. This loss usually results
from a mutation that disrupts a cell’s internal
“checks and balances” and changes the order
of nucleotides within the DNA code itself.
Later, other researching pioneers discov-
ered that cells can become malignant through
other routes that are not directly the result of
changes in DNA sequence. If the genetic code
is the cell’s “hardware,” there is a second code
– or a cell’s “software” – that dictates when and
how genes are turned on or off.
This second code, typically called epi-
genetics, provides the cell with information
on how the genetic code should be read and
accessed by the cell’s machinery. The epigen-
etic code is written on top of the DNA code,
designating some genes to be active while
silencing others.
Epigenetics is a complex topic, and what
constitutes epigenetics has evolved since
1939, when British developmental biologist
C.H. Waddington introduced the term. Now,
the modern definition covers heritable gene
expression changes that are not caused by
alterations in the DNA sequence. 1
“Epigenetics is not just the study of a
discrete mechanism used by certain cells
under specific conditions, but a fundamental
property of life that explains multicellular
organisms,” said Ari M. Melnick, MD, pro-
fessor of hematology and oncology at Weill
Cornell Medicine in New York City, whose
lab studies epigenetic programming is dis-
rupted in hematologic malignancies. “There
are more than 3,000 proteins that directly
mediate epigenetic programming in the cell,
which constitutes the largest gene functional-
ity category,” he told ASH Clinical News.
The U.S. Food and Drug Administration
(FDA) approved several cancer therapies that
target epigenetic mechanisms, including the
hypomethylating agents (HMAs) azacitidine
and decitabine, which are indicated for the
treatment of myelodysplastic syndromes
(MDS) and acute myeloid leukemia (AML)
with low blast percentage. Yet, the full scope of
how these agents work and whether they have
effects beyond their epigenetic functions is not
yet clear.
“The more we know about epigenetics, the
more questions we have,” said Thomas Prebet,
MD, PhD, associate professor of hematology
and oncology at the Yale Cancer Center in
New Haven, Connecticut, who studies epigen-
etic deregulation in hematologic malignancies.
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ASH Clinical News
“We are not at a point where we have
fully deciphered the exact mode
of action of these agents,” he
noted.
How does epigenetic
deregulation occur in
hematologic malig-
nancies, and how are
these mechanisms
being targeted by
investigational
treatment agents
for blood cancers?
ASH Clinical News
spoke with Dr.
Melnick, Dr. Prebet,
and other researchers
specializing in the epi-
genetics of hematologic
malignancies for answers.
Epigenetics 101
The DNA sequence of the genome
is the same throughout an individual’s
cells, but what makes one cell a heart, liver,
or a skin cell is the specific pattern of gene
expression that arises from the genome. The
sequence of events is as follows: DNA wraps
around proteins called histones to form chro-
matin. Epigenetic marks on the genome are
contained in chemical modifications of DNA
and the histones. Certain amino acids on his-
tones can be modified by methyl, acetyl, and
other chemical groups. All these modifications
constitute “the epigenetic code,” which dictates
whether, when, and how genes are expressed
in a cell.
Mutations in the genes that encode the