Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib

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BlankBlood, 20 January 2011, Vol. 117, No. 3, pp. 882-889.

Prepublished online as a Blood First Edition Paper on November 15, 2010; DOI

10.1182/blood-2010-04-282400.

Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in

response to CXCL12 that are sensitive to inhibition by sorafenib

Davorka Messmer1,*, Jessie-F. Fecteau1,*, O'Hayre2,*, Ila S. Bharati1,

M. Handel2, and J. Kipps1

1 s Cancer Center and 2 Skaggs School of Pharmacy and Pharmaceutical

Sciences, and School of Medicine, University of California San Diego, La Jolla,

CA

The chemokine CXCL12, via its receptor CXCR4, promotes increased survival of

chronic lymphocytic leukemia (CLL) B cells that express high levels of

(zeta)-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 Ca2+ 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.