The Microenvironment, Spring 2014

16 Pages·2014·4.91 MB·English

THE CANADIAN
HEMATOLOGY
SOCIETY
March 2014 NEWSLETTER
SOCIÉTÉ
C H CANADIENNE
H C
S D’HÉMATOLOGIE
Inside this Issue…
You will not be

charged a fee, but
President’s Message 1
Please register
Meet the new CHS Executive Board 2 by email RSVP

Welcome! CHS meets in Canada 3
Information inside:
Do you know the Diagnosis? 4
pages 3 & 12
Acknowledging Our Sponsors 5
Kennedy wins 2013 Crookston Award 5
2013 CHS Research Award Winners 6

History Corner: “Noble” Legacies 8
MINI REVIEW: Dr. Thomas Nevill 9
- Lymphedema in the context The past presidents of as the editor of the Microenvironment
of bone marrow failure the Canadian newsletter.

ASK THE HEMATOLOGIST 10 Hematology Society
Dr. Gail Rock remains a linchpin in the
- A new case of CML (CHS) include many
Society in her role as Executive Vice
Canadian hematology
Choosing Wisely Canada 12 President. I am thankful for the all of time
giants and I am
and effort our executive members devote to
privileged and humbled
Upcoming Events 13 the CHS. We are also fortunate to have
to follow in their
Jean and Lisa in our CHS head office.
Fellowships 14 footsteps as I assume the
Along with Dr. Rock, they are the glue that
presidency of the CHS.
Membership Matters 16 holds the Society together and keeps us
Dr. Aaron Schimmer First, I would like to moving forward.
President, Canadian thank our out-going
Over the next several months, the CHS will
2013 CHS Executive Committee Hematology Society president, Dr. Stephen
make a formal bid to host the 2018 ISH
Couban, for his hard
meeting in Vancouver. The bid process is
President Dr. Aaron Schimmer work and contributions to the CHS. Under
being spearheaded by Drs. Nevill and Rock
Past-President Dr. Tom Nevill
Stephen’s leadership, the CHS has embarked
Vice-President Dr. Lynne Savoie and early feedback from the ISH selection
on a number of new and exciting initiatives
Secretary Treasurer Dr. Molly Warner committee is encouraging. Hosting ISH
including re-establishing a Canadian
Executive Vice-President Dr. Gail Rock will be a significant honor and provide an
hematology meeting that will occur in June
opportunity to highlight the great
Editor: Microenvironment Dr. Tom Nevill 2014 and initiating a bid to host the 2018 hematology research being conducted in this
meeting of the International Hematology
country.
Society (ISH) in Vancouver. I look forward
Canadian Hematology Society
199—435 St. Laurent Blvd. to working with Stephen to bring these events Canada will also be hosting other major
Ottawa, ON K1K 2Z8 CANADA to fruition. international hematology meetings in the
Phone: [phone] next few years. For example, the
I would also like to extend a warm welcome
Website: canadianhematologysociety.org International Society for Hematology and
to Dr. Lynne Savoie who is our in-coming
Email: [email protected] Stem Cells will be held in Montreal in
Vice President. I am grateful that Dr. Molly
August of 2014 and the International
Warner continues to serve as our treasurer
Society for Thrombosis and Hemostasis
and secretary and Dr. Tom Nevill continues
continued, page 2
Page 2
will take place in Toronto in 2015. For example, I think the CHS can play a
leading role in collecting and
Canadian hematologists are leading the
communicating available hematology
organization of these meetings. In this
practice opportunities in the country.
issue of the Microenvironment, you can
Identifying open hematology positions
read more about these conferences and
in Canada, is an important step to
the roles of our CHS members in
determine hematology resources and
organizing these meetings. If you are
needs in the country. President
organizing similar meetings of

potential interest to Canadian These data, along with population trends

hematologists, you are encouraged to and projections, will help address the
Dr. Aaron
send us notices. question of how many hematologists do
Schimmer
we need and where are they needed.
Supporting research by hematology
Over the next few months, we will begin
trainees and junior faculty remains a
the process to collect this information.
priority of the CHS. We continue to
provide research awards related to We will be asking you to help identify
abstracts presented at ASH. In addition, open hematology practice opportunities
we offer small research grants in the in your community and hospital. Your
form of the R.K. Smiley awards. response is critical for our new
Past-President
hematology colleagues who are starting
With grant funding becoming ever
their careers.
tighter, we hope this funding will
support exciting and important Canadian I hear frequently about the anxiety Dr. Stephen
hematology research. among current and prospective Couban
hematology trainees who are concerned
In the 2014 competition, we received 25
about career opportunities upon
applications spanning the breadth of
completion of training. By helping us
hematology, including benign,
identify and communicate open
malignant, and laboratory hematology.
hematology positions, you will be
We received applications related to offering tremendous assistance to our
clinical, translational and fundamental new hematology colleagues.
Vice-President
hematology research. The review of
In addition, highlighting open
these applications is underway and the
hematology positions and fellowship
award recipients will be featured in the
opportunities will also help recruit the Dr. Lynn
next edition of the newsletter.
best and brightest medical students and Savoie
Over the next two years, we will also internal medicine residents to our field.
embark on new initiatives to promote
In closing, I would like to thank you for
Canadian hematology research and
your continued commitment to the CHS
details will be forthcoming in the future
and the hematology community in
editions of the Microenvironment.
Canada.
In February, I had the opportunity to
Your membership dues sustain the
represent the CHS at the National Secretary
educational and research activities of the
Employment Summit organized by the Treasurer
Society and allow CHS to be a hub for
Royal College Physicians and Surgeons
hematology in the country. For those
of Canada.
who may not be members yet, I would
Dr. Margaret
This meeting addressed issues of encourage you to visit our website
Warner
physician human resources and (www.canadianhematologysociety.org)

