ASH News Daily 2012 - Saturday, December 8, 2012 - (Page A-4)
Page A–4
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PEDIATRICS
Seeing Advancements in Pediatric Leukemias in 3-D
BY MICHAEL R. BISHOP, MD
E
very time a patient asks me
why he or she should participate
in one of my clinical
trials, or for that matter any clinical
trial, I share with him or her
the tremendous success of clinical
research in pediatric leukemias, particularly
in acute lymphocytic leukemia
(ALL). I remember older attending
physicians sharing with me that
there was a time when one quickly
walked by the rooms of patients with
acute leukemia while on rounds, as
there was nothing that could be done
except to keep them comfortable. Up
until recently, it made me think of
how we view patients with metastatic
pancreatic cancer. Now, acute
leukemia is one of the most curable
malignancies in children, which is a
result of careful and consistent dedication
to clinical trials by physicians
caring for these patients. However,
there are, unfortunately, children for
whom cure is elusive, and current
research focuses on how to improve
these outcomes through the translation
of biologic discoveries into clinical
protocols.
These discoveries and transla-
tional research efforts will be presented
today “in 3-D” at 7:30 a.m.
in Room A101, Level 1, Building
A of the Georgia World Congress
Center in the Education Program
session, “Dynamic Discoveries and
Directions in Pediatric Leukemias,”
which will be chaired by Elizabeth
Raetz, MD, from New York Univer-
Epigenetics
«« From Page A-2
expressed in multipotent HSCs, such
as Runx1, Gata3, and others, were
indeed hypomethylated; genes that
are expressed in committed progenitors,
on the other hand, were hypermethylated.
When Dnmt3a is delivered
exogenously in these null cells,
methylation and cell differentiation
are partially restored. Dr. Goodell
will build on this work and show
the data from double Dnmt3a and 3b
knockout mice. She will then bridge
normal and malignant hematopoiesis
by discussing malignant development
from the Dnmt3a knockout
mice in the context of oncogenes.
Dr. Goodell is also the William
Dameshek Prize winner this year.
Hypomethylation is only half of
the story. Hypermethylation in the
“wrong” set of genes (e.g., tumor
suppressors) can lead to cancer. The
ten-eleven translocation 2 (TET2)
gene resides on chromosome 4q, and
sity Medical Center. In planning this
session, Dr. Raetz shared that she
and her session presenters, Martin
Schrappe, MD, of University Medical
Center Schleswig-Holstein, Kiel,
Germany, and Renier J. Brentjens,
MD, PhD, of Memorial Sloan-Kettering
Cancer Center, “felt this topic
to be exciting, timely, and of considerable
interest and relevance to both
the pediatric and adult ALL communities.”
Dr. Schrappe, who serves as
chairman of the International BFM
Study Group (iBFM), will discuss
the clinical utility of monitoring
minimal residual disease (MRD) in
childhood ALL, as MRD response is
now a key determinant of treatment
assignment on many clinical protocols.
He will focus on the different
methodologies to monitor MRD,
emphasizing the need for reliability
and accuracy in MRD detection, as
well as discuss the prospect of using
MRD response as an endpoint for
clinical interventions.
Dr. Brentjens, who specializes
in the treatment of both acute and
chronic leukemias, will discuss the
“state of the art” in cellular therapies
for leukemia, focusing on adoptive
therapy with T cells genetically
modified to express tumor specific
chimeric antigen receptors (CARs),
particularly in regard to targeting
CD19, which is expressed in B-cell
ALL. Specifically, he will provide an
overview of this emerging technology
and discuss some early clinical
trials utilizing CARs and the chal-
TET2 oxidizes 5-methylcytosine
(5-mC) on
DNA to 5-hydroxymethylcytosine
(5-hmC),
resulting in natural demethylation.
Dr. Olivier
A. Bernard, PhD, Institut
Gustave-Roussy, in
Villejuif, France, who
will follow Lucy A. Godley, MD,
PhD, will further show the contribution
of TET2 mutations in myeloid
disorders, which leads to maintenance
of methylation, starts at the
stem cell level. He and his collaborators
have shown that these mutations
are present in a sizeable percentage
(~15%) of myelodysplastic
syndromes (MDS) and myeloproliferative
diseases (MPD). What is interesting
is that the TET2 mutations
alone are identified in MDS and
AML, but TET2 mutantions can precede
the JAK2 mutations in MPD.
But wait – TET2 mutations do not
just lead to myeloid, but also to lymphoid
malignancies. In the cohort of
subjects with T-cell lymphoma that
lenges in the interpretation of the
results of these trials, emphasizing
the need to harmonize clinical protocols
among investigators.
Finally, Dr. Raetz will discuss the
disparity in the outcomes that exist
in treating children with relapsed
ALL, in contrast to the steady improvements
that have been observed
in newly diagnosed disease. She
will note that outcomes for relapsed
ALL have largely remained static in
recent years and highlight how this
has prompted interest in identifying
and investigating new agents to
study in this patient population. Dr.
Raetz will also discuss the potential
for using early measures of disease
response to prioritize new therapies
and to allocate treatment.
If one included MRD Detection
to Dynamic Discoveries and Directions,
the session could almost be
considered to be presented in 4-D.
For those who miss the first session
or want to come back for a second
viewing, the session will be repeated
on Monday at 7:00 a.m. in Room
A103, Level 1, Building A. Unfortunately
you will have to provide
your own 3-D glasses.
Dr. Bishop indicated no relevant
conflicts of interest.
ASH NEWS DAILY
Saturday, December 8, 2012
Drs. Jennifer Davila and Julie Jaffray listen and take notes while Nancy
Heddle, MSc, FCSMLS(D), discusses “Defining the Hypothesis/Research
Question-Clinical Research” during Trainee Day on Friday afternoon.
Phenotype
Normal elderly individuals
with skewed clonal
hematopoiesis
CMML
AML
Mutations Detected
TET2 (in
granulocytes only)
TET2
TET2 or IDH
he studied, DNMT3a and TET2 mutations
were frequently observed
together.
Dr. Godley’s work at the University
of Chicago has focused on
how covalent cytosine modifications
regulate hematopoiesis. Her
laboratory has employed two techniques
that distinguish between
5-mC and 5-hmC: mass spectrometry,
which detects the total amount
of each DNA base in a sample; and
5-hmC-affinity-Seq,
which
relies
on chemical conjugation to isolate
DNA loci enriched in 5-hmC. With
these tools in hand, the Godley laboratory
has studied the dynamics of
5-hmC alterations in normal hematopoiesis.
She said, “The dramatic
changes seen in 5-hmC
content across hematopoietic
cell differentiation
emphasize how important
it is for scientists to
use techniques that can
distinguish among the
covalent cytosine modifications.”
The altered
balance of covalent cytosine modifications
have been observed by
Dr. Godley’s group in collaboration
with several other labs, resulting in
the phenotypes and mutations that
are listed in the table above.
Even if Dnmt3a knockout leads to
hypomethylation, or TET2/IDH mutations
leads to hypermethylation,
there must be a way to stay young
but somewhat in control. This special
forum may just give us those
clues. So while this is offered again
on Sunday as a ticketed session
(11:15 a.m., Omni Hotel at CNN
Center), don’t miss out!
Dr. Hsieh indicated no relevant conflicts
of interest.
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ASH News Daily 2012 - Saturday, December 8, 2012
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