Antagonism between granulocytic maturation and deacetylase inhibitor-induced apoptosis in acute promyelocytic leukaemia cells
| Autor: | Sylvia Müller, Manuel Grez, K Pietschmann, Dorle Hennig, Oliver H. Krämer, Gesine Bug, Thorsten Heinzel, Lisann Pelzl, Sebastian Drube, Christian Wichmann |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Indoles Cellular differentiation bcl-X Protein Antineoplastic Agents Tretinoin Biology Hydroxamic Acids chemistry.chemical_compound Leukemia Promyelocytic Acute HDAC hemic and lymphatic diseases Panobinostat Cell Line Tumor medicine Humans ATRA C/EBPɛ Ccaat-enhancer-binding proteins LBH589 apoptosis Cell Differentiation differentiation medicine.disease Gene Expression Regulation Neoplastic Histone Deacetylase Inhibitors Leukemia Oncology chemistry Apoptosis Cell culture Immunology Cancer research CCAAT-Enhancer-Binding Proteins Drug Screening Assays Antitumor Antagonism Translational Therapeutics medicine.drug Granulocytes |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | Background: Transcriptional repression is a key mechanism driving leukaemogenesis. In acute promyelocytic leukaemia (APL), the fusion protein promyelocytic leukaemia-retinoic acid receptor-α fusion (PML-RARα) recruits transcriptional repressors to myeloid differentiation genes. All-trans-retinoic acid (ATRA) induces the proteasomal degradation of PML-RARα and granulocytic differentiation. Histone deacetylases (HDACs) fall into four classes (I–IV) and contribute to the transcription block caused by PML-RARα. Methods: Immunoblot, flow cytometry, and May-Grünwald–Giemsa staining were used to analyze differentiation and induction of apoptosis. Results: A PML-RARα- and ATRA-dependent differentiation programme induces granulocytic maturation associated with an accumulation of the myeloid transcription factor CCAAT/enhancer binding protein (C/EBP)ɛ and of the surface protein CD11b. While this process protects APL cells from inhibitors of class I HDAC activity, inhibition of all Zinc-dependent HDACs (classes I, II, and IV) with the pan-HDACi (histone deacetylase inhibitor(s)) LBH589 induces apoptosis of immature and differentiated APL cells. LBH589 can eliminate C/EBPɛ and the mitochondrial apoptosis regulator B-cell lymphoma (BCL)-xL in immature and differentiated NB4 cells. Thus, BCL-xL and C/EBPɛ are newly identified molecular markers for the efficacy of HDACi against APL cells. Conclusions: Our results could explain the therapeutic limitations occurring with ATRA and class I HDACi combinations. Pro-apoptotic effects caused by pan-HDAC inhibition are not blunted by ATRA-induced differentiation and may provide a clinically interesting alternative. |
| Databáze: | OpenAIRE |
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