Inhibitor of apoptosis (IAP) proteins are highly expressed in chronic lymphocytic leukemia (CLL) cells and contribute to evasion of cell death and poor therapeutic response. Here, we report that Smac mimetic BV6 dose-dependently induces cell death in 28 of 51 (54%) investigated CLL samples, while B-cells from healthy donors are largely unaffected. Importantly, BV6 is significantly more effective in prognostic unfavorable cases with, e.g., non-mutated VH status and TP53 mutation than samples with unknown or favorable prognosis. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases respond to BV6, indicating that BV6 acts independently of p53. BV6 also triggers cell death under survival conditions mimicking the microenvironment, e.g., by adding CD40 ligand or conditioned medium. Gene expression profiling identifies cell death, NF-jB and redox signaling among the top pathways regulated by BV6 not only in CLL but also in core-binding factor (CBF) acute myeloid leukemia (AML). Consistently, BV6 stimulates production of reactive oxygen species (ROS), which are contributing to BV6-induced cell death, since antioxidants reduce cell death. While BV6 causes degradation of cellular inhibitor of apoptosis (cIAP)1 and cIAP2 and nuclear factor-kappaB (NF-jB) pathway activation in primary CLL samples, BV6 induces cell death independently of caspase activity, receptor-interacting protein (RIP)1 activity or tumor necrosis factor (TNF)a, as zVAD.fmk, necrostatin-1 or TNFa-blocking antibody Enbrel fail to inhibit cell death. Together, these novel insights into BV6-regulated cell death in CLL have important implications for developing new therapeutic strategies to overcome cell death resistance especially in poor prognostic CLL subgroups.Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western world. 1 Key prognostic factors besides the Rai and Binet stage are chromosomal aberrations like 17p or 11q deletion, TP53 mutation and immunoglobulin heavy-chain variable region gene (IGVH) mutation status. Although individualized therapeutic strategies have been developed, the disease is still incurable. Especially patients with 17p deletion and TP53 mutation have a very poor prognosis. 2 Therefore, new therapeutic targets that act independently of functional p53 in CLL are needed.CLL is characterized by the accumulation of Blymphocytes which has been largely attributed to defective cell death pathways rather than to aberrant proliferation. [3][4][5] Apoptosis represents one of the key forms of programmed cell death. 6 Necroptosis is a caspase-independent mode of programmed cell death that typically occurs when essential factors of apoptosis such as caspases are inhibited and is regulated by RIP1 and RIP3. 7 Inhibitor of apoptosis (IAP) proteins are major regulators of cell death and survival processes. X-linked inhibitor of apoptosis (XIAP) acts as direct caspase inhibitor, 8 while cIAP1 and -2 were shown to protect cells from cell death by acting primarily as E3 ubiquitin liga...

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