Submitted June 28, 2007
Accepted November 24, 2007
BCL-2 dependence and ABT-737 sensitivity
in acute lymphoblastic leukemia
Victoria Del Gaizo Moore, Krysta D Schlis, Stephen E. Sallan, Scott A Armstrong, and Anthony Letai*
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
Division of Hematology/Oncology, Children's Hospital, Boston, MA, United States
* Corresponding author; email: anthony_letai{at}dfci.harvard.edu.
Cancer cells acquire disruptions in normal signal transduction pathways and homeostatic mechanisms that would trigger apoptosis in normal cells. These abnormalities include genomic instability, oncogene activation, and growth factor independent proliferation. Therefore, cancer cells likely require a block in apoptosis in order to survive. Overexpression of the anti-apoptotic protein BCL-2 provides a block in apoptosis that is frequently observed in cancer cells. We have developed methods for the detection and analysis of BCL-2 dependence and here apply them to acute lymphoblastic leukemia (ALL). BH3 profiling, a mitochondrial assay that classifies blocks in the intrinsic apoptotic pathway, indicated a dependence on BCL-2 of both ALL cell lines and primary samples. This dependence predicted that BCL-2 would be complexed with select pro-death BH3 family proteins, a prediction confirmed by the isolation of BCL-2 complexes with BIM. Furthermore, the BH3 profiling and protein analysis predicted that ALL cell lines and primary cells would be sensitive to ABT-737 as a single agent. Finally, BH3 profiling and protein studies accurately predicted relative degree of sensitivity to BCL-2 antagonism in cell lines. The ALL cells studied exhibit BCL-2 dependence, supporting clinical trials of BCL-2 antagonists in ALL as single agents or combination therapies.
