title: Role of Bruton's tyrosine kinase in myeloma cell migration and induction of bone disease.
abstract: Myeloma cells typically grow in bone, recruit osteoclast precursors and induce their differentiation and activity in areas adjacent to tumor foci. Bruton's tyrosine kinase (BTK), of the TEC family, is expressed in hematopoietic cells and is particularly involved in B-lymphocyte function and osteoclastogenesis. We demonstrated BTK expression in clinical myeloma plasma cells, interleukin (IL)-6- or stroma-dependent cell lines and osteoclasts. SDF-1 induced BTK activation in myeloma cells and BTK inhibition by small hairpin RNA or the small molecule inhibitor, LFM-A13, reduced their migration toward stromal cell-derived factor-1 (SDF-1). Pretreatment with LFM-A13 also reduced in vivo homing of myeloma cells to bone using bioluminescence imaging in the SCID-rab model. Enforced expression of BTK in myeloma cell line enhanced cell migration toward SDF-1 but had no effect on short-term growth. BTK expression was correlated with cell-surface CXCR4 expression in myeloma cells (n = 33, r = 0.81, P < 0.0001), and BTK gene and protein expression was more profound in cell-surface CXCR4-expressing myeloma cells. BTK was not upregulated by IL-6 while its inhibition had no effect on IL-6 signaling in myeloma cells. Human osteoclast precursors also expressed BTK and cell-surface CXCR4 and migrated toward SDF-1. LFM-A13 suppressed migration and differentiation of osteoclast precursors as well as bone-resorbing activity of mature osteoclasts. In primary myeloma-bearing SCID-rab mice, LFM-A13 inhibited osteoclast activity, prevented myeloma-induced bone resorption and moderately suppressed myeloma growth. These data demonstrate BTK and cell-surface CXCR4 association in myeloma cells and that BTK plays a role in myeloma cell homing to bone and myeloma-induced bone disease. Am. J. Hematol. 88:463-471, 2013. © 2013 Wiley Periodicals, Inc.
authors: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors: Rakesh
authors: R
authors: Bam
authors: Wen
authors: W
authors: Ling
authors: Sharmin
authors: S
authors: Khan
authors: Angela
authors: A
authors: Pennisi
authors: Sathisha Upparahalli
authors: SU
authors: Venkateshaiah
authors: Xin
authors: X
authors: Li
authors: Frits
authors: F
authors: van Rhee
authors: Saad
authors: S
authors: Usmani
authors: Bart
authors: B
authors: Barlogie
authors: John
authors: J
authors: Shaughnessy
authors: Joshua
authors: J
authors: Epstein
authors: Shmuel
authors: S
authors: Yaccoby
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001847:Bone Diseases / Q000201:enzymology* / Q000473:pathology* / Q000517:prevention & control; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000201:enzymology* / Q000473:pathology*; D009570:Nitriles / Q000494:pharmacology; D010010:Osteoclasts / Q000201:enzymology / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000577:Amides; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C118451:LFM A13; D009570:Nitriles; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse