Membrane translocation of Bruton kinase in multiple myeloma cells is associated with osteoclastogenic phenotype in bone metastatic lesions


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Abstract

Using bone biopsy samples, we examined whether osteolytic cytokine profile is changed in situ in bone samples of metastatic multiple myeloma, and whether this creates an environment of lysis within the bone to which it has spread. This also produces the clinical features of increased circulating plasma calcium, and deleterious effects on the kidney.Using multiple myeloma biopsy and cell extracts from bone metastatic lesions, Bruton kinase, a tyrosine kinase, was demonstrated to be translocated to the membrane. Several transcription factors were upregulated included activin A, inflammatory transcription activator like such as nuclear factor kappa B, and specific bone lytic factor such as receptor activator of nuclear factor kappa-B ligand that is known to drive osteoclastogenesis as opposed to a osteogenic environment. The transcript for Bruton kinase was also elevated in its expression.Cytokines that support osteolytic activity such as a proliferation-inducing ligand, RANTES (regulated on activation, normal T cell expressed and secreted), interleukin-8, and activin A were upregulated. Tartrate resistant acid phosphatase (TRAP)-positive osteoclastic enzymatic activity was significantly elevated in the bone microenvironment in metastatic multiple myeloma. Several tyrosine kinase inhibitors, including inhibitors for Bruton kinase such as ibrutinib have been developed. The results of the present study provide evidence that multiple myeloma possess signal transduction mechanisms to support a bone lytic environment.The results provide a preliminary molecular basis to design specific inhibitors for management of bone metastasis of multiple myeloma.

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