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

DA Steimer, K Boyd, O Takeuchi… - Blood, The Journal …, 2009 - ashpublications.org
DA Steimer, K Boyd, O Takeuchi, JK Fisher, GP Zambetti, JT Opferman
Blood, The Journal of the American Society of Hematology, 2009ashpublications.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
proapoptotic Bim and Puma or by exogenous cytokine treatment. However, blockade of …
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.
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