physician underemployment with the and learn more about the benefits of
long-term goal of optimally aligning membership.
physician resources to ensure an
However, membership dues alone do not
adequate supply and distribution of
cover the full operating costs, and we are
physicians to meet the needs of our
very grateful for our Gold, Silver and
country in a fiscally responsible manner. Executive
Bronze industry partners.
It became clear through this meeting that Vice-President
achieving this goal will require an You will see their logos and names in
understanding of the current and future the Microenvironment. When you meet
needs of physician resources in Canada. the representatives of these companies, I Dr. Gail Rock
It was also evident that the national ask you to thank them for their support
of the CHS.
specialty societies, such as the CHS, will
have a critical role to play in this
process.
Page 3
Dear Colleagues, meeting in Canada. In addition
to the CBMTG and CHS, a Friday June 13, 2014
As announced at the CHS
number of other Canadian 9:00 am to 3:45 pm
Reception at ASH, many of you
hematology groups are meeting The Westin Nova Scotian—Halifax, NS
will know that the CHS and the
in Halifax on June 13, 2014
Canadian Blood and Marrow
PROGRAM
including the Canadian Apheresis
Transplant Group (CBMTG) are
Group (CAG), VECTOR (a group 8:45—9:00 am Welcome
hosting a combined symposium
of hematologists with interest in
in Halifax on Friday June 13, 9:00—10:00 am Dr. Neal Young
research in thrombosis) and the The Diagnosis and Treatment of
2014. I sincerely hope you will
CNTRP (a research group of Severe Aplastic Anemia
consider attending!
clinicians and scientists from the
Years ago until 1999, Canadian solid organ and BMT fields). 10:00—11:00 am Dr. Sudeep Shivakumar &
Dr. Marc Carrier
hematologists gathered together
At both the CHS and CBMTG, we Thrombosis Challenges in Patients
in Canada during the Royal
with Hematologic Malignancies
welcome you to this meeting and
College meeting to present data
hope that that this meeting will
and discuss issues of relevance. 11 am—noon Dr. Danièle Marceau
become a new Canadian
Then, for eight years the CHS Paroxysmal Nocturnal Hemoglobinuria
very successfully organized an tradition!
2:30 pm —3:15 pm Dr. Paul Moorehead
annual symposium in conjunction Please join us and have the
Hemophilia treatment: “In the Clinic
with a previous CBMTG or other members of your teams,
and In the Future”
subspecialty groups. including your trainees join us as
well! 3:15 pm—3:45 pm Dr. Eiad Kahwash
This year, after an eight year
Single Unit Transfusion
hiatus, I am very pleased to Stephen Couban, Chair
announce that we are again Scientific Organizing Committee
planning a Canadian hematology Registration Details, Page 12

