ASH News Daily 2017 - Issue 1 - A-3

Saturday, December 9, 2017

ASH News Daily

Page A-3
®

R E D C E L L B I O L O GY

Blood Is Red, Genes Are Blue: They Are
Being Contrived, Don't You Wanna Know!
By Farrukh T. Awan, MD

ntoni van Leeuwenhoek is
credited with the discovery
of red blood cells (RBCs) in
1674 when he described them as
"pliant globules" with an ability
to change forms. This observation
arguably led to the development
of the field of hematology. We have
since come a long way, and our
understanding of the physiology
of RBC production and pathology
has expanded substantially. This
has been made possible by substantial contributions from many
outstanding individuals, including hematology stalwarts and former president of ASH and recipient of the inaugural ASH Lifetime
Achievement Award, Dr. Ernest
Beutler. The field continues to
grow at an exponential rate and
now employs novel genetic and
molecular methodology to further improve our understanding
of normal physiology, which has

been instrumental in the development of novel therapeutic options.
To provide further discourse on
this topic, we will have the opportunity to participate in an exciting
scientific session organized by the
Scientific Committee on Red Cell
Biology on Saturday at 9:30 a.m. in
Room B312-B314 of the Georgia
World Congress Center. The session "Editing and Enhancing
Erythropoiesis" will evaluate the
use of the latest gene editing tools
and single cell transcriptomics
and their utility in understanding
erythropoiesis and development
of various therapeutic approaches. The session will be chaired by
Dr. Merav Socolovsky of the University of Massachusetts Medical
School. Dr. Mitchell Weiss of St.
Jude Children's Research Hospital will discuss gene editing as a
therapeutic tool for hemoglobinopathies with a special emphasis
on beta-hemoglobinopathies. He
will be followed by Dr. Jian Xu of

University of Texas Southwestern
Medical Center, who will discuss
erythroid transcriptional enhancers and their 3-D interactions in
native chromatin. Finally, Dr. Janis L. Abkowitz of the University
of Washington will discuss the
exciting development of singlecell transcriptomics as a tool for
the study of erythropoiesis, with
a specific focus on therapeutic approaches for Diamond-Blackfan
anemia and 5q- myelodysplastic
syndrome.
What is guaranteed to be an
exciting and informative session
is scheduled again on Sunday at
9:30 a.m. in Room B312-B314 of the
Georgia World Congress Center.
So, come join us to gain incredible
insight on the genetic mechanisms
of erythropoiesis and latest engineering methods that are being
employed as therapeutic tools.

An ASH attendee stops at an
Alexa display in the registration
area (Hall A1) to ask a question.
Start by saying "Alexa, ask ASH
meeting..."

Dr. Awan indicated no relevant
conflicts of interest.

AMYLOIDOSIS

From Prose to Proteins: How One Seminal Textbook
Inspired a Lifelong Career
By Nina Shah, MD

t all started with a book written
by Dr. Jan Waldenström titled
Monoclonal and Polyclonal Hypergammaglobulinemia: Clinical and Biological Significance. "It was a book
that changed my life ... a book of
cases, clinical manifestations related to monoclonal proteins. It was a
clear will to understand the molecular basis of the clinical manifestations and that really attracted me."
So began the extraordinary career
of Dr. Giampaolo Merlini, presenter of this year's Ham-Wasserman
Lecture "AL Amyloidosis: From
Molecular Mechanisms to Targeted
Therapies."
Dr. Merlini's piqued interest led
him to pursue a fellowship under Dr.
Waldenström where he continued
to try to connect the dots between
protein structure and the morbidity of protein deposition. Under the
advisement of Dr. Waldenström, Dr.
Merlini pursued a research fellowship at Columbia University under
Dr. Elliott Osserman. Dr. Merlini
was originally planning to study the
antibody activities of monoclonal
proteins but was redirected by Dr.
Osserman to focus instead on AL
amyloidosis.

Though initially hesitant to pursue this unknown field of study, Dr.
Merlini eventually began to answer
some of the very questions that had
been his original driving force. He
found that fragments of light chains
that were present in the serum and
urine of patients with AL amyloidosis were identical to fragments
found in the disease-causing fibrils,
indicating the possible role of proteolytic remodeling. This discovery
ignited his specific interest in AL
amyloidosis, as now he could link
a molecular change with a clinical
outcome.
From these first encounters with
the disease, Dr. Merlini has built a
career on the understanding and
treatment of this mysterious condition. As will be outlined in this afternoon's talk, AL amyloidosis is a
unique variant of amyloid disorders
- the only one with a malignant
monoclonal cell at its origin. Ironically, it is the malignant root of AL
amyloidosis that allows for potential
treatment and, as Dr. Merlini will
discuss, potential early detection.
Dr. Merlini has worked tirelessly
to bring together investigators and
clinicians from around the world to
better understand this disease and
learn how best to prevent the clinical

demise that so many patients experience. He initially formed an Italian
network of AL investigators in 1986.
Thereafter, he established the European network and is now working
on an international consortium.
As will be showcased in his lecture, Dr. Merlini is also passionate
about early diagnosis. "The most
challenging aspect is to reduce early
death," He's stated. "Even nowadays we still lose approximately 30
percent of patients in the first six
to 12 months due to advanced cardiac damage due to late diagnosis.
It's very difficult to recover organ
function up to a certain point, so our
research is focused on improving
early diagnosis." He is an advocate
for following N-terminal pro-brain
natriuretic peptide levels, even in
patients with monoclonal gammopathy of unknown significance
(MGUS), as he believes that many
AL amyloid patients are MGUS patients with clinical manifestations
due to AL protein deposition.
When asked about the most exciting recent discoveries for AL amyloidosis, Dr. Merlini beams about
the effect of proteasome inhibitors,
and now, some promising data
with daratumumab. He feels these
agents are the "game-changers"

and looks forward to a time when
combination therapy may eradicate
the causative malignant clone in 80
percent of patients. These agents
will be complementary to the antifibril agents such as NEOD001,
which work on the actual protein,
versus the malignant plasma cell.
He also believes this multifaceted
approach will potentially accelerate
rate of organ recovery.
Though this is a challenging disease, Dr. Merlini's optimism is inspiring. It is based on years of steady
inquiry and discovery; more importantly, it is based on his clinical experience. "I still see patients because
they are a constant source of inspiration. Some of the most important
findings came from patient observations." After all this time, Dr. Merlini
can still say that these observations
motivate him to continue his pursuit
of understanding the molecular basis of this disease. "My dream is to
cure this disease of course, but it's so
simple to say...We are approaching
it now because we have a powerful drug to get rid of the malignant
clone." This is a vision as inspiring
as the book from where it arose.
Dr. Shah indicated no relevant conflicts of interest.

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 1