Functional Activation of Osteoclast Commitment in Chronic Lymphocytic Leukaemia: a Possible Role for RANK/RANKL Pathway

Abstract

Skeletal erosion has been found to represent an independent prognostic indicator in patients with advanced stages of chronic lymphocytic leukaemia (CLL). Whether this phenomenon also occurs in early CLL phases and its underlying mechanisms have yet to be fully elucidated. In this study, we prospectively enrolled 36 consecutive treatment-naïve patients to analyse skeletal structure and bone marrow distribution using a computational approach to PET/CT images. This evaluation was combined with the analysis of RANK/RANKL loop activation in the leukemic clone, given recent reports on its role in CLL progression. Bone erosion was particularly evident in long bone shafts, progressively increased from Binet stage A to Binet stage C, and was correlated with both local expansion of metabolically active bone marrow documented by FDG uptake and with the number of RANKL + cells present in the circulating blood. In immune-deficient NOD/Shi-scid, γcnull (NSG) mice, administration of CLL cells caused an appreciable compact bone erosion that was prevented by Denosumab. CLL cell proliferation in vitro correlated with RANK expression and was impaired by Denosumab-mediated disruption of the RANK/RANKL loop. This study suggests an interaction between CLL cells and stromal elements able to simultaneously impair bone structure and increase proliferating potential of leukemic clone.

Assessment of Skeletal Tumor Load in Metastasized Castration-Resistant Prostate Cancer Patients: A Review of Available Methods and an Overview on Future Perspectives

“…As PSMA uptake in bone is considered to be very specific and all external PSMA sources have been taken out, it results that this method can provide a very accurate reading of bone tumor volume. Another approach, developed by our group on the basis of a bone marrow segmentation application [ 26 , 51 , 52 , 53 , 54 ], utilizes a CT-based adaptive threshold algorithm to discriminate between normal trabecular bone and metastases. These CT-based volumes are then translated onto the co-registered functional (PET or SPECT) images [ 26 ].…”

Characterization of Tissue-Engineered Human Periosteum and Allograft Bone Constructs: The Potential of Periosteum in Bone Regenerative Medicine

“…Detection of murine-specific gene expression in group 2 after implantation for up to 40 weeks indicated the contribution from hematopoietic progenitors sourced from vascularization by the host mice [Kido et al, 2003]. The notable expression of RANK and CTSK could originate from the macrophage-to-osteoclast lineage derived from host mouse marrow precursors or hematopoietic stem cells [Kido et al, 2003;Bar-Shavit, 2007;Marini et al, 2017;Park et al, 2017]. Presence of osteoblast-related murine gene expression suggested that the host vasculature contributes to the remodeling of these human periosteum-wrapped allograft bones.…”

Tumor Burden and Intraosseous Metabolic Activity as Predictors of Bone Marrow Failure during Radioisotope Therapy in Metastasized Prostate Cancer Patients

“…Segmentation of bone volumes on the CT images was based on the previously validated method [ 17 , 25 ]. The computational software analysis tool was progressively developed and adapted by the joint effort of the Department of Mathematics and the Department of Health Sciences of the University of Genoa [ 17 , 25 – 27 ]; it was later improved thanks to the collaboration with the Nuclear Medicine Unit of the University of Tübingen. The algorithm is based on the principle of segmentation analysis with adaptive threshold: it segments the osseous tissue not by aprioristically defining a Hounsfield value for bone, but by rather identifying the bone border, on each separate slice, by recognizing the sharp variation of attenuation value between soft and bone tissue.…”