title: Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib.
abstract: The chemokine CXCL12, via its receptor CXCR4, promotes increased survival of chronic lymphocytic leukemia (CLL) B cells that express high levels of ζ-chain-associated protein (ZAP-70), a receptor tyrosine kinase associated with aggressive disease. In this study, we investigated the underlying molecular mechanisms governing this effect. Although significant differences in the expression or turnover of CXCR4 were not observed between ZAP-70(+) and ZAP-70(-) cell samples, CXCL12 induced greater intracellular Ca(2+) flux and stronger and more prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase/ERK kinase (MEK) in the ZAP-70(+) CLL cells. The CXCL12-induced phosphorylation of ERK and MEK in ZAP-70(+) CLL cells was blocked by sorafenib, a small molecule inhibitor of RAF. Furthermore, ZAP-70(+) CLL cells were more sensitive than ZAP-70(-) CLL cells to the cytotoxic effects of sorafenib in vitro at concentrations that can readily be achieved in vivo. The data suggest that ZAP-70(+) CLL cells may be more responsive to survival factors, like CXCL12, that are elaborated by the leukemia microenvironment, and this sensitivity could be exploited for the development of new treatments for patients with this disease. Moreover, sorafenib may have clinical activity for patients with CLL, particularly those with ZAP-70(+) CLL.
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. dmessmer@ucsd.edu
authors.forename: Davorka
authors.initials: D
authors.lastname: Messmer
authors.forename: Jessie-F
authors.initials: JF
authors.lastname: Fecteau
authors.forename: Morgan
authors.initials: M
authors.lastname: O'Hayre
authors.forename: Ila S
authors.initials: IS
authors.lastname: Bharati
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Handel
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D013997:Time Factors; D014407:Tumor Cells, Cultured; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001557:Benzenesulfonates; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D019718:Receptors, CXCR4; D009536:Niacinamide; D000077157:Sorafenib; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium