Published online first on November 17, 2009
[Cancer Research, 10.1158/0008-5472.CAN-09-2604]
A Novel Paradigm to Trigger Apoptosis in Chronic Lymphocytic Leukemia
Sandra Loeder1, Thorsten Zenz2, Andrea Schnaiter2, Daniel Mertens2, Dirk
Winkler2, Hartmut Döhner2, Klaus-Michael Debatin1, Stephan Stilgenbauer2 and
Simone Fulda1
1 University Children's Hospital; 2 Department of Internal Medicine III, Ulm
University, Ulm, Germany

Requests for reprints: Simone Fulda, University Children's Hospital, Eythstr.
24, D-89075 Ulm, Germany. Phone: 49-731-5005-7034; Fax: 49-731-5005-7058;
E-mail: simone.fulda@... .


Evasion of apoptosis is a hallmark of chronic lymphocytic leukemia (CLL),
calling for new strategies to bypass resistance. Here, we provide first evidence
that small-molecule X-linked inhibitor of apoptosis (XIAP) inhibitors in
combination with the death receptor ligand tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL) present a novel approach to trigger apoptosis
in CLL, including subgroups with resistant disease or unfavorable prognosis.
XIAP, cellular IAP (cIAP) 1, and cIAP2 are expressed at high levels in primary
CLL samples. Proof-of-concept studies in CLL cell lines show that subtoxic
concentrations of XIAP inhibitors significantly enhance TRAIL-induced apoptosis
and also sensitize for CD95-mediated apoptosis. Importantly also in primary CLL
samples, XIAP inhibitor acts in concert with TRAIL to trigger apoptosis in 18 of
27 (67%) cases. This XIAP inhibitor-induced and TRAIL-induced apoptosis involves
caspase-3 activation and is blocked by the caspase inhibitor zVAD.fmk. The
cooperative interaction of XIAP inhibitor and TRAIL is even evident in distinct
subgroups of patients with poor prognostic features (i.e., with 17p deletion,
TP53 mutation, chemotherapy-refractory disease, or unmutated VH genes).
Interestingly, cases with unmutated VH genes were significantly more sensitive
to XIAP inhibitor-induced and TRAIL-induced apoptosis compared with VH
gene-mutated samples, pointing to a role of B-cell receptor signaling in
apoptosis regulation. By showing that XIAP inhibitors in combination with TRAIL
present a new strategy to trigger apoptosis even in resistant forms and poor
prognostic subgroups of CLL, our findings have important implications for the
development of apoptosis-based therapies in CLL. [Cancer Res
2009;69(23):8977-86]



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