Over the past three decades, considerable progress has been made in the treatment of pediatric acute lymphoblastic leukemia (ALL). Combination chemotherapy and corticosteroids administered in complicated regimens have greatly improved outcomes, with the majority of children being cured. Unfortunately, a subset of patients are either resistant to primary therapy or relapse from their disease. In each of these settings, a high proportion of corticosteroid resistance exists, which to date has been poorly characterized. The typical pathway through which most cancer therapeutics work, including those utilized in the treatment of adult ALL, is programmed cell death via caspase enzymes. In resistant ALL and other cancers, caspase activation is blocked. A recently discovered mechanism by which death can still be provoked in such cells is by induction of autophagy. Autophagy is a protective mechanism in which normal cells engulf and digest internal organelles in times of starvation or stress to promote survival. The role of autophagy in cancer, including leukemia, is somewhat variable, with some studies demonstrating a protective effect from stress, whereas others have shown it to generate a pro-death effect. Bonapace and colleagues from the lab of Jean-Pierr Bourquini in Zurich demonstrated that treatment of corticosteroid and chemotherapy-resistant ALL cells with the BCL-2 inhibitor obatoclax dramatically converted them to a very responsive state. Whereas cytotoxic therapy with obatoclax treatment promoted cell death through apoptosis, with corticosteroids the autophage pathway of autophagy was activated, leading to caspase-independent cell death. Blockade of autophagy by antagonizing expression of key autophagy-mediating genes antagonized ALL cell chemosensitization to corticosteroids, thereby demonstrating the importance of this pathway in converting cells from steroid-resistant to steroid-responsive. The molecular details underlying these phenomena were further defined by showing that obatoclax interaction with the BCL-2 family member protein MCL-1 was essential to the process, resulting in its disassociation from the BH3 domain protein Beclin-1. Initiation of authophagy followed and was dependent on the activity of a specific kinase, RIP, that in turn was tightly controlled by the cylindromatosis de-ubiquitinase. Collectively, these studies provide a new therapeutic avenue for treating corticosteroid-resistant ALL with obatoclax.
In Brief
The importance of this paper to the fields of molecular pharmacology, autophagy, and the biology of pediatric ALL are numerous. Whereas the number of papers that have linked the BCL-2 family member protein MCL-1 to disrupting apoptosis are numerous, herein the authors show that this same protein also interacts with the BH3 domain protein Beclin-1, thereby preventing initiation of autophagy. Although obatoclax and dexamethasone have no direct interaction with mTOR, their combination in ALL cells inhibits this enzyme through uncertain mechanisms with similar down-stream effects including induction of autophagy. Finally, whereas autophagy in CML is actually a protective mechanism of death from therapeutics such as imatinib, the authors demonstrated that this process facilitates tumor death with relative selectivity with the therapeutic agent obatoclax. The compelling in vitro and in vivo data with steroid-resistant ALL cells provide strong justification of clinical trials combining corticosteroids with obatoclax in relapsed, resistant ALL. Given the poor outcome of such patients, it is hoped that this outstanding study will favorably affect survival of some patients with refractory ALL.
Competing Interests
Dr. Byrd indicated no relevant conflicts of interest.
