title: FLT3-ITD-, but not BCR/ABL-transformed cells require concurrent Akt/mTor blockage to undergo apoptosis after histone deacetylase inhibitor treatment.
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.
authors.affiliation: Universitätsklinikum Marburg und Giessen, Standort Marburg, Klinik für Hämatologie, Onkologie, und Immunologie, Marburg, Germany.
authors.forename: Dali
authors.initials: D
authors.lastname: Cai
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Ottmann
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barth
authors.forename: Andreas
authors.initials: A
authors.lastname: Neubauer
authors.forename: Andreas
authors.initials: A
authors.lastname: Burchert
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D014212:Tretinoin; D014635:Valproic Acid; D011494:Protein Kinases; C546842:MTOR protein, human; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D016044:Fusion Proteins, bcr-abl; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D020169:Caspases