Bone marrow microenvironment in myelomagenesis: its potential role in early diagnosis

Abstract

Multiple myeloma (MM) is the second most common hematological malignancy, with an overall survival of 4–6 years. It is always preceded by a premalignant stage called monoclonal gammopathy of unknown significance (MGUS). Importantly, at this time we lack reliable predictors to determine who will progress from MGUS to MM, and who will remain stable. The bone marrow microenvironment plays a key role in myelomagenesis (growth, survival and migration of malignant plasma cells). In the present review, we summarize and discuss our current understanding of the bone marrow microenvironment and its compartments in relation to myelomagenesis. Although it remains to be proven, we believe that an improved characterization of the cellular constituents, the extracellular matrix components and the soluble factors of the bone marrow could open up novel avenues to better understand underlying mechanisms of the transformation from MGUS to MM. Ultimately, this will lead to the development of early treatment of high-risk precursor disease aimed to delay/prevent MM.

Keywords::

• angiogenesis
• bone marrow microenvironment
• bone turnover
• extracellular matrix
• monoclonal gammopathy of unknown significance
• multiple myeloma
• multiplex ELISA
• osteoclast
• proteoglycans
• RANK ligand
• Wnt signaling

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Notes

^†Related organ and tissue impairment: 1. Hypercalcemia: serum calcium >2.75 mmol/l; 2. Renal dysfunction: serum creatinine >173 mmol/l; 3. Anemia: hemoglobin 2 g/dl below lower limit of normal; 4. Lytic bone lesions (CT and MRI may be used to identify suspicious findings on plain films); 5. Symptomatic hyperviscosity; 6. Amyloidosis; 7. Recurrent bacterial infections (more than two episodes in 1 year).

MGUS: Monoclonal gammopathy of unknown significance.

Adapted from [134].

Under each subcategory we have provided well-characterized cells, proteins and factors in the literature. The list is not always complete and the nomenclature is constantly under development.

^†All of the above listed extracellular matrix and soluble components can be detected by western blot, ELISA, gene expression and quantitive PCR. In addition, some matrix metalloproteases can be detected by zymogen assays.

MMP: Matrix metalloproteinase; SIBLING: Small integrin-binding ligand N-linked glycoprotein; TIMP: Tissue inhibitors of metalloproteinase.