A High Percentage of CD16+ Monocytes Correlates with the Extent of Bone Erosion in Chronic Lymphocytic Leukemia Patients: The Impact of Leukemic B Cells in Monocyte Differentiation and Osteoclast Maturation

Abstract

Significant skeletal alterations are present in Chronic Lymphocytic Leukemia (CLL) patients; bone erosion, particularly evident in the long bone shaft, appeared increased in the progressive disease stage. Moreover, the partial colonization of the bone with reactive bone marrow we documented via PET-FDG imaging suggests that neoplastic cell overgrowth contributes to bone derangement. Indeed, cytokines released by leukemic B cells impair osteoblast differentiation and enhance osteoclast formation in vitro. CD16, Fcγ-RIIIa, has been previously indicated as a marker of osteoclast precursors. We demonstrate, here, that the percentage of circulating monocytes, CD16+, is significantly higher in CLL patients than in normal controls and directly correlated with the extent of bone erosion. When we assessed if healthy monocytes, treated with a CLL-conditioned medium, modulated RANK, RANKL and CD16, we observed that all these molecules were up-regulated and CD16 to a greater extent. Altogether, these findings suggest that leukemic cells facilitate osteoclast differentiation. Interestingly, the evidence that monocytes, polarized toward the M2 phenotype, were characterized by high CD16 expression and showed a striking propensity to differentiate toward osteoclasts may provide further explanations for the enhanced levels of bone erosion detected, in agreement with the high number of immunosuppressive-M2 cells present in these patients.

Unraveling the Bone Tissue Microenvironment in Chronic Lymphocytic Leukemia

“…It is worth noting that a higher number of monocytes expressing CD16 appeared capable of generating a higher number of large osteoclasts, and, indeed, the addition of an anti-CD16 neutralizing antibody counteracted osteoclast differentiation. We further demonstrated that monocytes polarized toward the M2 phenotype, in particular M2c, were more prone to differentiate toward osteoclasts [8]. In agreement with our observations, Jihyun Yang et al [66] observed that M2 monocytes differentiated into osteoclasts more efficiently than M1, especially when pre-activated with IL-10.…”

“…In agreement with our observations, Jihyun Yang et al [66] observed that M2 monocytes differentiated into osteoclasts more efficiently than M1, especially when pre-activated with IL-10. Gene expression profile analysis of public data showed that the key osteoclastogenic transcription factor NFATC1 was also significantly higher in M2 versus M1 monocytes in CD16+ versus CD16-monocytes and in intermediate and non-classical versus classical monocytes, further supporting the results from our experiments [8]. Collectively, these findings suggest that the expression of CD16 facilitates the differentiation of monocytes toward osteoclasts and that CD16 could represent a marker of osteoclast precursors in CLL, as was previously indicated for psoriatic arthritis [67].…”

“…Indeed, we demonstrated that leukemic cells impair osteoblast differentiation while stimulating osteoclastogenesis [7]. In addition, in CLL patients, the expansion of CD16+ monocytes correlates with the rate of bone erosion [8], thus suggesting that these cells are more prone to differentiate toward osteoclasts. The present review summarizes all data that evidences a potential link between the progressive accumulation of leukemic cells and bone tissue degeneration in CLL patients.…”

“…Additionally, it was demonstrated that the number of bone marrow CD14+ CD16+ cells was higher in patients with active myeloma than in those with monoclonal gammopathy of undetermined significance [64]. CD16 is a RANK co-receptor, contributing to the amplification of osteoclast differentiation [65]; this evidence, along with the previous observations, prompted us to evaluate, first, the percentage of monocyte subtypes in a cohort of PBMCs from 35 CLL patients, and second, whether the eventual expansion of a particular subset could be related to the enhanced rate of bone erosion previously reported [8]. We confirmed that the percentages of the two subsets expressing CD16 (intermediate and non-classical) were significantly higher in CLL cases than in PBMCs from normal donors, and we found a direct correlation between the percentage of intermediate monocytes and the levels of bone erosion.…”