title: BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia.
abstract: Bruton's tyrosine kinase (BTK) is involved in the regulation of B-cell growth, migration and adhesion. The importance of BTK in cell trafficking is emphasized by the clonal contraction proceeded by lymphocytosis typical for the enzyme inhibitor, ibrutinib, in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Here, we investigated BTK regulation of leukemic B-cell trafficking in a mouse model of aggressive TCL1 CLL-like disease. Inhibiting BTK by ibrutinib reduced surface membrane (sm) levels of CXCR4 but not CXCR5, CD49d and other adhesion/homing receptors. Decreased smCXCR4 levels resulted from blocking receptor signal transduction, which in turn aborted cycling from and to the membrane. This resulted in rapid re-distribution of CLL cells from spleens and lymph nodes into the circulation. CLL cells with impaired smCXCR4 from BTK inhibition failed to home to spleens. These functional changes mainly resulted from inhibition of CXCR4 phosphorylation at Ser339, mediated directly by blocking BTK enzymatic activity and indirectly by affecting the function of downstream targets PLCγ2 and PKCμ, and eventually synthesis of PIM-1 and BTK itself. Our data identify CXCR4 as a key regulator in BTK-mediated CLL-cell retention and have elucidated a complex set of not previously described mechanisms responsible for these effects.
authors.affiliation: Karches Center for CLL Research, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: S-S
authors.initials: SS
authors.lastname: Chen
authors.affiliation: Pharmacyclics, Inc, Sunnyvale, CA, USA.
authors.forename: B Y
authors.initials: BY
authors.lastname: Chang
authors.affiliation: Pharmacyclics, Inc, Sunnyvale, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chang
authors.affiliation: Karches Center for CLL Research, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tong
authors.affiliation: Karches Center for CLL Research, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ham
authors.affiliation: Center for Immunology and Inflammation, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Sherry
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: Karches Center for CLL Research, Feinstein Institute for Medical Research, Manhasset, NY, USA.|Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA.|Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Rai
authors.affiliation: Karches Center for CLL Research, Feinstein Institute for Medical Research, Manhasset, NY, USA.|Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA.|Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA.
authors.forename: N
authors.initials: N
authors.lastname: Chiorazzi
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007942:Leukemia, Experimental / Q000378:metabolism / Q000473:pathology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D019718:Receptors, CXCR4; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse