Abstract
Leukemias are differentially sensitive to histone deacytelase inhibitor (HDI)-induced apoptosis, but molecular reasons for this remain unclear. We here show that BCR/ABL-, but not FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-transformed 32D cells or primary acute myeloid leukemia (AML) blasts undergo apoptosis after treatment with the HDI valproic acid (VPA) plus all-trans retinoic acid (VPA/ATRA). A particular VPA/ATRA responsiveness of Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) was confirmed in a therapy-refractory patient in vivo. HDI-stimulated apoptosis in Ph+ cells was caspase dependent, but independent from Akt pathway inhibition. Conversely, separate blockage of the Akt/mTor-signaling pathway was a prerequisite for overcoming apoptosis resistance to VPA/ATRA in FLT3-ITD cells, and primary AML blasts (n = 9). In conclusion, constitutive Akt activation causes apoptosis resistance to VPA/ATRA in AML, but not in Ph+ leukemia. This warrants the application of HDI-based therapies in poor-risk Ph+ ALL, and the use of Akt/mTor inhibitors to overcome HDI resistance in AML.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects*
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Apoptosis / genetics
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Caspases / metabolism
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Fusion Proteins, bcr-abl / metabolism
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Histone Deacetylase Inhibitors
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Humans
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Leukemia, Myelomonocytic, Acute / drug therapy
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Leukemia, Myelomonocytic, Acute / genetics
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Leukemia, Myelomonocytic, Acute / metabolism
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Mutation
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Oncogene Protein v-akt / antagonists & inhibitors
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Oncogene Protein v-akt / metabolism
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Philadelphia Chromosome
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
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Protein Kinases / metabolism
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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TOR Serine-Threonine Kinases
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Tretinoin / pharmacology*
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Tretinoin / therapeutic use
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Tumor Cells, Cultured
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Valproic Acid / pharmacology*
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Valproic Acid / therapeutic use
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fms-Like Tyrosine Kinase 3 / genetics
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fms-Like Tyrosine Kinase 3 / metabolism
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Histone Deacetylase Inhibitors
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Tretinoin
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Valproic Acid
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Protein Kinases
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MTOR protein, human
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FLT3 protein, human
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fms-Like Tyrosine Kinase 3
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Fusion Proteins, bcr-abl
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Oncogene Protein v-akt
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TOR Serine-Threonine Kinases
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Caspases