Bone Tissue Microenvironment in Chronic Lymphocytic Leukemia: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Paolo Giannoni
,
Cecilia Marini
,
Giovanna Cutrona
,
Gian Mario Sambuceti
,
Franco Fais
,
Daniela de Totero

Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in Western countries. Although characterized by the progressive expansion and accumulation of leukemic B cells in peripheral blood, CLL cells develop in protective niches mainly located within lymph nodes and bone marrow. Multiple interactions between CLL and microenvironmental cells may favor the expansion of  the malignant B cell clone, further driving immune cells toward an immunosuppressive phenotype.  Recent studies have further highlighted that the active crosstalk between leukemic B cells and bone tissue components may lead to the alteration of bone homeostasis in CLL patients.

  • bone tissue
  • chronic lymphocytic leukemia
  • tumor microenvironment

1. Introduction

Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in Western countries, mainly occurring in the elderly and showing heterogeneous outcomes. Although characterized by the progressive expansion and accumulation of leukemic B cells in peripheral blood, CLL cells develop in protective niches mainly located within lymph nodes and bone marrow. The close interactions between malignant B cells and the surrounding tissue microenvironment play a critical role in leukemic cells’ survival and growth, as well as in drug resistance. Microenvironmental cells favoring the expansion of the leukemic B cell clone include T cells, monocytes/macrophages, nurse-like cells, endothelial cells and mesenchymal stromal cells [1][2][3].

2. Bone Tissue Erosion in Chronic Lymphocytic Leukemia Patients

Although macroscopic skeletal involvement was previously considered rare in CLL, several cases of patients presenting osteolytic lesions were more recently reported. Indeed, after a full literature revision, Bacchiari and co-workers concluded that bone lesions appear to be not-so-rare events [4]. In this research, the authors observed that in 11 out of 22 cases described in the literature, the osteolytic lesions were localized in the axial skeleton or proximal long bones, while only in rare cases, they were localized in the skull or facial bones. Moreover, multiple fractures were observed in eight cases. It is of interest to note here that the authors stated that in 13 CLL cases described, the patients developed bone metastasis/symptomatic bone lesions as the first presentation of the disease [4]. In addition, hypercalcemia appeared to be frequently associated with osteolysis and mostly related to Richter’s transformation or co-occurring with multiple myeloma [4]. However the pathogenesis of bone involvement in CLL is still not completely understood, and deeper investigations could be of help to clarify the underlying mechanisms causing bone remodeling under the influence of the expansion of malignant B cells. In a previous retrospective study, F. Fiz and collaborators observed structural skeletal alterations in advanced CLL patients: a significant trabecular bone volume enlargement, paralleled by a decrease in the compact bone volume, was more evident in patients with respect to controls, as quantified using the computational analysis of CT images [5]. Structural bone alterations were particularly evident in the appendicular bones, and, interestingly, the degree of bone erosion appeared significantly related to a poor outcome [5]. This finding may suggest that radiologic risk assessment could be useful to predict disease aggressiveness and to better tailor patient-specific treatment protocols. One more study was therefore performed to specifically clarify whether bone erosion characterized only patients in the advanced stage or also those at an earlier disease stage [6]. A cohort of 36 treatment-naive CLL patients (16 Binet A, 12 Binet B, 8 Binet C) were enrolled to analyze their skeletal structure and bone marrow distribution using a computational approach to PET/CT scan images. Skeletal alterations were observed in all risk classes, apparently independent from Binet stages, when the whole skeleton was analyzed. However, a correlation with the clinical disease stage emerged when the appendicular districts were examined: shaft cortical thinning progressively increased with a raise in the clinical index of disease severity from Binet A to Binet C and appeared related to the number of RANKL+ CLL cells. PET-FDG imaging found that the same long bone shafts were colonized by metabolically reactive bone marrow (RBM), thus suggesting that CLL cells may contribute to skeletal derangement, promoting osteoclast differentiation. The experiments performed in a xenograft NOD-SCID-γ-null mouse model further confirmed that the administration of CLL cells was associated with the thinning of the femoral cortex. Moreover, this in vivo model supported the hypothesis that the activation of the RANK/RANKL is involved in bone erosion by CLL cells. The anti-RANKL mo-Ab Denosumab was in fact capable of sparing leukemic cells since the number of neoplastic B-cells detected in the bone marrow (BM) and spleen was significantly higher in untreated than in treated mice [6].

