RANKL Expression, Function, and Therapeutic Targeting in Multiple Myeloma and Chronic Lymphocytic Leukemia

Abstract

Bone destruction is a prominent feature of multiple myeloma, but conflicting data exist on the expression and pathophysiologic involvement of the bone remodeling ligand RANKL in this disease and the potential therapeutic benefits of its targeted inhibition. Here, we show that RANKL is expressed by primary multiple myeloma and chronic lymphocytic leukemia (CLL) cells, whereas release of soluble RANKL was observed exclusively with multiple myeloma cells and was strongly influenced by posttranscriptional/posttranslational regulation. Signaling via RANKL into multiple myeloma and CLL cells induced release of cytokines involved in disease pathophysiology. Both the effects of RANKL on osteoclastogenesis and cytokine production by malignant cells could be blocked by disruption of RANK-RANKL interaction with denosumab. As we aimed to combine neutralization of RANKL with induction of antibody-dependent cellular cytotoxicity of natural killer (NK) cells against RANKL-expressing malignant cells and as denosumab does not stimulate NK reactivity, we generated RANK-Fc fusion proteins with modified Fc moieties. The latter displayed similar capacity compared with denosumab to neutralize the effects of RANKL on osteoclastogenesis in vitro, but also potently stimulated NK cell reactivity against primary RANKL-expressing malignant B cells, which was dependent on their engineered affinity to CD16. Our findings introduce Fc-optimized RANK-Ig fusion proteins as attractive tools to neutralize the detrimental function of RANKL while at the same time potently stimulating NK cell antitumor immunity. Cancer Res; 73(2); 683-94. Ó2012 AACR.

Adipose, Bone, and Myeloma: Contributions from the Microenvironment

“…For example, osteoblasts have been found to be supportive or inhibitory for MM depending on the MM patient cell source [66, 67]. Additionally, osteoanabolic agents have yielded conflicting conclusions in regards to MM cell growth, with in vivo and clinical efficacy dependent on model system and treatment used [65, 68]. Overall, further research is required to determine how best to target osteoblasts to alter tumor cell engraftment, survival, dormancy, and growth.…”

PTHrP-Induced Refractory Malignant Hypercalcemia in a Patient With Chronic Lymphocytic Leukemia Responding to Denosumab

“…9,10 Furthermore, investigators have shown reduced viability of CLL in vitro during incubation with RANKL antagonists including denosumab. 10 These studies, coupled with the patient's clinical course, suggests that hypercalcemia in CLL and other hematologic malignancies associated with PTHrP expression may benefit from denosumab therapy, especially in the setting of bony lesions and RANKL expression. 11 Our patient developed mycobacterial pneumonia and chose to undergo hospice care.…”

Role of osteocytes in multiple myeloma bone disease

“…In multiple myeloma, the balance of RANKL and OPG, key determinant for osteoclast differentiation, is disrupted, promoting activation of osteoclasts differentiation and consequently bone destruction [41,42,43 ▪▪ ]. Further, increased levels of soluble RANKL in multiple myeloma patients were shown to be associated with disease activity [44].…”