Submitted May 23, 2008
Accepted November 16, 2008
Selective roles for anti-apoptotic MCL-1 during granulocyte development and macrophage effector function
Desiree A. Steimer, Kelli Boyd, Osamu Takeuchi, Jill K. Fisher, Gerard P. Zambetti, and Joseph T. Opferman*
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN, United States
Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN, United States
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, United States
* Corresponding author; email: joseph.opferman{at}stjude.org.
During hematopoiesis, myeloid cell leukemia-1 (MCL-1) mediates the survival of bone marrow progenitors and lymphocytes. However, its requirement during myeloid cell differentiation, development, and effector function is less clear. Lineage-specific deletion of MCL-1 in myeloid precursors results in neutropenia due to death during differentiation. The loss of mature neutrophils induced by Mcl-1-deletion was not rescued by genetic deletion of pro-apoptotic Bim and Puma or by exogenous cytokine treatment. However, blockade of intrinsic apoptosis by lineage-specific deletion of both multi-domain pro-apoptotics Bax and Bak was capable of rescuing the neutropenia associated with Mcl-1-deletion. In the monocytic lineage, despite efficient Mcl-1-deletion, monocytes and macrophages undergo normal development. During the phagocytosis of extracellular bacteria, macrophages concomitantly increase the expression of both MCL-1 and BIM. However, Mcl-1-deficient macrophages exhibit increased sensitivity to death during bacterial phagocytosis that can be abolished by co-deletion of Bim. These data suggest that MCL-1 may be necessary to antagonize BIM during macrophage effector responses. Thus, MCL-1 plays selective roles in myeloid development, being required for neutrophil development and setting the threshold for apoptosis during a macrophage effector response.
