ASH News Daily 2017 - Issue 2 - A-3

ASH NEWS DAILY

Sunday, December 10, 2017

Page A-3
®

MYELOID NEOPL ASMA

The Clone Wars
By hugh young rienhoFF, Jr., Md

lonal Evolution in Myeloid
Malignancy" was one topic of
the Joint Scientific Committee on Myeloid Biology and Scientific
Committee on Myeloid Neoplasia
discussed on Saturday. Dr. Christina
Curtis discussed her population genetics approach to the quantification
of evolutionary dynamics of tumor
progression identifying signals of
clonal selection. Dr. Daniel Link presented his thoughts on clonal hematopoiesis and what genetic and nongenetic factors precipitate evolution
to clinical disease. Dr. Anna Brown
described the germline mutations
that predispose to or, in some cases,
dictate myeloid malignancy, presenting evidence that the clonal architecture of AML derived from germline
mutations is distinct from that derived from somatic mutations. Dr.
Timothy Ley described his continued
research into clonal evolution focusing on AML patients with intermediate risk whose outcomes are the most
unpredictable. Examination of the
subclonal structure and the changes
in those populations with treatment
offer the prospect of improved risk
prediction.
Hardly a week goes by without a
report finishing with the statement

Cardio-Hematology
«« From Page A-1

10 percent of people older than
65 years. The most commonly involved genes include TET2, DNMT3A, and ASXL1, and initiating
mutations in these and other genes
can be detected prior to the onset
of clinical signs and symptoms of
disease, which often results from
the development of additional cooperating mutations. With the improvements in sequencing technology, these mutations can now
be easily identified in small clones
of hematopoietic cells present in
the peripheral blood. Not only
does this clonal hematopoiesis result in the development of hematologic malignancies, but it is also
associated with increased mortality. This increased mortality can be
explained by the development of
both myeloid and lymphoid malignancies and also, interestingly,
by an increase in cardiovascular
mortality.
Dr. Benjamin L. Ebert of Brigham
and Women's Hospital discussed
the evidence of the increased risk of
cardiovascular mortality in patients
with clonal hematopoiesis in his
talk titled "Clonal Hematopoiesis
Influences Cardiovascular Risk."

that "protein X is a promising new
target for the treatment of Y." Nevertheless, are those promises actually
kept? A disturbingly high percentage of the nonclinical findings cannot be reproduced in the clinic.
How do you get it right? Today,
from 9:30 to 11:00 a.m., Dr. Ross
Levine will chair a session to attempt an answer, "What is the Best
Target?"
In it, Dr. Neil Shah will discuss
the activated kinases in the context
of AML. His lab at UCSF elucidated
one mechanism of resistance to the
FLT3 inhibitor quizartinib. He used
the FLT3 inhibitor AC220 (quizartinib) as a probe to validate the FTL3
internal tandem duplication (FLT3ITD) mutation as a driver mutation
in human AML. The observation
that three mutations in the FLT3
kinase domain arising de novo in
FLT3-ITD AML patients treated
with quizartinib monotherapy was
compelling evidence that FLT3-ITD
was indeed a driver mutation and
that the mutated resistant form of
FLT3 offered a "high-value" target for future drug development.
Further, resistance arose from both
on- and off-target mechanisms. Dr.
Shah makes it clear that understanding the contribution to clinical
resistance that on and off-target ef-

fects make will be the key to developing effective agents and combination regimens for AML.
The second speaker, Dr. Mark
Dawson, will focus on the epigenetic regulators of transcription that
lend themselves to therapeutic targeting in AML, in particular the bromodomain and extra-terminal (BET)
proteins that are recruited to acetylated histones. He has reported that
resistance to multiple BET inhibitors
is accompanied not by mutations in
the target or drug disposition but
to selection for a more immature
cell type and the up-regulation of
Wnt/β-catenin signaling sufficient
to maintain the expression of oncogenic proteins such as Myc, a prime
example of epigenetic plasticity in
the face of selection. Drilling down
deeper into BET biology, Dawson
and his collaborators used a method
that enabled labeling of distinct BET
inhibitors allowing them to trace the
variable genomic and tissue locations of the compounds as each interacted with BET family members
and different sites therein. Among
their findings, they also validate previous data showing that BET inhibitors target BRD4 located at enhancer
sites and that poor penetration into
bone likely explains the clinical failure of BET inhibitors in the treat-

