Abstract
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 V(H) genes). Interestingly, cases with unmutated V(H) genes were significantly more sensitive to XIAP inhibitor-induced and TRAIL-induced apoptosis compared with V(H) 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.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults in western societies [1]
Western blot analysis showed that the inhibitor of apoptosis (IAP) proteins X-linked inhibitor of apoptosis (XIAP), cIAP1, cIAP2, and survivin as well as the endogenous IAP antagonists second mitochondriaderived activator of caspase (Smac)/DIABLO and Omi/high-temperature requirement protein A2 (HtrA2) were all expressed in CLL cell lines (Fig. 1A, left)
We examined the effect of small-molecule XIAP inhibitors on apoptosis induction in CLL cell lines using two distinct small-molecule XIAP inhibitors that bind to the BIR3 domain of XIAP with high affinity at nanomolar concentrations [26]
Summary
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults in western societies [1]. CLL is characterized by the abnormal accumulation of malignant monoclonal B cells, which has been largely attributed to defective apoptosis programs rather than aberrant proliferation [2,3,4]. Ligation of death receptors of the tumor necrosis factor (TNF) receptor superfamily, such as CD95 (APO-1/Fas), by their cognate ligands or agonistic antibodies results in caspase-8 activation at the death-inducing signaling complex, which induces direct cleavage of downstream effector caspases, such as caspase-3 [8]. The release of cytochrome c, second mitochondriaderived activator of caspase (Smac)/direct inhibitor of apoptosis (IAP) binding protein with low isoelectric point (DIABLO), or Omi/high-temperature requirement protein A2 (HtrA2) from mitochondria into the cytosol results in caspase-3 activation via formation of the cytochrome c/Apaf-1/caspase-9–containing apoptosome complex and via Smac-mediated neutralization of caspase inhibition by IAP proteins [9]
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