Would the real myeloma cell please stand up?

The immunophenotypic antigenic expression profile of myelomatous plasma cells is highly heterogeneous, and clearly different from that of normal plasma cells [1,2]. In some patients with multiple myeloma (MM), ≤ 30%, plasma cells retain the expression of progenitor cell-associated marker CD117 or myeloid-associated marker CD33, as well as B-lineage associated antigens CD19, CD20 or CD45. CD28, a molecule involved in cell–cell interactions, is expressed in approximately a quarter of patients, and CD56, an adhesion molecule that induces anchorage between plasma cells and bone marrow (BM) stromal cells, is present in around two-thirds of patients with MM [2]. This antigenic diversity not only may be associated with different clinical features, but also, and probably more important, may reflect variable genetic changes in plasma cells.

Pozdnyakova et al. report in their study that the expression of CD56 and CD117 was strongly associated with hyperdiploidy, and absence of CD117 expression was associated with immunoglobulin heavy chain gene (IGH) rearrangements [3]. In addition, the CD117-negative group could be further subclassified based on CD56 expression. Cyclin D1/IGH rearrangement was most exclusively seen in the CD117-negative, CD56-negative group, while cases that in addition to Cyclin D1/IGH rearrangement included FGFR3 and MAF rearrangements were seen in the CD117-negative, CD56-positive group [3].

MM is characterized by a proliferation of plasma cells (PCs) with a strong dependence on the bone marrow (BM) microenvironment. The BM microenvironment plays a key role in the pathogenesis of MM by triggering signaling cascades that mediate myeloma-cell proliferation, migration and survival, contributing to myeloma growth and the homing of malignant PCs within the BM. These signaling cascades are activated through both soluble factors such as interleukin-6 (IL-6), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), tumor necrosis factor α (TNF-α) or stromal-derived factor 1α (SDF-1α), and the adhesion of myeloma cells to cellular components, including BM stromal and endothelial cells [4]. Furthermore, the interaction between MM cells and BM endothelial cells up-regulates a number of angiogenic cytokines, which further stimulate BM angiogenesis and myeloma progression [5].

Adhesion of MM cells to the BM endothelium induces the expression of several molecules in plasma cells such as VLA-4, CD56 and CD44, and they interact with their receptors expressed on BM endothelium, helping BM homing [6]. Decreased expression of adhesion molecules, such as VLA-4, and CD44, as well as loss of CD56, is associated with extramedullary spreading, aggressive disease and adverse outcome [7]. In previous studies, down-regulation of CD56 in myelomatous PCs correlated with a tendency to short progression-free survival, but not different overall survival [8].

The c-kit receptor (CD117) is a tyrosine kinase expressed in hematopoietic progenitor cells and involved in cell growth. CD117 is absent in normal PCs, but can be detected in one-third of patients with myeloma. Information on the prognostic impact of CD117 in MM is scant [8]. San Miguel et al. have shown in previous studies including 685 patients with MM that CD117-positive MM represents a poor-risk category, indicating that patients with CD117-positive MM could have a better outcome [8]. Moreover, in this study they showed relevant associations between this marker and several characteristics of the disease. Patients lacking CD117 expression showed high BM PC infiltration, more frequent renal impairment, anemia and advanced clinical stage [8]. In line with previous reports, CD117-negative patients were associated with a higher frequency of non-hyperdiploidy and del(13q). In addition, CD117-negative patients were also associated with a higher frequency of t(4;14) [8].

In summary, the analysis of the antigenic profile of malignant cells has been shown to be a valuable tool for both the diagnosis and the identification of prognosis markers in different hematologic diseases [8]. In contrast, in MM, attempts directed to investigate the prognosis value of the immunophenotypic characteristics of PCs have frequently led to conflicting results, probably due to technical pitfalls or short series of heterogeneously treated patients.

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.