Clonal plasma cells from monoclonal gammopathy of undetermined significance, multiple myeloma and plasma cell leukemia show different expression profiles of molecules involved in the interaction with the immunological bone marrow microenvironment

Abstract

The immunological bone marrow (BM) microenvironment plays a major role in controlling growth and survival of clonal plasma cells (PC); this might translate into different patterns of expression of molecules involved in immune responses on PC from different types of monoclonal gammopathies (MG). We have studied the expression of a group of nine such molecules on both BMPC and the plasma of 61 newly diagnosed MG patients (30 MG of undetermined significance (MGUS), 27 multiple myeloma (MM) and four plasma cell leukemia (PCL)) and five normal individuals. Clonal PC from all MG displayed significantly increased levels of CD56, CD86 and CD126, and decreased amounts of CD38 (Po0.001). Additionally, HLA-I and b2-microglobulin were abnormally highly expressed in MGUS, while CD40 expression was decreased in MM and PCL (Po0.05). Interestingly, a progressive increase in the soluble levels of b2-microglobulin was found from MGUS to MM and PCL patients (P ¼ 0.03). In contrast, all groups showed similar surface and soluble amounts of CD126, CD130 and CD95, except for increased soluble levels of CD95 observed in PCL. Overall, those phenotypic differences are consistent with increased antigen presentation and costimulatory capacities in MGUS, which progressively deteriorate in malignant MG (MM and PCL).

Utility of flow cytometry immunophenotyping in multiple myeloma and other clonal plasma cell‐related disorders

“…2) and other clonal B-cell chronic lymphoproliferative disorders (24,56,57); in contrast, no clear phenotypic differences have been reported so far between aberrant PC from MGUS, MM, and PCL cases except for molecules involved in the interaction between PC and their BM microenvironment. Among others, these include greater expression of CD38, HLA-I, b2microglo-bulin, and CD40 in MGUS versus MM and PCL and higher soluble levels of CD95 in the latter group (21). Interestingly, preliminary data suggests that in MM, the expression of several of these markers, particularly CD126 (IL-6a chain receptor) (83), B-lymphocyte stimulator (BLyS) (84) and the CCR1, CCR2, and CXCR4 chemokine receptors (85) on clonal PC could be associated with patient outcome, probably reflecting the role of the BM microenvironment on malignant transformation and disease progression/aggressiveness.…”

“…Phenotypically aberrant PC typically show: (i) underexpression of CD19, CD27, CD38, and CD45; (ii) overexpression of CD28, CD33, and CD56; and (iii) asynchronous expression of CD20, CD117, and surface immunoglobulins (sIg) ( Table 2) (13,14,(18)(19)(20)(21)23,35,(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49). Immunophenotypic panels containing simultaneous stainings for at least four markers in multicolor combinations are typically required for the identification and characterization of PC (50).…”

“…Despite this, immunophenotyping has also shown to provide accurate assessment of the expression of multiple markers and their fluorescence intensity in thousands of PC/tube, specific information being provided on individual PC, and to allow clear discrimination between aberrant and both normal and reactive PC, even when they are present at low or very low frequencies in a sample (17)(18)(19)(20)(21)(22). This is a unique feature of MFC since conventional morphological approaches fail to distinguish clonal from normal PC and molecular approaches mainly focus on the detection of specific genetic markers in whole BM and not in single cells.…”

Competition between clonal plasma cells and normal cells for potentially overlapping bone marrow niches is associated with a progressively altered cellular distribution in MGUS vs myeloma

“…[15][16][17] In addition, no clear phenotypic differences have been reported so far among clonal PC from MGUS, SMM and MM, 18 except for a few molecules involved in the interaction between PC and their microenvironment. 19 We have previously shown that the proportion of normal PC within the bone marrow (BM) PC compartment (normal PC/BM PC) is an efficient single parameter for discrimination between MGUS and MM; 20 at diagnosis, most MGUS cases (480%) display 45% normal PC/BM PC, 21 whereas the great majority (485%) of symptomatic MM show o5% normal PC/BM PC. 22 Additionally, the presence of 45% normal PC/BM PC at diagnosis is associated with both a lower risk of progression of MGUS and SMM, 21 and a favorable outcome in MM.…”

Report on the second Latin American consensus conference for flow cytometric immunophenotyping of hematological malignancies

“…Consensual recommendation was the addition of CD45, surface IgM as well as kappa and lambda light chains, to the previously recommended panel consisting of CD19, CD38, and CD56 (15). The main goal of these additions is the detection of clonally restricted IgM þ plasma cells in cases of Waldenström's macroglobulinemia within this group of patients; in addition, CD45 has been considered as useful in helping to distinguish normal and clonal plasma cells in multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS).…”