3. Chronic Lymphocytic Leukemia Cells Affect Osteoblast and Osteoclast Differentiation

Ex vivo co-cultures of CLL cells with differentiating osteoblasts/osteoclasts helped researchers to clarify the potential role played by leukemic cells in bone tissue derangement in the disease [7]. BMSCs from healthy donors and differentiated toward osteoblasts in an osteogenic medium did not reach complete maturation upon co-culture with CLL cells or with the addition of CLL-cell-derived conditioned media (CLL-cm). The inhibition of osteoblast differentiation was documented by decreased levels of RUNX2 and osteocalcin mRNAs, increased osteopontin and DKK-1 mRNA levels, and a marked reduction in mineralized matrix deposition (Figure 1A,C,E). CLL-cm added to the medium culture instead enhanced the differentiation of normal monocytes toward osteoclasts. However, the presence of exogenous RANKL in the induction phase of differentiation appeared necessary to generate a high number of large multinucleated cells that were fully competent in resorbing the bone surface (Figure 1B,D,F). When CLL-cm was added without previous RANKL activation, healthy monocytes could only differentiate toward a state of osteoclast precursors (small trinucleated cells) [7]. Indeed, previous observations from Chappard D. and Rossi J.F. and co-workers are consistent with our in vitro data [8][9]. Histologic and electron microscopy studies from these authors showed that B cell malignancies presenting bone alterations, including CLL, displayed a discrete number of osteoclasts, identified as tartrate-resistant acid phosphatase (TRAP)+ cells and close to bone trabeculae, but smaller than those detected in multiple myeloma (MM): these cells induced areas of micro-resorption and appeared very close to malignant lymphoid cells. The cytomorphometric analysis of bone biopsies further confirmed the heterogeneity in the size of TRAP+ cells, showing a bimodal distribution [10].
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Figure 1. Comparison of osteoblastogenesis and osteoclastogenesis in normal and CLL bone tissue. (A,B) schematic representation of in vitro induced MSC osteoblastogenesis or HSC osteoclastogenesis, with/without the addition of CLL-conditioned medium (CLL-cm). (C) The addition of CLL-cm to osteoblast precursors inhibited deposition of mineralized matrix (Alizarine red staining). (D) RANKL-dependent pre-activation was necessary to induce the formation of mature large osteoclasts (Alkaline phosphatase tartrate-resistant activity detection (TRAP)). Red arrows indicate small osteoclast-progenitors, while yellow arrows indicate large multinucleated mature osteoclasts. Magnification are 40X and 100X, as indicated. (E) Modulation of the levels of expression of RUNX2, Osteocalcin (OC), Osteopontin (OP) and DKK-1 in osteo-induced BMSC cultured with CLL-cm (red bars) or CLL-sera (blue bars). Data represent the mean of 10 CLL patients evaluated using quantitative RT-PCR and normalized to the housekeeping gene (GAPDH) and to BMSC used as control. (F) The addition of CLL-cm to osteoclast-induced monocytes enhanced the number of osteoclast precursors (small trinucleated TRAP+ cells) but RANKL appeared necessary to allow for a complete osteoclast maturation (large multinucleated TRAP+ cells). (G) In bone biopsies from CLL patients (n = 2), the presence of small (red enlargements and arrows) and large (yellow enlargement and arrows) TRAP+ osteoclasts was evident instead of being homogeneously large in multiple myeloma (MM) biopsy. (H) Resulting imbalance of bone homeostasis in CLL patients versus normal subjects. (Graphics and images of live cells displayed here were not previously published.).
The presence of a heterogeneous population of TRAP+ cells within the BM of CLL patients was also evident in bone biopsy sections derived from CLL cases and examined in our study [7] (Figure 1G). Collectively, the in vivo and in vitro observations may indicate that altered bone homeostasis can be a feature of CLL (Figure 1H) and that a higher number of active small osteoclasts can be necessary to cause a rate of resorption similar to those observed in MM patients. It is further known that MM malignant B cells may release high amounts of RANKL, while in CLL, the shedding of RANKL by leukemic cells was rarely found [11]. This observation may suggest that, initially, CLL-monocytes may differentiate toward osteoclastic precursors under the influence of cytokines secreted by leukemic or microenvironmental cells, but then fail to reach complete maturation due to low RANKL levels. The study of Borge M. and collaborators [12] provides support to this hypothesis. Here, the authors described the case of a 72-year-old CLL patient showing extensive lytic bone lesions at X-ray and MRI examinations, a diffuse infiltrate of small mononuclear cells with features of CLL cells (CD20+, CD23+, CD5+, CD138−) in a bone biopsy, and the presence of high levels of RANKL in plasma (888 pg/mL). In order to clarify whether high concentrations of soluble RANKL might contribute to bone damage, the authors demonstrated that the addition of 10% of the plasma from this patient to the in vitro culture of the monocytic cell line THP1 significantly stimulated osteoclast formation. At difference with other CLL cases tested, the amount of RANKL released by purified CD19+ leukemic B cells was already detectable in basal conditions (102 pg/mL) and aberrantly increased after CPG activation (1600 pg/mL). Therefore, RANK/RANKL interaction, as well as the overproduction of some cytokines by CLL cells, such as IL-8, TNFα and IL-6, may influence bone metabolism, further creating interactive niches sustaining leukemic cell proliferation. The importance of the RANK–RANKL interaction as a microenvironmental signal promoting CLL cell development and survival in the murine and human systems was also recently highlighted by expressing a human lymphoma-derived RANKK240E variant in mice B lymphocytes [13]. B cell-intrinsic RANKK240E drove a fully penetrant systemic lupus erythematosus (SLE)-like disease and facilitated B cell transformation and CLL development, which was not driven by an altered expression of the mutated RANK but rather its aberrant signaling in response to microenvironmental RANKL. Moreover, murine B cells expressing the RANK variant survived in vitro significantly better than their wild type counterparts cells in in vitro settings, even in the absence of exogenous stimulation. RANKL stimulation, on the other hand, induced more pronounced JNK, ERK and PI3K/AKT activation in the transgenic cells, resulting in higher expressions of the antiapoptotic molecule Bcl-2 and cell cycle regulator Cyclin-D1 [13].

