Bcl-2 Sequesters Pro-Apoptotic BIM in CLL

[Guest guest]

Clin. Invest. 117:112-121 (2007). doi:10.1172/JCI28281.

Copyright ©2007 by the American Society for Clinical Investigation

---------------------------------------------------------------------

-----------

Research Article

Chronic lymphocytic leukemia requires BCL2 to sequester prodeath

BIM, explaining sensitivity to BCL2 antagonist ABT-737

Del Gaizo 1, R. Brown1, Certo1, Tara

M. Love2, Carl D. Novina2 and Letai1

1Department of Medical Oncology and 2Department of Cancer Immunology

and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Received for publication February 20, 2006, and accepted in revised

form November 14, 2006.

Antiapoptotic B cell leukemia/lymphoma 2 (BCL2) family proteins are

expressed in many cancers, but the circumstances under which these

proteins are necessary for tumor maintenance are poorly understood.

We exploited a novel functional assay that uses BCL2 homology domain

3 (BH3) peptides to predict dependence on antiapoptotic proteins, a

strategy we call BH3 profiling.

BH3 profiling accurately predicts sensitivity to BCL2 antagonist ABT-

737 in primary chronic lymphocytic leukemia (CLL) cells. BH3

profiling also accurately distinguishes myeloid cell leukemia

sequence 1 (MCL1) from BCL2 dependence in myeloma cell lines.

We show that the special sensitivity of CLL cells to BCL2 antagonism

arises from the requirement that BCL2 tonically sequester

proapoptotic BIM in CLL. ABT-737 displaced BIM from BCL2's BH3-

binding pocket, allowing BIM to activate BAX, induce mitochondrial

permeabilization, and rapidly commit the CLL cell to death.

Our experiments demonstrate that BCL2 expression alone does not

dictate sensitivity to ABT-737. Instead, BCL2 complexed to BIM is

the critical target for ABT-737 in CLL. An important implication is

that in cancer, BCL2 may not effectively buffer chemotherapy death

signals if it is already sequestering proapoptotic BH3-only

proteins.

Indeed, activator BH3-only occupation of BCL2 may prime cancer cells

for death, offering a potential explanation for the marked

chemosensitivity of certain cancers that express abundant BCL2, such

as CLL and follicular lymphoma.