Abstract
AbstractSrc family kinases (SFKs) were described to be overexpressed in chronic lymphocytic leukemia (CLL). We wished to examine the effects of the Src and Abl kinase inhibitor dasatinib on the intracellular signaling and survival of CLL cells. Dasa-tinib 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 approximately 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 = .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.
Highlights
B-cell chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of CD5-positive monoclonal B cells, which escape apoptosis.[1]
The aim of this study was to assess the influence of the Src/Abl inhibitor dasatinib on signal transduction and survival of CLL cells
In 2 CLL cell lines and a set of freshly isolated CLL cell samples we showed that Src family kinases (SFKs) inhibition by dasatinib is correlated with apoptosis induction
Summary
B-cell chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of CD5-positive monoclonal B cells, which escape apoptosis.[1]. Because the B-cell receptor (BCR) and many of its coreceptors as well as cytokine receptors are devoid of intrinsic kinase activity, non-receptor kinases such as Src family kinases (SFKs) are expected to play crucial roles for the intracellular transduction of survival signals. A SFK that binds to the signaltransducing subunits of the BCR, is aberrantly expressed in CLL cells, which correlates with their apoptosis defects.[7]. A role for SFKs in the pathogenesis of Bcr-Abl-positive leukemias was demonstrated by combination of experimentally induced disease models and triple-knockout mice deficient in the SFKs Lyn, Hck, and Fgr for B-cell acute lymphocytic leukemia (B-ALL), but not for chronic myeloid leukemia (CML).[8] The treatment of CML has been revolutionized by the availability of the ATP-competitive Abl inhibitor imatinib mesylate, which targets the constitutive kinase activity of the Bcr-Abl fusion protein. The better accessibility of the hydrophobic inhibitor binding pocket for dasatinib as compared with imatinib leads to a wider spectrum of inhibited kinases, comprising SFKs and the receptor tyrosine kinases EGFR and c-kit.[18]
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