BIM-mediated apoptosis and oncogene addiction

addiction is a phenomenon whereby suppression of a driver oncogene is associated with dramatic tumor regression that has been observed in experimental models and in response to targeted therapies [1]. However, the mechanism by which oncogene inactivation induces this massive reduction in tumor burden is not clear. In tumors addicted to the MYC oncogene, suppression of this oncogene leads to tumor regression that is associated with a marked increase in apoptosis. This at first glance appears to be paradoxical since generally oncogene activation, and MYC activation in particular, is associated with increased apoptosis. Recently, we have described a possible mechanism that may explain why inactivation of pro-apoptotic oncogenes, such as MYC, induce apoptosis [2]. To understand our recent results, we must first note that apoptosis is regulated by both pro-apoptotic and anti-apoptotic proteins. The pro-apoptotic protein, BIM (BCL2L11), is a BCL2 family member with three major isoforms (BIM-EL, BIM-L, and BIM-S) that can be generated from mRNA alternative splicing [3]. BIM works in concert with other pro-apoptotic proteins, such as PUMA, BAD, BAX, and anti-apoptotic proteins, such as BCL2, BCLXL, and MCL1, to regulate cell death and survival essential to normal tissue homeostasis. The precise regulation of BIM expression has been shown to be essential to normal development [3, 4]. Reduced BIM expression can disrupt normal development, induce autoimmunity and accelerate tumorigenesis [3, 5]. The relative dosage of BIM is critical, and its expression and activation is tightly regulated at many different levels, depending on the cellular context. BIM expression can be regulated transcriptionally by multiple transcriptional factors, posttrancriptionally by alternative splicing and microRNA binding, translationally by upstream open reading frames, posttranslationally by phosphorylation and degradation, as well as spatial localization and sequestration [6]. During normal physiological development, these regulatory mechanisms assure the precise control of BIM activation for tissue homeo-stasis. However, the same control mechanisms can also be perturbed by oncogenes that can contribute to tumorigenesis. Editorial We found in multiple transgenic mouse models of oncogene (MYC, BCR-ABL, RAS) induced acute lymphocytic leukemia (ALL), that BIM was the key mediator of apoptosis observed upon oncogene inactivation [2]. In all of these mouse models, close examination of the expression of apoptotic regulatory proteins revealed that, BIM was the key regulator of the apoptosis that was observed. Importantly, at least two different mechanisms were involved, including a microRNA mediated mechanism but also a cell signaling based mechanism (Figure 1). Thus, just …