Les anciens présidents de la Société canadienne nos membres exécutifs dévouent à la SCH. De dans leur organisation, dans cette publication du
d’hématologie (SCH) inclus plusieurs géants d’hé- plus, nous sommes chanceux d’avoir Jean et Lisa Microenvironnement. Si vous organisez des ren-
matologie et je suis privilégié et humble de suivre au bureau de la SCH. Travaillant avec Dr. Rock, contres semblables, d’intérêt potentiel aux hémato-
dans leurs pas en assumant la présidence de la elles gardent la société ensemble et aident à conti- logues Canadiens, vous êtes encouragés de nous
SCH. Premièrement, j’aimerais remercier notre nuer le cheminement en avant. contacter.
président départant, Dr. Stephen Couban, pour son
Pendant les prochains mois, la SCH va soumettre L’appui pour la recherche des stagiaires en héma-
travail et ses contributions à la SCH.
une proposition formelle pour accueillir la rencontre tologie et la faculté junior, reste une haute priorité
Sous la dirigeance de Stephen, la SCH s’est em- de la Société internationale d’hématologie (SIH) à pour la Société canadienne d’hématologie.
barquée sur un nombre d’initiatives nouveaux et Vancouver, en 2018. Dr. Nevill et Dr. Rock sont en
Nous continuons de fournir des prix de recherches
excitants incluant le rétablissement de la rencontre tête du processus de soumission et la rétroaction
reliés aux sommaires présentés à ASH. De plus,
annuelle d’hématologie qui va avoir lieu en Juin du comité de sélection est encourageante. Ac-
nous offrons des petites bourses de recherches R.
2014 ainsi que l’initiation d’une proposition pour cueillir la SIH sera un grand honneur et va fournir
K. Smiley. Avec des bourses de recherches de
accueillir la rencontre de la Société internationale une opportunité de surligner la recherche formida-
plus en plus difficile à obtenir, nous espérons que
d’hématologie à Vancouver en 2018. J’espère ble qui se déroule dans ce pays.
ces bourses fourniront des recherches importantes
travailler avec Stephen pour continuer le progrès
Le Canada va aussi accueillir d’autres majeurs dans le domaine d’hématologie au Canada. Dans
sur ces évènements.
rencontres internationales d’hématologie dans les la compétition en 2014, nous avons reçu 25 appli-
J’aimerais aussi faire un accueil chaleureux à Dr. prochaines années. Par exemple, la rencontre de cations étendue largement dans l’hématologie,
Lynne Savoie qui est maintenant notre nouvelle la Société internationale d’hématologie et Cellules incluant l’hématologie, bénin, malin et laboratoire.
vice-présidente. Je suis reconnaissant que Dr. souches sera à Montréal en Août 2014 et la Socié- Nous avons reçu des applications reliées à la
Molly Warner continue de servir comme trésorière té internationale de thrombose et hémostase aura recherche hématologique clinique, translative et
et secrétaire et Dr. Tom Nevill qui continue comme sa rencontre à Toronto en 2015. Certains hémato- fondamentale. La revue de ces applications est en
éditeur de la publication Microenvironnement. logues seront en tête de l’organisation de ces marche et les lauréats seront inclus dans la pro-
rencontres. chaine édition de la publication. Pendant les pro-
Dr. Gail Rock continue comme pivot dans la socié-
chains 2 ans, nous allons aussi embarquer sur des
té dans son rôle de vice-présidente exécutive. Je Vous pouvez en lire plus sur ces conférences, ainsi
nouvelles initiatives pour promouvoir la recherche
suis reconnaissant pour tout le temps et l’effort que que sur le rôle que nos membres de la SCH ont
hématologique Canadienne et plus de détails se-
continue, page 2
Page 4
ront disponibles dans des publications futures du population et des projections, vont aider à adresser matologie. De plus, surligner les positions ouvertes
Microenvironnement. la question de combien d’hématologistes que l’on a en hématologie et les opportunités postdoctoraux
besoin et où on en a de besoin. va aussi aider à recruter les meilleurs étudiants en
En février, j’ai eu l’occasion de représenter la SCH
médecine et résidents de médecine interne à notre
au Sommet national sur l’emploi des médecins Au courant des
domaine.
organisé par le Collège royal des médecins et prochains quel-
chirurgiens du Canada. ques mois, nous Pour conclure, j’aimerais vous remercier pour votre
allons commencer support continu de la SCH et la communauté d’hé-
Cette rencontre a adressé la question des ressour-
le processus de matologie au Canada.
ces humaines et sous-emploi de médecins et avait
collectionner cette
comme bût d’aligner, à long terme, les ressources Vos cotisations soutien les activités éducatives et
information. Nous
de médecins pour s’assurer une provision adéquate de recherche de la société et permet à la SCH
allons vous de-
et la distribution de médecins pour rencontrer les d’être le pivot pour l’hématologie au pays. Pour
mander de nous
besoins de notre pays avec une bonne responsabi- ceux qui ne sont pas encore membre, je vous en-
aider à identifier
lité fiscale. courage à visiter notre site web
des emplois ou-
(www.canadianhematologysociety.org) pour ap-
C’est devenue clair à la rencontre qu’obtenir ce bût verts en hématolo-
Aaron Schimmer prendre à propos des avantages de devenir mem-
va nécessiter une compréhension des besoins gie dans votre
Président SCH bre.
immédiats et futurs des ressources de médecins au communauté et
Canada. C’était aussi évident pendant cette ren- vos hôpitaux. Cependant, les cotisations elles-mêmes ne cou-
contre que les sociétés spéciales nationales, tel vrent pas tous les coûts d’opérations, et nous som-
Votre réponse sera critique pour nos nouveaux
que la SCH, va avoir un rôle important à jouer dans mes très reconnaissants pour les associations
collègues en hématologie qui débutent leurs carriè-
ce processus. Par exemple, je crois que la SCH partenaires au niveaux Or, Argent, et Bronze. Vous
res. J’entends fréquemment à propos de l’anxiété
peut jouer un rôle principal à collectionner et com- allez voir leurs logos et noms dans le Microenviron-
auprès des stagiaires en hématologies, courants et
muniquer des opportunités d’emplois en hématolo- nement. Lorsque vous rencontrez les représen-
prospectifs, qui sont inquiet à propos de leurs pos-
gie dans le pays. tants de ces organisations, je vous demande de les
sibilités d’emplois après la complétion de leurs
remercier pour leur support de la SCH.
Un pas important pour déterminer les ressources et stages.
besoins hématologiques dans le pays est d’identi- En nous aidant à identifier et communiquer des Aaron Schimmer, Président
fier des positions ouvertes de positions en hémato-
positions ouvertes en hématologie, vous allez offrir
logie. Ces données, ainsi que des statistiques de
énormément d’assistance à nos collègues en hé-