4. Monocyte Polarization by Leukemic B Cells and Bone Tissue Remodeling in Chronic Lymphocytic Leukemia Patients

Monocytes/macrophages assume a critical role in the maintenance and progression of CLL cells. Many studies highlighted that neoplastic B cells shape the phenotypical and functional features of the monocytes/macrophages of the CLL microenvironment. The crosstalk between leukemic B cells and monocytes leads to the polarization of monocytes toward an immunosuppressive M2 phenotype, simultaneously enhancing the survival and expansion of CLL cells. Moreover, a particular population of myeloid cells, namely, nurse-like cells (NLCs), was described in this disease. NLCs are cells of monocytic origin that spontaneously differentiate in vitro in high-density cultures of CLL peripheral blood mononuclear cells (PBMCs) [14][15]. These cells support leukemic B cell survival, further creating a permissive microenvironment [16][17]. Importantly, NLCs were also observed in vivo in the lymphoid organs of patients with CLL [15]. Since their original description [14], NLCs/CLL cell co-cultures have been used extensively to dissect key cellular and molecular interactions between leukemic B cells and their microenvironment. Researchers reported that NLCs and CLL monocytes display features of the alternative type-2 subset (M2) [18]. NLCs are characterized by high CD11b, CD163, CD206, HLA- DR and c-MET expression and by the dysregulation of genes involved in immunocompetence [18][19][20][21]. In addition, researcehrs demonstrated that NLCs and CLL monocytes showed higher expressions of indoleamin 2,3 dioxygenase (IDO) than monocytes from normal controls [18], and IDO is regarded as a key endogenous immunologic checkpoint with a pivotal impact on tumor-associated immune tolerance [22]. In line with their immunosuppressive phenotype, CLL monocytes or NLCs significantly inhibited T cell proliferation, and this inhibition was counteracted by the concomitant addition of neutralizing anti-TGFβ or -IL-10 antibodies or IDO inhibitors in cultures. Indeed, healthy monocytes upregulated IDO after their co-culture with CLL cells [18]. Interestingly, IDO also appeared upregulated in NLCs cultured in hypoxic conditions [23]. Jitschin R. and collaborators [24] further reported that untreated CLL patients show a significantly increased frequency of monocytes CD14 + DRlow, which are defined as myeloid-derived suppressor cells (MDSCs) and characterized by high IDO levels expression, that induced the suppression of T cell activation while expanding T regulatory cells (Tregs); the MDSC-mediated modulation of T cells was attributed to their increased IDO activity. The presence in CLL patients of a higher percentage of MDSCs characterized by immunosuppressive features and expressing IDO together with others immunoregulatory molecules/cytokines, such as arginase 1 (ARG1), nitric oxide synthase (NOS2), TGF-β and IL-10, was also described by Zarobkiewicz M and co-author [25]. It is of further interest to note that the kynurenine–tryptophan ratio, which reflects increased IDO activity, was found to be higher in sera from CLL patients than in normal donors [26]. Maffei and co-authors [27] also observed the functional and phenotypic deregulation of monocytes in CLL patients: the gene expression profile analysis of CLL monocytes compared with monocytes from healthy donors, other than suggesting the deregulation of genes involved in phagocytosis and inflammation, evidenced the ability of CLL B cells to “educate” these cells, skewing