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CLL cells affect osteoblastogenesis/osteoclastogenesis
cm. Interestingly, gene expression profile analysis of available in silico datasets32 highlights that, in human mes- enchymal stem cells (MSC), different molecules, involved in the regulation of osteoblast differentiation, become modulated after co-culture with CLL cells: a trend to a decrease in RUNX2 and significant decreases in the expression of collagen 1A, BMP-4 and BMP-6, along with increases in DKK-1 and osteopontin have been demon- strated (Online Supplementary Figure S10). These observa-
tions further point to interactive crosstalk between CLL cells and MSC possibly leading to niche modifications. Suppression of osteoblast differentiation by leukemic cells has been reported in acute lymphocytic leukemia, chronic myeloid leukemia and multiple myeloma33-35 through alteration of the NOTCH signaling pathway.
It is also known that TNFα stimulates bone resorp- tion.36,37 In our model TNFα, acting in synergism with RANKL, increased differentiation of fully multinucleated
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Figure 8. Typical TRAP+ large osteoclasts and also smaller TRAP+ cells are present in bone biopsies from CLL patients. (Ai) Large TRAP+ cells (brown; red arrows) were observed on trabeculae rims ‘B’ while smaller TRAP+ cells were detectable in the marrow stroma ‘BM’. Representative images from two CLL patients (LSA01, DA06) are shown. (Aii) TRAP and CD79a co-immunostaining revealed that TRAP+ osteoclasts (brown) are often proximal to CD79a+ leukemic B cells (pink), as shown in the enlargements. (Aiii) Positive controls for TRAP immunostaining: two patients with multiple myeloma and myelofibrosis. The bar represents 125 mm except in the inserts in which they represent 32 μm. (B) Number of TRAP+ osteoclasts, related to the number of bone trabeculae, as observed in bone biopsies sections from three patients with CLL (LSA01, DA06, BS13), one patient with multiple myeloma and one normal control. Among CLL patients, LSA01 and DA06 had unmutated IGVH and were in Binet stage B and C, respectively, while BS13 was in Binet stage C.
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