MOLECULAR AND BIOLOGICAL FUNCTIONAL OF CD40 IN MYELOMA

Project: Research project

Project Details

Description

Multiple myeloma is a universally fatal disease characterized by the
accumulation of malignant plasma cells in the bone marrow. Interleukin 6
(IL-6) promotes normal B lymphocyte differentiation into plasma cells, but
is ineffective in supporting B cell growth. In contrast, IL-6 is a potent
growth factor for malignant plasma cells in patients with aggressive
multiple myeloma. In addition, whereas normal plasma cells no longer
express IL-6, evidence suggests that expression of IL-6 in malignant
plasma cells may be deregulated. Currently, there is no effective
treatment for this disease. Because myeloma cells display an aberrant
proliferative response to IL-6, it is crucial to identify the molecular
changes that result in deregulation of IL-6 expression during malignant
transformation. We have established a panel of new human myeloma cell
lines that exhibit phenotypes representative of myeloma cells isolated
from patients with aggressive disease, i.e., proliferation in response to
IL-6. We have demonstrated that our panel of myeloma cell lines and
primary cultures of patient myeloma cells express CD40, an important cell
surface receptor in normal B cells, that has been reported to be absent in
plasma cells. Moreover, CD40 stimulation of myeloma cell lines results in
enhanced proliferation. In this proposal, we hypothesize that CD40
stimulation contributes to myeloma cell proliferation by inducing the
autocrine production of IL-6. We also hypothesize that this pathway
becomes available to the tumor cell as a result of loss or alteration of
transcriptional control of the IL-6 gene during tumor progression. We
have, therefore, proposed 3 specific aims to test these hypotheses. In
Specific Aim #1, we will attempt to block CD40 stimulated proliferation of
myeloma cells with anti-IL-6 neutralizing antibodies and determine the
effects of anti-CD40 stimulation on transcription of the IL-6 gene. In
Specific Aim #2, we will systematically test which elements in the IL-6
promoter are crucial in allowing CD40 stimulated transcription of the IL-6
gene. In Specific Aim #3, we will extend our studies of the proposed link
between CD40 and IL-6 to patients' cells by examining expression levels of
CD40 and CD40 ligand and determining the effects of CD40 stimulation on
IL-6 expression. Utilization of the invaluable myeloma cell line panel for
the proposed in vitro studies, and extension of these studies to myeloma
patient samples, will provide much needed insight into the regulation of
IL-6 expression in myeloma cells.
StatusFinished
Effective start/end date9/30/944/30/04

ASJC

  • Medicine(all)