REVIEW Strategies targeting apoptosis proteins to improve therapy of chronic lymphocytic leukemia Samaher Besbes, Massoud Mirshahi, Marc Pocard, Christian Billard ⁎ INSERM U965, Hôpital Lariboisière, Paris, France Université Paris Diderot-Paris 7, UMR S965, Paris, France abstract article info Available online xxxx Keywords: CLL Apoptosis reactivation Targeting proteins regulating apoptosis Bcl-2 family IAP proteins BH3 mimetics A typical feature of chronic lymphocytic leukemia (CLL) is the impaired ability of the leukemic cells to execute their apoptotic suicide program. Various strategies have been developed to restore apoptosis in CLL cells ex vivo. This article reviews the strategies targeting proteins that directly regulate the mitochondrial pathway of apoptosis and caspase activation: (i) inhibiting the expression or activity of prosurvival proteins of the Bcl-2 and IAP (inhibitor of apoptosis protein) families, which are overexpressed in CLL cells and (ii) upregulating proapoptotic BH3-only members of the Bcl-2 family (which are antagonists of the prosurvival members). Preclin- ical and clinical data have revealed that inhibiting the activity of prosurvival Bcl-2 proteins with BH3 mimetics (so-called because they mimic BH3-only proteins) is an attractive strategy for CLL therapy. Recent results suggest that the development of BH3 mimetics capable of directly activating the apoptosis effectors Bax and Bak may also be envisaged. © 2015 Elsevier Ltd. All rights reserved. 1. Introduction Apoptosis is a cell death program occurring in either physiological or pathological conditions to eliminate useless and dangerous cells. The apoptotic program is executed by specific proteases belonging to the family of caspases, which are activated in response to various stress sig- nals through two distinct pathways: the extrinsic or death receptor pathway and the intrinsic or mitochondrial pathway [1]. In the latter, the permeabilization of the mitochondrial outer membrane elicits the release in the cytoplasm of two critical molecules: cytochrome c that triggers the cascade of caspase activation and second mitochondria- derived activator of caspases (SMAC) that neutralizes the activity of caspase antagonists called inhibitors of apoptosis proteins (IAP). The mitochondrial outer membrane permeabilization (MOMP) is strictly regulated by proteins of the Bcl-2 family (sharing one to four domains of Bcl-2 homology, BH1 to BH4). This family is divided into three subfamilies: antiapoptotic members (Bcl-2 and the closely related Bcl-xL, Bcl-w, Mcl-1 and A1) and two proapoptotic subfamilies: first, BH3-only proteins (so-called because they have only the BH3 domain, such as Puma, Bim, Noxa, Bid), which are antagonists of the antiapoptotic members, and second, the MOMP executioners (mainly Bax and Bak). Specific interactions between proteins of the three subfamilies control Bax and Bak activation and thus MOMP: notably antiapoptotic members sequester Bax and Bak, and the interactions of BH3-only proteins with the antiapoptotic members induce Bax/Bak release and activation; some of the BH3-only proteins can also directly activate Bax and Bak [1]. Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion and accumulation of a CD5-positive subpopulation of B cells in the blood, bone marrow, lymph node and spleen. This condition is thought to derive from an imbalance between proliferation and apoptosis. Contrarily to normal B lymphocytes, the leukemic cells accumulating in the blood are mostly unable to trigger their suicide pro- gram. This typical feature of CLL results from both defective mecha- nisms in the leukemic cells and an excess of survival signals delivered by microenvironment cells [2–6]. Hence, the transcription factor nucle- ar factor-κB (NF-κB), the phosphatidylinositol-3-kinase (PI3K)/AKT pathway (that leads to the phosphorylation of many apoptosis-related proteins) and pathways involved in the B-cell receptor (BCR) signaling are constitutively activated, which stimulates the transcription of numerous antiapoptotic proteins and their overexpression. The main overexpressed antiapoptotic factors in CLL cells are members of the IAP family such as X-linked IAP (XIAP) and the Bcl-2 family proteins Bcl-2 and Mcl-1 [4–6]. The crucial role of Mcl-1 in drug resistance, dis- ease progression and outcome in CLL patients is now well documented [7]. In some CLL cases, losses of micro-interfering RNAs miR-15a and miR-16 due to the common deletion 13q14 (resulting in Bcl-2 overex- pression) [8] and inactivation of p53 (allowing the transcription of proapoptotic molecules, including the BH3-only proteins Puma and Noxa) also contribute to the apoptosis deficiency. Blood Reviews xxx (2015) xxx–xxx ⁎ Corresponding author at: INSERM U.965, Hôpital Lariboisière, 41 Bd de la Chapelle, 75010 Paris, France. Tel.: +33 1 5321 6750; fax: +33 1 5321 6739. E-mail address: christian.billard@inserm.fr (C. Billard). YBLRE-00389; No of Pages 6 http://dx.doi.org/10.1016/j.blre.2015.03.005 0268-960X/© 2015 Elsevier Ltd. All rights reserved. Contents lists available at ScienceDirect Blood Reviews journal homepage: www.elsevier.com/locate/blre Please cite this article as: Besbes S, et al, Strategies targeting apoptosis proteins to improve therapy of chronic lymphocytic leukemia, Blood Rev (2015), http://dx.doi.org/10.1016/j.blre.2015.03.005