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

Steimer DA, Boyd K, Takeuchi O, Fisher JK, Zambetti GP, Opferman JT
Blood. 2009 113 (12): 2805-15

PMID: 19064728 · PMCID: PMC2661864 · DOI:10.1182/blood-2008-05-159145

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.

MeSH Terms (27)

Animals Apoptosis Apoptosis Regulatory Proteins bcl-2 Homologous Antagonist-Killer Protein bcl-2-Associated X Protein Bcl-2-Like Protein 11 Bone Marrow Cells Escherichia coli Filgrastim Gene Deletion Granulocyte Colony-Stimulating Factor Granulocytes Macrophage Activation Macrophages, Peritoneal Membrane Proteins Mice Mice, Inbred C57BL Mice, Knockout Myeloid Cell Leukemia Sequence 1 Protein Myelopoiesis Organ Specificity Phagocytosis Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Recombinant Proteins Specific Pathogen-Free Organisms Tumor Suppressor Proteins

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