c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL; Implications for therapeutic targeting of chemoresistant niches

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Blood First Edition Paper, prepublished online September 16, 2008; DOI

10.1182/blood-2008-03-146704.

c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL;

Implications for therapeutic targeting of chemoresistant niches

Delfine YH Hallaert, Annelieke Jaspers, Carel J van Noesel, Marinus HJ van Oers,

Arnon P Kater, and Eldering*

Department of Hematology, Academic Medical Center, Amsterdam, Netherlands

Department of Pathology, Academic Medical Center, Amsterdam, Netherlands

Department of Experimental Immunology, Academic Medical Center, Amsterdam,

Netherlands

* Corresponding author; email: e.eldering@... .

In lymph node (LN) proliferation centers in chronic lymphocytic leukemia (CLL),

the environment protects from apoptotic and cytotoxic triggers. Here, we aimed

to define the molecular basis for the increased drug resistance and searched for

novel strategies to circumvent it. The situation in CLL LN could be mimicked by

prolonged in vitro CD40 stimulation, which resulted in upregulation of

anti-apoptotic Bcl-xL, A1/Bfl-1 and Mcl-1 proteins, and afforded resistance to

various classes of drugs (fludarabine, bortezomib, roscovitine). CD40

stimulation also caused ERK-dependent reduction of Bim-EL protein, but ERK

inhibition did not prevent drug resistance. Drugs combined with sublethal doses

of the BH3-mimetic ABT-737 displayed partial and variable effects per individual

CD40-stimulated CLL. The anti-apoptotic profile of CD40-triggered CLL resembled

BCR-Abl-dependent changes seen in CML, which prompted application of c-Abl

inhibitors imatinib or dasatinib. Both compounds, but especially dasatinib,

prevented the entire anti-apoptotic CD40 program in CLL cells, and restored drug

sensitivity. These effects also occurred in CLL samples with dysfunctional p53.

Importantly, ex vivo CLL LN samples also displayed strong ERK activation

together with high Bcl-xL and Mcl-1 but low Bim levels. These data indicate that

CLL cells in chemoresistant niches may be sensitive to therapeutic strategies

that include c-Abl inhibitors.