Multiple myeloma: evolving genetic events and host interactions

Abstract

Multiple myeloma is a neoplasm of terminally differentiated B cells (plasma cells) in which chromosome translocations frequently place oncogenes under the control of immunoglobulin enhancers. Unlike most haematopoietic cancers, multiple myeloma often has complex chromosomal abnormalities that are reminiscent of epithelial tumours. What causes full-blown myeloma? And can our molecular understanding of this common haematological malignancy be used to develop effective preventive and treatment strategies?

Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

“…Stable epigenetic changes in ECs have been already described in mice tumor models (Hellebrekers et al, 2006). However, literature data show that little characterization of MM at the epigenetic level (for example gene methylation and acetylation) has been performed (Kuehl and Bergsagel, 2002). How plasma cells, other microenvironment cells and extracellular matrix components concur to the epigenetic changes may be an object for future investigation.…”

“…In patients with multiple myeloma (MM), the emergence of a neoplastic plasma cell clone involves genetic lesions, that is, translocations between immunoglobulin (Ig) enhancers and oncogenes, and secondary events including activation of bidirectional tumor-microenvironment interactions (Kuehl and Bergsagel, 2002). In this context, plasma cells function as primary inducers of angiogenesis and are crucial in the activation of bone marrow stromal cells, including endothelial cells (ECs), osteoclasts, fibroblasts, macrophages and mast cells, via production of major angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2) and hepatocyte growth factor (HGF; Ribatti et al, 2006).…”

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

“…Reciprocal positive and negative interactions between plasma cells and bone marrow stromal cells (BMSC), namely hematopoietic stem cells, fibroblasts, osteoblasts/osteoclasts, chondroclasts, EC, EC progenitor cells, T lymphocytes, macrophages and mast cells, are mediated by an array of cytokines, receptors and adhesion molecules. The MM microenvironment is formed by clonal plasma cells, ECM proteins and BMSC, which are intimately involved in all biological stages of intramedullary growth (Table 2) (Kuehl and Bersagel, 2002). Interactions between these components determine the proliferation, migration and survival of plasma cells, as well as their acquisition of drug resistance and the development of diseases (Damiano et al, 1999;Hazlehurst et al, 2000Hazlehurst et al, , 2003.…”

Transcriptional repression by the HDAC4–RelB–p52 complex regulates multiple myeloma survival and growth

“…M ultiple Myeloma (MM) is a monoclonal tumour of plasma cells (PCs) that develops from post germinalcenter (GC) B cells 1,2 . While MM tumours have been classified into different genetic subgroups based on several genetic abnormalities [1][2][3][4][5][6][7] , several of them are divided into three distinct groups of chromosomal translocations involving (1) Cyclin D (2) MAF and (3) MMSET/FGFR3 genes 2 .…”

“…While MM tumours have been classified into different genetic subgroups based on several genetic abnormalities [1][2][3][4][5][6][7] , several of them are divided into three distinct groups of chromosomal translocations involving (1) Cyclin D (2) MAF and (3) MMSET/FGFR3 genes 2 . To develop novel therapeutic approaches to target all the genetic subgroups of MM, it is important to identify the molecular requirements and the survival signals that are common to all genetic subgroups of MM tumours.…”