A 23-year-old woman presented with a 2-week history progressive abdominal and lower extremity
swelling with associated fatigue and an 8 kg weight loss.
 A CBC showed a hemoglobin of 62 g/L, a WBC of 16.5 x 109/L and platelets of 70 x 109/L.
 Chemistry revealed: potassium of 3.2 mmol/L, normal serum creatinine of 95 umol/L, uric acid 450 umol/L (upper normal 360),
alkaline phosphatase of 643 U/L (upper normal 125), GGT 400 U/L (upper normal 65), total/direct bilirubin of 84/60 umol/L and an
LDH of 260 U/L (upper normal 240).
 CT scan showed extensive lymphadenopathy in the neck, axillae, mediastinum, mesentery and pelvis as well as
hepatosplenomegaly, marked ascites and peritoneal seeding.
 Peripheral blood and bone marrow examinations are shown in Figures 1 and 2, respectively. Do you know the diagnosis?
… SEE PAGE 14
Figure 1 Figure 2
Page 5
 Dr. James Kennedy cytogenetic risk group.
 University of Toronto
Xenografts were generated in only 4/30
 Supervisor: Dr. Jean Wang
patients (13%) with favourable karyotypes,
63/153 patients (41%) with intermediate-
NOD.SCID xenotranspantation assays are
risk karyotype and 23/43 patients (53%)
a powerful tool for studying the biology of
with adverse karyotypes (p=0.002).
acute myeloid leukemia (AML).
Furthermore, in normal karyotype AML
The investigators transplanted peripheral patients, FLT3-ITD-positive patients
blood or bone marrow cells from 307 AML established xenografts in 50% of samples
patients into sublethally irradiated compared to 27% of FLT3-ITD-negative
NOD.SCID mice and were able to achieve cases (p=0.04).
myeloid engraftment in 134 cases (44%).
Clinical outcome was shown to be closely
This included 40% of samples taken at correlated with ability to generate Dr. James Kennedy, LEFT, University of Toronto,
AML diagnosis and 66% of samples taken xenografts with only ~50% of patients accepts the 2013 John H. Crookston Award at the
at AML relapse although only 2 patients entering complete remission if their
2013 CHS Annual Awards Dinner in New Orleans.
failed to generate a graft at diagnosis but samples produced engraftment compared
Presenting the award is CHS Past-President, Dr.
did generate a graft at relapse. with 80% of patients with non-engrafting
Stephen Couban, who completed his two-year term
samples (p <0.0001). This resulted in a
Engraftment was associated with a higher as President at the meeting, immediately preceding
difference in both event-free and overall
WBC count (p=0.01) but, most striking was the 2013 Awards Dinner, December 7, 2013 in New
survival between the two groups (p
the correlation of engraftment with Orleans. Looking on is Dr. Molly Warner, Secretary-
<0.0001).
Treasurer of the CHS.
The authors have convincingly demonstrated that the ability to engraft NOD.SCID mice with cells from an AML patient does correlate with clinical
outcome. However, further work is needed to provide insight into the underlying determinants of this engraftment ability and to clarify if the engraftment
behaviour is truly an independent prognostic indicator in AML. -ed.
 Alexion Pharma Canada
 Celgene
 Lundbeck
 Janssen
 Sanofi
 Pfizer
 Roche
 Bayer
 Octapharma
 Bristol-Myers Squibb
 Baxter
 CSL Behring
 Amgen
Page 6
Normal range of bleeding scores for the ISTH-BAT: adult and
pediatric data from the merging project

