Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology
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Apoptosis Regulatory Proteins / deficiency
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / physiology
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Bcl-2-Like Protein 11
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Bone Marrow Cells / cytology
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Escherichia coli
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Filgrastim
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Gene Deletion
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Granulocyte Colony-Stimulating Factor / pharmacology
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Granulocytes / cytology*
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Macrophage Activation / physiology*
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Macrophages, Peritoneal / cytology*
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Macrophages, Peritoneal / physiology
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Membrane Proteins / deficiency
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Membrane Proteins / genetics
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Membrane Proteins / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Cell Leukemia Sequence 1 Protein
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Myelopoiesis / drug effects
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Myelopoiesis / physiology*
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Organ Specificity
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Phagocytosis
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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Recombinant Proteins
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Specific Pathogen-Free Organisms
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology
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bcl-2 Homologous Antagonist-Killer Protein / deficiency
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bcl-2 Homologous Antagonist-Killer Protein / genetics
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bcl-2 Homologous Antagonist-Killer Protein / physiology
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bcl-2-Associated X Protein / deficiency
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / physiology
Substances
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Apoptosis Regulatory Proteins
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Bak1 protein, mouse
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Bax protein, mouse
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Mcl1 protein, mouse
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Membrane Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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PUMA protein, mouse
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Proteins
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Tumor Suppressor Proteins
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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Granulocyte Colony-Stimulating Factor
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Filgrastim