SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R I M M U N O L O G Y P R O G R A M
HIGHLIGHTS/DISCOVERIES
• Discovered Pum genes as an evolutionarily conserved
intrinsic mechanism that supports the
self-renewal of HSC and multipotent progenitors
by regulating the SCF/c-kit signaling pathway.
• Discovered a new E3 ubiquitin ligase that affects
proliferation and differentiation of HSC
and multipotent progenitors by regulating
steady-state cytokine receptor levels through
ligand independent degradation, and that may
be involved in etiology of hematological malignancies.
• Found that the Wnt5a gene negatively regulates
B-cell proliferation, and that inactivation of
Wnt5a leads to development of myeloid leukemias
and B-cell lymphomas. Discovery of the
deletion of the WNT5a gene and/or loss of
WNT5a expression in human primary leukemias,
demonstrating for the first time that the
WNT5a gene functions as a tumor suppressor
(in collaboration with Stephen Jones, Ph.D.,
University of Massachusetts Medical School).
KELVIN P. LEE, M.D.
Associate Professor of Microbiology
and Immunology
DESCRIPTION OF RESEARCH
Research in Dr. Lee’s laboratory focuses on
the cells and the molecules that play central
roles in initiating the adaptive immune response.
Understanding these interactions is essential for
developing effective immune-based therapies
against cancer. At the cellular level, they are specifically
studying the dendritic cells (DC), which
are thought to be the most important professional
antigen presenting cell (APC). Because
DC monitor the local environment for immunologic
“danger” signals and control what antigens
are presented to T cells to activate them, they are
positioned to regulate the initiation of immune
responses. Their work has examined how DC
arise from hematopoietic progenitors and their
intracellular/genetic characteristics. They previously
have reported that activation of the protein
kinase C (PKC) intracellular signal transduction
pathway in human hematopoietic CD34 + stem
cells causes direct differentiation to a pure population
of DC. Thus, PKC signaling specifically
triggers the DC differentiation “program” in
these cells. Additionally, specific isoforms of PKC
appear to regulate specific aspects of DC differentiation.
Ongoing studies are seeking to completely
characterize the components of the PKC
signaling pathway and what genetic events are
triggered by this signal.
From a translational standpoint, researchers
in Dr. Lee’s laboratory have found that in
addition to normal cells, PKC activation can
drive DC differentiation in acute and chronic
myeloid leukemic blasts. Because these “leukemic”
DC retain the ability to activate T cells and
are endogenously loaded with leukemia antigens,
they can potentially be used as “cellular” antileukemia
vaccines by re-infusion back into patients.
This work aims to bring this approach to
clinical trials.
In addition to the DC studies, a clinical trial
(headed by Dr. Lee) and basic laboratory research
currently are looking at novel agents against multiple
myeloma (MM). The NCI-sponsored phase
I/II clinical trial is examining arsenic trioxide +
ascorbic acid in the treatment of refractory/relapsed
MM. Initial results demonstrate that this
combination is effective against myeloma that is
resistant to standard chemotherapy (including
thalidomide) with acceptable toxicity. The laboratory
component of these studies seeks to understand
how arsenic kills myeloma, how ascorbic
acid potentiates that killing, how myeloma cells
become resistant to arsenic, and which host (i.e.,
patient) factors may actually help the myeloma
survive in the bone marrow.
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UM/Sylvester Comprehensive Cancer Center Scientific Report 2004