 Dr. Malak Elbatarny ISTH-BAT have not been determined and this study
sought to establish the normal range for this tool in both
 Queens University, Kingston, ON
adult and pediatric patients.
 Supervisor: Dr. Paula James
The investigators compiled bleeding score data from
Standarized quantitative bleeding different studies that utilized Vicenza-based BATs using a
assessment tools (BATs) are utilized specifically created bioinformatics system. The proposed
to report hemorrhagic symptoms and normal ranges were then determined by removing outliers
the International Society on (> 3 standard deviations from the mean) and then selecting
Thrombosis and Hemostasis (ISTH) the mid-95th percentile.
assessment tool (ISTH-BAT) was
The authors analyzed demographic and bleeding score
introduced in 2010 to consolidate and
data on 1079 adult (mean age 43 years) and 343 pediatric
optimize previously described BATs,
(mean age 9 years) subjects.
including the Vicenza Bleeding
Questionnaire. Normal ranges for the ISTH-BAT were established as 0-4
Dr. Malak Elbatarny in adults and 0-2 for children less than age 18 years of age.
However, the normal ranges of the
This study definitively established normal ranges for the ISTH-BAT, a critical step in objectively assessing bleeding
symptoms. This should aid researchers in investigating the correlation between bleeding symptoms and genotypic,
molecular and environmental data. -ed.
Genomic rearrangements involving programmed death ligands are
recurrent in primary mediastinal large B-cell lymphoma
 David Twa, MSc analysis on 551 clinical samples [125 PMBCL patients,
134 nodal diffuse large cell lymphoma patients (DLBCL),
 British Columbia Cancer Agency, Vancouver, BC
130 primary CNS DLBCL patients, 82 testicular DLBCL
 Supervisor: Dr. Christian Steidl and 80 other lymphoma patients] and 20 established cell
Primary mediastinal large B-cell lines. FISH analysis revealed that 20% of the PMBCL
lymphoma (PMBCL) is an samples were positive for one of the two PDL genes,
aggressive malignancy typically seen significantly more than in any other lymphoma (p <0.05).
in young woman. This compared with 1% in CNS DLBCL, 3% in nodal
Analysis of genomes and DLBCL and 7% in testicular DLBCL; none of the other
transcriptomes have highlighted lymphomas were positive for a PDL FISH abnormality.
inactivating mutations of TP53, Further analysis revealed PDL locus amplification in
amplification of chromosome 9p and 45/125 (36%) of PMBCL samples.
chromosomal translocations
Following analysis of whole genome and whole RNA
involving CIITA as being linked to
David Twa transciptome libraries, the authors were able to
the pathogenesis of PMBCL.
characterize four novel fusion transcripts involving 9p24.1
The researchers decided to explore the link between two locus found in one clinical case and three PMBCL cell
programmed death ligands located at 9p24.1, PDL1 and lines.
PDL2, and PMBCL. They performed break-apart FISH
This interesting study suggests that rearrangements involving the PDL locus are recurrent and relatively unique
to PMBCL, leading to overexpression of PDL transcripts. This may well provide a therapeutic avenue to explore
in this particular malignancy. -ed.
Page 7
Determining cell-of-origin subtypes in diffuse large B-cell
lymphoma using gene expression profiling on formalin-fixed
paraffin-embedded tissue – an L.L.M.P.P. project

training cohort and 68 in a validation
 Dr. David Scott
cohort) that had previously had COO
 British Columbia Cancer Agency, Vancouver, BC assigned by gold-standard frozen-GEP
 Supervisor: Dr. Randy Gascoyne analysis; all but 3 samples provided
gene expression data of sufficient
The cell-of-origin (COO) can separate diffuse large B-cell
quality. COO was assigned in parallel
lymphoma (DLBCL) into germinal centre B cell (GCB)
at two different sites, the BCCA in
and activated B cell (ABC) subtypes based upon
Vancouver, BC and the NCI in
molecular characteristics.
Frederick, Maryland and showed 98%
With new therapeutic agents being developed with concordance.
selective activity against GCB and ABC DLBCL, this Dr. David Scott
The COO for all gold-standard GCB
study sought to create a robust and accurate molecular
cases was 100% concordant when tested with NanoString
gene expression profile (GEP) assay (using a NanoString
on FFPET. ACB DLBCL samples were correctly
technology 20 gene assay) that could be applied to
assigned in 93% of cases using the same NanoString
formalin-fixed paraffin-embedded tissue (FFPET). The
technology.
investigators examined 119 cases of DLBCL (51 in a
This study demonstrates that accurate and rapid classification of COO is possible for DLBCL cases at diagnosis
using routinely obtained FFPET. The value of this testing will depend upon the development of COO-specific
therapy in DLBCL. -ed.
Epidemiology of post-transplant lymphoproliferative disorders fol-
lowing solid organ transplant in a major Canadian transplant centre
 Dr. Anthea Peters years had the highest risk of early

PTLD, perhaps because there was an
 University of Alberta, Edmonton, AB
increased risk of early PTLD in EBV-
Post-transplant lymphoproliferative disorder (PTLD) can negative recipients receiving organs
be a serious early or late complication in patients that from EBV-positive donors.
undergo solid organ transplantation (SOT).
Furthermore, the highest risk of early
This project involved the review of over 4500 patients that PTLD was in patients transplanted
underwent SOT between 1984 and 2011 and identified between 1984 and 1991 and the lowest
133 cases of PTLD. risk in patients transplanted in the last
decade of the study.
The PTLD cohort included 61 cases that were classified as Dr. Anthea Peters
“early” (< 2 years after SOT), 31 cases as “late” (2-7 Multivisceral SOT and lung
years after SOT) and 39 cases as “very late” (> 7 years transplantation conferred the highest risk of PTLD,
after SOT). particularly late PTLD, and kidney transplant recipients
had the lowest risk of any PTLD.
The cumulative incidence of PTLD was 2.6% at 5 years,
4.3% at 10 years and 7.9% at 20 years. Patients aged 0-5
This study provides an excellent retrospective overview of PTLD in the SOT setting. The cumulative incidence of
PTLD is significant following SOT although it is decreasing with time and is dependent upon recipient age, EBV
serostatus and organ transplanted. -ed.
Page 8

