Abstract
Sustained engagement of the B-cell receptor (BCR) increases apoptosis resistance in chronic lymphocytic leukemia (CLL) B cells, whereas transient stimulation usually has an opposite effect. The antiapoptotic BCR signal has been associated with prolonged activation of the PI3K/Akt and MEK/ERK pathways, which are key regulators of survival and proliferation in various cell types. To further define the relative contribution of the Akt and ERK kinases in regulating CLL B-cell survival, we introduced constitutively active mutants of Akt and MEK in primary CLL B cells and evaluated changes in the expression of relevant pro- and antiapoptotic proteins. Sustained activation of Akt resulted in increased leukemic cell viability and increased expression of the antiapoptotic proteins Mcl-1, Bcl-xL, and X-linked inhibitor of apoptosis protein (XIAP), thus largely recapitulating the effects of sustained BCR stimulation. Constitutively active MEK2 also up-regulated XIAP, but did not show a significant impact on leukemic cell survival. Down-regulation of Mcl-1 by siRNA treatment induced rapid and potent apoptosis in CLL B cells and blocked the antiapoptotic effect of sustained BCR stimulation, whereas down-regulation of Bcl-xL and XIAP did not affect leukemic cell viability. These data demonstrate that Akt and Mcl-1 are major components of a survival pathway that can be activated in CLL B cells by antigen stimulation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis*
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B-Lymphocytes / metabolism*
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B-Lymphocytes / pathology
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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MAP Kinase Kinase 2 / genetics
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MAP Kinase Kinase 2 / metabolism
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MAP Kinase Signaling System* / drug effects
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MAP Kinase Signaling System* / genetics
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Male
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / pharmacology
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Receptors, Antigen, B-Cell / genetics
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Receptors, Antigen, B-Cell / metabolism*
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X-Linked Inhibitor of Apoptosis Protein / genetics
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X-Linked Inhibitor of Apoptosis Protein / metabolism
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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BCL2L1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Receptors, Antigen, B-Cell
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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bcl-X Protein
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MAP2K2 protein, human
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase 2