English - International Waldenstrom's Macroglobulinemia Foundation

IWMF RESEARCH UPDATE
b y Tom Myers, Vice President for Research
New IWMF Grants Awarded
The Waldenstrom’s Macroglobulinemia Foundation Canada
(WMFC) and the Leukemia & Lymphoma Society (LLS)
have agreed to jointly fund the proposal of Dr. Ruben
Carrasco of the Dana-Farber Cancer Institute to develop a
mouse model with the MYD88 L265P gene mutation. The
IWMF will play a supporting role in providing technical
oversight of the project. See below for reports on continuing
research on the MYD88 mutation and on mouse modeling
previously funded by the IWMF.
In a new IWMF-supported research project, Dr. Kareem
Azab at Washington University in St. Louis is studying “The
Role of Hypoxia in the Dissemination of Waldenstrom’s
Macroglobulinemia.” Hypoxia is a condition of low oxygen
concentration. By exposing WM cells to low oxygen
environments and then measuring their ability to move from
one area to another, Dr. Azab has demonstrated that hypoxic
conditions decrease the adhesion of WM cells to the bone
marrow stroma (connective tissue) and increase their ability
to migrate. He hypothesizes that hypoxia can thus cause WM
cells to move to uninvolved areas in the bone marrow where
oxygen is more plentiful. Dr. Azab will investigate the role of
hypoxia in cell signaling and the identification of compounds
affecting hypoxia.
IWMF-Supported Research in Progress
In 2011 the IWMF awarded a research grant to Dr. Steven
Treon at the Dana-Farber Cancer Institute (DFCI) for a
project entitled “Genomic Studies into Sporadic and Familial
WM.” Using whole genome sequencing, Dr. Treon’s group
demonstrated that over 90% of WM patients have a mutated
gene designated MYD88 L265P. It was also determined that
the mutated MYD88 gene was part of a signaling pathway
containing several other components that affect the growth
of WM cells. One of these components is designated as
BTK (Bruton’s tyrosine kinase). Pharmacyclics and Janssen
Biotech have developed an oral agent called ibrutinib that
inhibits BTK. This agent appears very promising in recently
announced preliminary studies treating WM, and as a result
the FDA has granted Breakthrough Therapy Designation to
ibrutinib in order to expedite the development and review
time for this drug. At this time there is no FDA-approved
drug for treating WM.
Dr. Treon has submitted a grant request to the IWMF Research
Committee to investigate the mechanisms whereby MYD88
L265P is involved in causing or controlling WM. This project
would also study various agents that could affect the manner
in which MYD88 reacts with proteins that influence the
growth and death of WM cells. The grant request is currently
under review.
With heightened research interest in MYD88, it becomes
important to have cell lines and mouse models that exhibit
this mutated gene.
The WM cell line projects supported by the Leukemia &
Lymphoma Society (LLS) and the IWMF have been very
successful. Originally four researchers working independently
attempted to develop cell lines. Dr. Stephen Ansell at Mayo
Clinic and Dr. Asher Chanan-Kahn at Roswell Park (now at
Mayo Clinic) have both produced lines that were judged to
be useful in evaluating treatments for Waldenstrom’s since
both cell lines exhibited the MYD88 L265P mutation. This
is the third year of the cell line development project, and the
IWMF is continuing support for Dr. Ansell and for Dr. Irene
Ghobrial at DFCI. Dr. Ghobrial gave a preliminary report
on her project to develop cell lines utilizing a mouse model
at the IWMF 2012 Ed Forum. She has had success with
growing mice that were injected with WM cells. In addition,
Dr. Ghobrial reported the successful in vitro production of
WM cells using growth compounds. A final report on her
progress will be forthcoming this spring.
The mouse model developed by Dr. Siegfried Janz at the
University of Iowa, in a research project also supported by the
IWMF, does not exhibit the mutated MYD88 gene. This model
may be of value in WM research as some patients do not have
the mutated gene. As noted above, the newly awarded grant to
Dr. Ruben Carrasco, funded jointly by the IWMF, WMFC, and
LLS, is for the development of a mouse model that exhibits the
mutated MYD88 gene.
The IWMF-funded project at Mayo Clinic led by Dr. Ansell
shows continued progress in tracking down the proteins and
transcription factors associated with the production of IgM in
WM. In research completed under a previous IWMF grant,
Dr. Ansell demonstrated that in WM patients the proteins
BLyS and IL-6 were expressed in higher concentrations and
that STAT5 was also over-expressed. His current research has
studied the effect of STAT5 on the increases in BLyS and IL-6
and shown that the use of agents minimizing the performance
of STAT5 also reduce the secretion of IgM. Two forms of
STAT5, labeled STAT5A and STAT5B, were identified.
These two proteins are encoded by separate genes but are
90% identical at the amino acid level. However, “knocking
down” STAT5A in the serum appeared to be more effective
in reducing IgM production than using STAT5B. This finding
may open up new avenues in the treatment of WM.
The tissue bank project that Dr. Ghobrial initiated in 2010
is a major effort by IWMF to provide tissue samples and
epidemiological data for researchers all over the world.
The most recent report indicates that over 500 WM patients
have prepared the epidemiological survey––with more than
100 completing the survey at the 2012 IWMF Ed Forum.
This information, in combination with blood, bone marrow
samples, and buccal (cheek) cells, can be used to identify
responses to therapy and the mechanisms of resistance. It is
hoped that the causes of WM and the risks of developing the
cancer will become clearer as a result of this project.
Patient support of Dr. Ghobrial’s tissue bank project is vital.
See the October 2012 issue of the Torch, pages 3 and 31, to
learn how you can register. A representative from the tissue
bank project will be available at the upcoming 2013 Ed Forum
in San Diego to answer questions and sign up participants.
IWMF TORCH Volume 14.2
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