Robert L. Noble and E. Clark Noble were In October 1923, Banting and, somewhat together they isolated and purified a potent
brothers born into a prominent medical family, ironically, J. J. R. MacLeod were awarded the alkaloid extract in 1958 that they called
Robert (b. February 3, 1910), 10 years junior to Noble Prize for the discovery of insulin. “Vinblastine”.
Clark (b. December 29, 1900).
Clark Noble went on to spend the summer of The team worked with Eli Lilly Co. to develop a
1923 evaluating the feasibility of using fish as a small supply of Vinblastine for clinical trials, with
commercial source of insulin. the first occurring at Princess Margaret Hospital
in Toronto in 1959.
He did extensive work in the cod fish industry
but ultimately, evidence began to accumulate Vinblastine and a related vinca alkaloid,
that large-scale production of fish insulin was Vincristine, both went on to become mainstays
impractical. of chemotherapy in a number of different
cancers, especially lymphoblastic leukemia and
Charles Best and Clark Noble disagreed on
lymphoma.
this point and, not surprisingly, the former had
a long and distinguished career in medical In honour of
research while the latter became a GP in this ground-
Toronto. bre ak i n g
discovery,
Major contribution to hematology
Their father, Robert T. Noble, was a GP who The National
served as president of the Ontario Medical It was a result of his ongoing interest in diabetes C a n c e r
Association, the Canadian Medical Association, that led to Clark and his brother Robert to make Institute of
the College of Physicians and Surgeons of a major contribution in the field of hematology. C a n a d a
Ontario and the Medical Council of Canada. subsequently
In 1952, a patient of Clark Noble’s visited
Clark Noble entered University of Toronto in named its
Jamaica and collected 25 leaves from the Dr. Robert L. Noble
1918, majoring in physiology and biochemistry. m o s t
Madagascar periwinkle plant (Vinca rosea),
He would go on to medical school and prestigious award for excellence in research the
which was commonly made into a tea to treat
graduated with honours in 1925. Robert L. Noble Prize.
patients with diabetes, and sent it to him in an
A brush with fame envelope. Clark was no longer involved in Robert L. Noble became the Director of Cancer
research and had no facilities to test the leaves Research and Professor of Physiology at the
However, he had his first brush with fame that
for medicinal value so, he sent the envelope to University of British Columbia in 1960. He
began with his undergraduate classmate and
his brother, Robert. was a skilled experimentalist and his research
best friend, Charles Best, and both were
generated more than 200 publications.
talented semi-pro baseball players. Robert L. Noble graduated from University of
Toronto Medical School in 1934 before pursuing He retired in 1975 but continued his research as
Clark Noble and Charles Best began work as
a PhD at the University of London in England. an honorary member of the Division of Cancer
summer students in J. J. R. MacLeod’s
Endocrinology at the BC Cancer Agency until his
laboratory in 1921 and were joined by a young In another twist of irony, he returned to Canada
death on December 11, 1990. In 1997, Dr.
surgeon, Frederick Banting. It was decided (by in 1937 and began to work with Dr. J. B. Collip
Robert L. Noble was inducted into The
a coin toss!) that Best would assist Banting for who, by now, was studying endocrine-related
Canadian Medical Hall of Fame along with Dr.
the first month and Noble for the second. cancers at McGill University.
Charles Beer.
In an experiment that Macleod was skeptical In 1947, he became the Associate Director of
Dr. E. Clark Noble continued his interest in fish
about in the first place, Banting and Best the Collip Medical Research Institute at the
insulin and was interviewed by the Toronto Star
performed canine pancreatectomies, made University of Western Ontario.
in 1974 during an impending insulin shortage.
extracts, injected them into diabetic dogs and
With the arrival of the envelope of leaves sent Despite his assurances, “…we’ve done all the
measured blood glucose levels.
by his brother Clark, Robert began studying the work on it and its already to go, if anyone is
Dr. J.B. Collip was brought in to help purify the effects of the leaf extracts on blood glucose interested…”, commercial supply of fish insulin
extracts but left in a dispute with Banting. Clark levels. never came to pass.
Noble’s month of assistance never came to be
It turned out that the leaf extracts had little effect Dr. E. Clark Noble died on May 18, 1978 and
and Best was subsequently put in charge of
on glucose levels but did have inhibitory effects while there was no mention of his passing in the
insulin production in Toronto. Nevertheless,
on white blood cells and the bone marrow. CMAJ at the time, an article did appear on his
Clark Noble’s laboratory efforts contributed to
life and brushes with fame in December 2002.1
the rapid increase in knowledge about insulin in Vinblastine isolated and purified
the months after its discovery and co-authored 1 Wright J.R. Almost famous: E. Clark Noble,
In 1954, Charles T. Beer, an organic chemist,
10 early papers on this hormone between 1922 the common thread in the discovery of insulin
and 1925. joined Robert Noble’s research team and and vinblastine. CMAJ 167:1391-1396, 2002.
Page 9

