Abstract
Simple SummaryWe investigated the distribution of different subsets of monocytes (Mo) in blood and bone marrow (BM) of newly-diagnosed untreated monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM) and active multiple myeloma (MM), and its relationship with immune/bone serum-marker profiles. Our results showed decreased production of BM Mo with decreased counts of classical Mo (cMo) in BM and blood of SMM and MM, but not MGUS. Conversely, intermediate and non-classical Mo were significantly increased in MGUS, SMM and MM BM. In parallel, increased levels of interleukin (IL)1β were observed in a fraction of MGUS and SMM, while increased serum IL8 was characteristic of SMM and MM, and higher serum IL6, RANKL and bone alkaline phosphatase concentrations, together with decreased counts of FcεRI+cMo, were restricted to MM presenting with bone lesions. These results provide new insights in the pathogenesis of plasma cell neoplasms and the potential role of FcεRI+cMo in normal bone homeostasis.Background. Monocyte/macrophages have been shown to be altered in monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM) and active multiple myeloma (MM), with an impact on the disruption of the homeostasis of the normal bone marrow (BM) microenvironment. Methods: We investigated the distribution of different subsets of monocytes (Mo) in blood and BM of newly-diagnosed untreated MGUS (n = 23), SMM (n = 14) and MM (n = 99) patients vs. healthy donors (HD; n = 107), in parallel to a large panel of cytokines and bone-associated serum biomarkers. Results: Our results showed normal production of monocyte precursors and classical Mo (cMo) in MGUS, while decreased in SMM and MM (p ≤ 0.02), in association with lower blood counts of recently-produced CD62L+ cMo in SMM (p = 0.004) and of all subsets of (CD62L+, CD62L− and FcεRI+) cMo in MM (p ≤ 0.02). In contrast, intermediate and end-stage non-classical Mo were increased in BM of MGUS (p ≤ 0.03), SMM (p ≤ 0.03) and MM (p ≤ 0.002), while normal (MGUS and SMM) or decreased (MM; p = 0.01) in blood. In parallel, increased serum levels of interleukin (IL)1β were observed in MGUS (p = 0.007) and SMM (p = 0.01), higher concentrations of serum IL8 were found in SMM (p = 0.01) and MM (p = 0.002), and higher serum IL6 (p = 0.002), RANKL (p = 0.01) and bone alkaline phosphatase (BALP) levels (p = 0.01) with decreased counts of FcεRI+ cMo, were restricted to MM presenting with osteolytic lesions. This translated into three distinct immune/bone profiles: (1) normal (typical of HD and most MGUS cases); (2) senescent-like (increased IL1β and/or IL8, found in a minority of MGUS, most SMM and few MM cases with no bone lesions); and (3) pro-inflammatory-high serum IL6, RANKL and BALP with significantly (p = 0.01) decreased blood counts of immunomodulatory FcεRI+ cMo-, typical of MM presenting with bone lesions. Conclusions: These results provide new insight into the pathogenesis of plasma cell neoplasms and the potential role of FcεRI+ cMo in normal bone homeostasis.
Highlights
Plasma cell (PC) neoplasms consist of a wide spectrum of end-stage antibody-producingB-cell tumors [1,2] that range from pre-malignant conditions such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), to symptomatic multiple myeloma (MM) and PC leukemia [3].Tumor PC control and growth kinetics in both MGUS and MM depend both on the intrinsic characteristics of neoplastic PC and their close interaction with the tumor microenvironment [4,5]
The distribution of monocytic precursors, as well as mature Mo and their subsets was first analyzed in bone marrow (BM) aspirated samples of 19 MGUS, 13 SMM and 81 MM patients vs. 15 healthy donors (HD)
Such increased numbers of mature Mo in BM of MGUS was at the expense of the major compartment of recently produced classical Mo (cMo)-median of 3.6% (1.9–4.4) in MGUS vs. 2.4% (1.4–3.3) in HD (p = 0.005), 2.4% (1.2–3.4) in SMM (p = 0.02) and 2.2% (0.6–5) in MM (p = 0.005), respectively- (Figure 2E), altough no differences were observed among cMo subsets (Figure 2F–H)
Summary
Plasma cell (PC) neoplasms consist of a wide spectrum of end-stage antibody-producingB-cell tumors [1,2] that range from pre-malignant conditions such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), to symptomatic multiple myeloma (MM) and PC leukemia [3].Tumor PC control and growth kinetics in both MGUS and MM depend both on the intrinsic characteristics of neoplastic PC and their close interaction with the tumor microenvironment [4,5]. Upregulation of the RANKL-receptor activator of nuclear factor κ B ligand-pro-osteoclastogenic factor, in parallel to decreased osteoprotegerin (OPG) levels, have been described in BM of MM [11,12,13,14,15] and MGUS patients [16], in association with an accelerated turnover of BM osteoblasts and increased bone alkaline phosphatase (BALP) and RANKL levels in serum of these patients [17,18] These alterations might result from an increased differentiation of monocytes (Mo) into osteoclasts [19] associated with higher secretion of interleukin (IL)6 [20], CXCL12 [21,22] and RANKL by both BM stromal cells [23] and activated T cells [24]. Conclusions: These results provide new insight into the pathogenesis of plasma cell neoplasms and the potential role of FcεRI+ cMo in normal bone homeostasis
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