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 Blood, 19 March 2009, Vol. 113, No. 12, pp. 2805-2815.
Prepublished online as a Blood First Edition Paper on December 8, 2008; DOI 10.1182/blood-2008-05-159145.

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PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS

Selective roles for antiapoptotic MCL-1 during granulocyte development and macrophage effector function

Desiree A. Steimer1, Kelli Boyd2, Osamu Takeuchi3, Jill K. Fisher4, Gerard P. Zambetti1, and Joseph T. Opferman1

1 Department of Biochemistry, and 2 Veterinary Pathology Core, St Jude Children's Research Hospital, Memphis, TN; 3 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Japan; and 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA

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 proapoptotic Bim and Puma or by exogenous cytokine treatment. However, blockade of intrinsic apoptosis by lineage-specific deletion of both multidomain proapoptotics 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 codeletion 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.


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