ment of AML.
Dr. Kim Stegmaier will illuminate
a third pathway to the validation of
targets: analogical reasoning based
on what already works. She reviews
the history of acute promyelocytic
leukemia (PML or APL) and the
mechanism by which all-trans retinoic acid and arsenic trioxide do the
miraculous, cure. In essence, the two
drugs induce the degradation of the
mutant fusion oncoprotein PMLRARα allowing promyelocytes to
differentiate to a mature, post-mitotic state. Is differentiation therapy
feasible in non-APL AML? Agents
ranging from inhibitors of mutant
IDH1, DOT1L, and LSD1, all display
an ability to induce differentiation
of AML cells to more mature cells.
The challenge is to not only induce
proliferative cells to a more mature,
nondividing state but to nudge the
immature leukemic initiating cells to
do the same.
While these speakers do not provide the definitive answer to the
question of "What is the Best Target?" (for the treatment of AML),
their distinct approaches may
straighten out what has been a long
and winding road.

He shared with us the work of his
group in analyzing whole-exome
sequencing data for determining
the association with early-onset
myocardial infarction from two
retrospective case-control studies,
the Atherosclerosis, Thrombosis,
and Vascular Biology Italian Study
Group (ATVB) and the Pakistan
Risk of Myocardial Infarction Study
(PROMIS). Data were also analyzed
from Jackson Heart Study (JHS), the
Finland-United States Investigation
of Non-Insulin-Dependent Diabetes Mellitus Genetics (FUSION),
and the Framingham Heart Study
(FHS). Data from this international
collaborative effort were extremely
provocative and revealed that people with evidence of clonal hematopoiesis had a significantly higher
risk of coronary heart disease, early-onset myocardial infarction, and
coronary artery calcification. These
results were further validated with
the help of mouse models harboring these mutations, which recapitulated the same phenotype. To a
question about whether clonal hematopoiesis has a clinical role, Dr.
Ebert replied that there could be a
role in predicting risk and providing a prognosis for our patients, but
ultimately it would be great to use
this information to guide therapy

selection for patients, in an attempt
to eliminate the malignant clone.
Following this remarkable presentation, Dr. Andy Weyrich of the
University of Utah filled in for Dr.
E. Dale Abel of University of Iowa,
who was stuck in Detroit as more
flights to Atlanta were cancelled.
He gave us an excellent review of
Dr. Abel's work in the presentation titled "Sex Matters: The Hormonal Milieu Regulates Thrombosis." This was especially impressive
since he only had a couple of hours
to look at the slides and prepare the
presentation. He shared with us the
findings from Dr. Abel's lab regarding the observation of increased
mitochondrial
inner-membrane
protein optic atrophy-1 (OPA1) in
female patients, which was predictive of coronary artery disease and
diabetes, possibly through its impact on platelet aggregation. The
decreased risk of thrombosis was
also seen in female mice with selective platelet deletion of OPA-1
and this effect was reversed with
gonadectomy. Male mice, however, demonstrated a pro-thrombotic
phenotype which was reversed
by the transfer of platelets from
the OPA-1-deficient female mice.
These intriguing results suggest an
estrogen-dependent, OPA-1-medi-

ated platelet activation and provide
a possible explanation of gender
differences in cardiovascular risk.
We finished early, but that was
because we missed the presentation
by Dr. Alan Tall of Columbia University on "Lipids, Hematopoiesis,
and Athero-Thrombosis." We were
looking forward to hearing about
his interesting data about the role
of LNK mutations with cardiovascular risk and functional data that
demonstrate its association with increased proliferation of hematopoietic stem cells and increased megakaryopoiesis due to augmented
signaling by thrombopoietin. However, all of this will hopefully be for
another day and with much better
weather.
Despite the abridged session,
these presentations covered important advances in the field and
endeavored to consolidate our understanding of the role of hematopoiesis and cardiovascular disease.
The session also helped to identify
opportunities to perform impactful
research to improve outcomes of
cardiovascular disease and cancer
- two major causes of human morbidity and mortality.

Dr. Rienhoff indicated no relevant
conflicts of interest.

Dr. Awan indicated no relevant conflicts of interest.

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 2