them toward an immunosuppressive phenotype. Using cytofluorimetric analysis, these authors further evaluated the proportions of the three subtypes of monocytes present in CLL PBMCs: classical (CD14+ CD16−), intermediate (CD14+ CD16+) and non-classical (CD14+/− CD16++). In contrast with normal donors, they observed a significant increase in the intermediate and non-classical populations and a reduced percentage of classical monocytes. Of further note is the finding that healthy monocytes, co-cultured with CLL cells or with their conditioned medium, were induced to upregulate CD16, which is the Fcγ type III low-affinity receptor for IgG (FcγRIIIa). A higher number of monocytes expressing CD16 in CLL patients was also described by Kowalska and co-authors [28]. Bolzoni M and co-workers [29] further interestingly reported that sorted bone marrow CD14+ CD16+ cells from myeloma patients were more pro-osteoclastogenic than CD14+ CD16− cells in cultures ex vivo. 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 [29]. CD16 is a RANK co-receptor, contributing to the amplification of osteoclast differentiation [30]; this evidence, along with the previous observations, prompted researchers 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 [31]. Researchers 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 researcehrs found a direct correlation between the percentage of intermediate monocytes and the levels of bone erosion. Researchers also demonstrated that the percentage of healthy monocytes expressing CD16, and to a lesser extent RANK and RANKL, was significantly enhanced when they were cultured with CLL-cm alone, IL-10 or TGFβ. 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. Researcehrs further demonstrated that monocytes polarized toward the M2 phenotype, in particular M2c, were more prone to differentiate toward osteoclasts [31]. In agreement with our observations, Jihyun Yang et al. [32] 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 [31]. 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 [33]. It is also worth noting that, in particular contexts, myeloid-derived suppressor cells (MDSCs) may differentiate toward osteoclast precursors, as demonstrated in breast cancer, rheumatoid arthritis or multiple myeloma [34][35][36][37][38][39]. The observations presented here are schematically summarized in Figure 2.
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Figure 2. Cytokines produced by leukemic B cells or present in the microenvironment may drive monocyte differentiation, leading to enhanced osteoclastogenesis. (A) CLL-cm (containing TGFβ and IL-10), as well as exogenously added TGFβ and IL-10, upregulates the expression of the RANK co-receptor CD16 in monocytes, thus eliciting osteoclastogenesis. (B) IL-4 and IL-10 activation, which polarizes monocytes toward M2a and M2c subtypes and simultaneously enhances CD16 expression, favors complete osteoclastogenesis [31]. (Graphics displayed here were not previously published).
The above-reported data may suggest that myeloid cells, expanded under the influence of leukemic B cells and acquiring an immunosuppressive phenotype, may directly or indirectly contribute to bone derangement in CLL patients: together with the production of cytokines, such as TGFβ and IL-10, the upregulation of the FcγRIIIa (CD16) antigen also appeared to contribute to the amplification of osteoclasts differentiation.

This entry is adapted from the peer-reviewed paper 10.3390/cancers15205058

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