Abstracts of 4th Annual UKMF Scientific Meeting on 07-Feb-2003
The Inaugural Michael Morley Memorial Lecture: Intercellular communication signals in human multiple myeloma
Bernard Klein, INSERM U475 and Unit for cellular and Gene Therapy, University Hospital, Montpellier.
Malignant plasma cells survive and proliferate in close contact with the bone marrow environment, i.e. monocytes, myeloid cells, T cells, stromal cells in particular osteoblasts and osteoclasts. A consensus is that interleukin-6 (IL-6) is a major multiple myeloma (MM) cell survival and proliferation factor, produced by the bone marrow environment, mostly monocytes. This is the case mainly for patients with extramedullary proliferation. For patients with chronic disease, IL-6 is not sufficient alone to promote myeloma cell growth and other factors are necessary. We have looked for these factors using a comparison of gene expression profiling between malignant and normal plasma cells.
As normal plasma cells are rare cells in bone marrow or tonsil, a first step was to produce normal plasma cells. Using a double step culture system, we are able to produce 107 polyclonal plasmablastic cells (PPC) starting from MM patient's peripheral blood B cells. PPC are actually derived from memory CD27+ B cells. They express most plasma cell membrane markers and transcription factors and no B cell markers.
Using Atlas macroarrays or Affymetrix microarrays, we found that malignant plasma cells overexpress several genes coding for intercellular communication signals compared to PPC or B cells. One of these molecules is a member of Epidermal Growth Factor (EGF) family, the heparin binding EGF-like growth factor (HB-EGF) and its coreceptors, the proteoglycan syndecan-1 and the tetraspanin CD9. We found that HB-EGF is an important myeloma cell growth factor working in synergy with IL-6 to promote myeloma cell growth in myeloma cells that express its receptors, ErbB1 and ErbB4. Tyrphostin inhibitors of ErbB kinase activity can block myeloma cell growth. Of importance, these inhibitors can induce apoptosis of primary myeloma cells in synergy with dexamethasone or anti-IL-6 antibodies without affecting the viability of the bone marrow environment or the growth of hematopoietic progenitors. These tyrphostin EGF inhibitors are already used in the treatment of epithelial cancer and might be of interest in MM.
Other genes coding for intercellular communication signals are also overexpressed in malignant plasma cells. For some of them, we have checked that the encoded proteins were expressed by myeloma cells and we are looking for their putative function in myeloma cell biology.
We are confident that gene expression profiling will make it possible to identify new tailored therapeutic targets in patients with MM.