Dr. Thomas Nevill, Professor their differentiation as well as in the regulation of termination of GATA2 gene translation.9
tissue and alveolar macrophages.2 Murine
University of British Columbia As this exciting new work was unfolding in North
experiments show that GATA2 mutations, when
America, the UK Lymphoedema Consortium
Vancouver, BC homozygous, are fatal during gestation and,
was making progress of their own in
when heterozygous, induce stem cell apoptosis
understanding the link between MDS and
thereby reducing absolute stem cell numbers.4
lymphedema by describing 7 new cases of
A 32-year-old woman is referred with a
The GATA2 gene is located at 3q21.3 and its autosomal dominant AML with lymphedema
mild, non-progressive pancytopenia first protein product consists of two DNA-binding zinc (“Emberger syndrome”).10 These case had some
identified at age 14 when she presented finger domains (ZF) and four flanking sequences common and interesting features – close set
with idiopathic lymphedema of the left [two transactivation domains (TAD), a nuclear eyes, epicanthic folds, web neck, long tapering
lower extremity. localization signal (NLS) and a negative fingers, preceding MDS (often with monosomy
regulatory domain (NRD)] (Figure 1).5 7), recurrent cellulitis in the affected limb and
She had three bone marrow
generalized warts. Concurrent with the
GATA2 mutations were first shown to play a role
examinations over the subsequent two
discovery of GATA2 mutations as underlying
in hematologic disease in a CML patient with
decades which showed increasingly MonoMAC syndrome was a publication from the
blast phase transformation.6
prominent trilineage dysplasia but no Consortium clearly linking the AML/lymphedema
increase in blast cells and a normal The key breakthrough in the linking of GATA2 disorder with similar GATA2 mutations.11
mutations to hematologic disorders was an
female karyotype.
The publication of these two seminal papers in
abstract presented at the American Society of
She reports a several year history of Hematology Annual Meeting in 2010. This September 2011 led to a better understanding of
the spectrum of diseases that can be linked to
severe warts on her hands and feet as paper described four families with autosomal
GATA2 mutations, shown
well as frequent respiratory tract
diagrammatically in Figure 2. It is
infections.
now clear that GATA2 mutations
Current blood work reveals a mild may manifest as recurrent non-TB
neutropenia an absolute lymphopenia mycobacterial/fungal infections
(due to the monocytopenia)
and monocytopenia.
associated with sinopulmonary
An association bacterial infections/alveolar
between myeloid proteinosis (due to alveolar/tissue
malignancy and macrophage dysfunction) – the
Figure 1. GATA2 protein structure
i d i o p a t h i c dominant MDS/AML that were shown to have MonoMAC phenotype.8 However,
lymphedema was these same identical mutations may produce
mutations in the second zinc finger of the
first observed by GATA2 gene.7 This report followed on a Emberger syndrome (lymphedema, cellulitis and
Emberger in 1979,1 panniculitis), dendritic cell-monocyte-B/NK
publication earlier that year from the National
although a Institutes of Health in Bethesda, MD describing lymphoid (“DCML”) deficiency syndrome
pathogenetic link a novel condition, MonoMAC syndrome, an (papillomavirus and EBV infections with
was initially elusive. associated anogenital malignancies), familial
autosomal dominant and sporadic
Not surprisingly, monocytopenia with a predisposition to MDS/AML (without any other associated
Dr. Thomas Nevill progress in papillomavirus, fungal and non-tuberculous manifestations), all with considerable potential
molecular genetics for overlap, and even an apparently normal
mycobacterial infections.8 Researchers at the
provided the impetus that has led to a better NIH, who were searching for a causative gene, phenotype.12 The common hematologic link for
understanding of the connection between these
were intrigued by the Scott abstract and began
two uncommon disorders. …. continued, page 10
examining their
The GATA gene family is a group of six zinc patient cohort for
finger-containing transcription factors found in G A T A 2
multiple tissues. GATA1, GATA2 and GATA3 mutations. They
are primarily expressed in hematopoietic tissue quickly identified
and are lineage specific; GATA1 is expressed in that all of those
erythroid cells, eosinophils and megakaryocytes affected with
and GATA3 is expressed in T-cells.2 GATA1 M o n o M A C
has been linked to hematologic disease and syndrome had N
mutations of this gene are seen in acute - t e r m i n a l
megakaryocytic leukemia and the transient m u t a t i o n s
myeloproliferation seen in Down syndrome.3 around the two
zinc fingers
GATA2 (short for GATA-2 binding protein) is
leading to
expressed in hematopoietic stem cells and
prem at ure
myeloid progenitors and plays a critical role in
Page 10

