The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic leukemia cells in vitro with preference for a subgroup of patients with unmutated IgVH genes

[Guest guest]

Blood First Edition Paper, prepublished online June 12, 2008; DOI

10.1182/blood-2007-11-123984.

The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic leukemia

cells in vitro with preference for a subgroup of patients with unmutated IgVH

genes

Aditya Veldurthy, a Patz, ne Hagist, Christian P. Pallasch,

Clemens- Wendtner, Hallek, and Gunter Krause*

Department I for Internal Medicine, University Hospital Cologne, Cologne,

Germany

* Corresponding author; email: guenter.krause@... .

Src family kinases (SFKs) were described to be overexpressed in chronic

lymphocytic leukemia (CLL). Therefore, we wished to examine the effects of the

Src and Abl kinase inhibitor dasatinib on the intracellular signaling and

survival of CLL cells. Dasatinib showed a dose and time dependent reduction of

global tyrosine phosphorylation and of activating phosphotyrosine levels of

SFKs. Treatment with 100 nM dasatinib led to decreased levels of the activated,

phosphorylated forms of Akt, Erk1/2 and p38, and induced PARP cleavage through

caspase activity. In Mec1 and JVM-3 cell lines, dasatinib increased p53 protein

levels and inhibited proliferation. In freshly isolated CLL cells, dasatinib

reduced the expression of Mcl-1 and Bcl-xL. Combination of 5 µM dasatinib and

fludarabine increased the apoptosis induction of each by ~50 %. In 15 primary

CLL samples, cells with unmutated immunoglobulin variable heavy chain (IgVH)

genes were more sensitive to dasatinib than those with mutated IgVH genes

(p=0.002). In summary, dasatinib shows potent inhibitory effects on the survival

of CLL cells in vitro most prominently in samples obtained from patients with

unfavorable prognostic features.