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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.

Titel:	FLT3-ITD-, but not BCR/ABL-transformed cells require concurrent Akt/mTor blockage to undergo apoptosis after histone deacetylase inhibitor treatment.
Autor/in / Beteiligte Person:	Cai, D ; Wang, Y ; Ottmann, OG ; Barth, PJ ; Neubauer, A ; Burchert, A
Zeitschrift:	Blood, Jg. 107 (2006-03-01), Heft 5, S. 2094
Veröffentlichung:	2021- : [New York] : Elsevier ; <i>Original Publication</i>: New York, Grune & Stratton [etc.], 2006
Medientyp:	academicJournal
ISSN:	0006-4971 (print)
DOI:	10.1182/blood-2005-08-3317
Schlagwort:	Antineoplastic Agents therapeutic use Apoptosis genetics Caspases metabolism Cell Transformation, Neoplastic genetics Cell Transformation, Neoplastic metabolism Drug Resistance, Neoplasm drug effects Drug Resistance, Neoplasm genetics Enzyme Inhibitors therapeutic use Fusion Proteins, bcr-abl metabolism Histone Deacetylase Inhibitors Humans Leukemia, Myelomonocytic, Acute drug therapy Leukemia, Myelomonocytic, Acute genetics Leukemia, Myelomonocytic, Acute metabolism Mutation Oncogene Protein v-akt antagonists & inhibitors Oncogene Protein v-akt metabolism Philadelphia Chromosome Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy Protein Kinases metabolism Signal Transduction genetics TOR Serine-Threonine Kinases Tretinoin therapeutic use Tumor Cells, Cultured Valproic Acid therapeutic use fms-Like Tyrosine Kinase 3 genetics fms-Like Tyrosine Kinase 3 metabolism Antineoplastic Agents pharmacology Apoptosis drug effects Enzyme Inhibitors pharmacology Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism Signal Transduction drug effects Tretinoin pharmacology Valproic Acid pharmacology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Blood] 2006 Mar 01; Vol. 107 (5), pp. 2094-7. <i>Date of Electronic Publication: </i>2005 Nov 22. MeSH Terms: Antineoplastic Agents / pharmacology ; Apoptosis / drug effects ; Enzyme Inhibitors / pharmacology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism ; Signal Transduction / drug effects ; Tretinoin / pharmacology ; Valproic Acid / *pharmacology ; Antineoplastic Agents / therapeutic use ; Apoptosis / genetics ; Caspases / metabolism ; Cell Transformation, Neoplastic / genetics ; Cell Transformation, Neoplastic / metabolism ; Drug Resistance, Neoplasm / drug effects ; Drug Resistance, Neoplasm / genetics ; Enzyme Inhibitors / therapeutic use ; Fusion Proteins, bcr-abl / metabolism ; Histone Deacetylase Inhibitors ; Humans ; Leukemia, Myelomonocytic, Acute / drug therapy ; Leukemia, Myelomonocytic, Acute / genetics ; Leukemia, Myelomonocytic, Acute / metabolism ; Mutation ; Oncogene Protein v-akt / antagonists & inhibitors ; Oncogene Protein v-akt / metabolism ; Philadelphia Chromosome ; Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy ; Protein Kinases / metabolism ; Signal Transduction / genetics ; TOR Serine-Threonine Kinases ; Tretinoin / therapeutic use ; Tumor Cells, Cultured ; Valproic Acid / therapeutic use ; fms-Like Tyrosine Kinase 3 / genetics ; fms-Like Tyrosine Kinase 3 / metabolism Substance Nomenclature: 0 (Antineoplastic Agents) ; 0 (Enzyme Inhibitors) ; 0 (Histone Deacetylase Inhibitors) ; 5688UTC01R (Tretinoin) ; 614OI1Z5WI (Valproic Acid) ; EC 2.7.- (Protein Kinases) ; EC 2.7.1.1 (MTOR protein, human) ; EC 2.7.10.1 (FLT3 protein, human) ; EC 2.7.10.1 (fms-Like Tyrosine Kinase 3) ; EC 2.7.10.2 (Fusion Proteins, bcr-abl) ; EC 2.7.11.1 (Oncogene Protein v-akt) ; EC 2.7.11.1 (TOR Serine-Threonine Kinases) ; EC 3.4.22.- (Caspases) Entry Date(s): Date Created: 20051124 Date Completed: 20060403 Latest Revision: 20211203 Update Code: 20240513

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FLT3-ITD-, but not BCR/ABL-transformed cells require concurrent Akt/mTor blockage to undergo apoptosis after histone deacetylase inhibitor treatment.