Dr. Brian Leber, Professor How should this patient be managed?
McMaster University, Hamilton, ON

and
CML is a rare disease with an incidence of 1-
Dr. Christopher Hillis, Hematology
2 cases per 100,000 people per year. It is
Fellow, McMaster University
characterized by the obligatory presence of a

reciprocal chromosomal translocation t(9;22)
A 58-year-old man presents with a 3 month
(q34;11) that leads to fusion of the ABL gene
history of fatigue, night sweats and left
from chromosome 9 and the BCR gene from
upper quadrant pain.
chromosome 22. The resulting Philadelphia
He has a history of having had a chromosome (Ph) produces the BCR-ABL1
myocardial infarction 5 years previously at fusion protein with dysregulated tyrosine
which point he was found to have kinase activity mediating the leukemic
hypertension and hypercholesterolemia. phenotype.
His CBC shows a Hemoglobin of 102 g/L, The diagnosis of CML is confirmed by
WBC of 156 x 10e9/L with a left shift cytogenetically identifying the Ph
including 2% blasts and a platelet count of chromosome in the bone marrow; potentially
769 x 10e9/L. along with other karyotypic abnormalities that
Physical examination reveals a spleen that may have prognostic significance. Staging Dr. Christopher Hillis, Hematology
is 8 cm below the left costal margin. (phase) is based on blast percentage in the Fellow, McMaster University
blood and marrow, degree of basophilia,
Bone marrow examination shows 100%
platelet count, and presence of determined by clinical scoring systems (i.e.
cellularity with eosinophilia, 9% basophils
extramedullary blast proliferation. Patients are Sokal, Hasford, and EUTOS). The EUTOS
and 3% blast cells.
diagnosed as chronic phase (CP), score is based on prognosis with imatinib
Cytogenetics reveal t(9;22) in all 50 accelerated phase or blast phase. Prognosis therapy and is appropriate for this context to
metaphases analyzed. is largely determined by stage; however, in
chronic phase prognostic information is …. continued, page 11
…. Continued from page 9 area of treatment, with prevention of infection GATA2 mutations appear to play an important
this spectrum of diseases is bone marrow failure through prophylaxis and immunization and the role in the pathogenesis of a number of
with a predisposition to develop hypocellular use of stem cell transplantation to treat the overlapping clinical syndromes characterized by
MDS/AML with monosomy 7 or trisomy 8 associated bone marrow failure.13 predisposition to MDS/AML, lymphedema and
(although even chronic myelomoncytic leukemia recurrent infections.
There have also been important developments
has been seen in patients with GATA2
in understanding the pathogenesis of the Evidence is accumulating that GATA2 mutations
mutations).12
lymphedema and MDS/AML combination. An lead to a disturbance in the VEGFR3 signalling
Following the description of the GATA2 mutation abnormality in vascular endothelial growth factor pathway, resulting in both bone marrow failure
-related disease spectrum, subsequent research (VEGF) has long been suspected as a unifying and lymphatic endothelial cell dysfunction.
has focused on treatment and attempting to concept that could explain the Emberger

understand how GATA2 mutations produce both syndrome phenotype.
a predisposition to MDS/AML and unusual 1. Emberger JM et al. Journal de Génétique Humaine
A recently published study involving 78 patients 27:237-245, 1979.
infections as well as lymphedema.
with autosomal recessive or dominant familial 2. Rodrigues NP et al. Blood 106 :477-484, 2005.
3. Maqalhaes IQ et al. Cancer Genetics and
There has been considerable progress in the lymphedema supports this suspected link.14
Cytogenetics 166:112-116, 2006.
These investigators found 4. Tsai FY et al. Nature 371:221-226, 1994.
that 36% of familial 5. Rodrigues NP et al. International Journal of
Biochemistry and Cell Biology 44:457-460, 2012.
lymphedema patients had a
6. Zhang SJ et al. Proceedings of the National
mutation in one of five genes Academy of Sciences of the USA 105:2076-2081,
involved in the VEGFR3 2008.
7. Scott HS et al. ASH Annual Meeting Abstracts.
signalling pathway. The
116: LBA-3, 2010.
mutated genes included FLT4
8. Vinh DC et al. Blood 115:1519-1529, 2010.
(the gene actually encoding 9. Hsu AP et al. Blood 118:2653-2655, 2011.
the transmembrane receptor, 10. Mansour S et al. American Journal of Medical
Genetics. Part A. 152A:2287-2296, 2010.
VEGFR3), as well as GATA2,
11. Ostergaard P et al. Nature Genetics 43:929-931,
FOXC2, SOX18, CCBE1 and 2011.
GJC2. The signalling pathway 12. Spinner MA et al. Blood 123:809-821, 2014.
13. Cuellar-Rodriguez J et al. Blood 118:3715-3720,
and the genes and protein
2011.
products potentially affected 14. Mendola A et al. Molecular Syndromology 4:257-
are shown in Figure 3. 266, 2013.