ZRF1-mediated transcriptional regulation in acute myeloid leukemia
Acute myeloid leukemia (AML) is frequently linked to epigenetic abnormalities and deregulation of gene transcription, which lead to aberrant cell proliferation and accumulation of undifferentiated precursors. ZRF1, a recently characterized epigenetic factor involved in transcriptional regulation, is...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2014 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/283478 |
| Acceso en línea: | http://hdl.handle.net/10803/283478 |
| Access Level: | acceso abierto |
| Palabra clave: | ZRF1 Acute myeloid leukemia Transcription Chromatin Differentiation Retinoic acid RARα Leucèmia mieloide aguda Transcripció Cromatina Diferenciació Àcid retinoic 616 |
| Sumario: | Acute myeloid leukemia (AML) is frequently linked to epigenetic abnormalities and deregulation of gene transcription, which lead to aberrant cell proliferation and accumulation of undifferentiated precursors. ZRF1, a recently characterized epigenetic factor involved in transcriptional regulation, is highly overexpressed in human AML, but it is not known whether it plays a role in leukemia progression. In this thesis, we have investigated the function of ZRF1-mediated transcriptional regulation in AML. We demonstrate that ZRF1 depletion decreases cell proliferation, increases apoptosis and induces cell differentiation in human AML cells. Treatment with retinoic acid (RA), a differentiating agent currently used to treat certain AMLs, leads to a functional switch of ZRF1 from a negative regulator to an activator of differentiation. At the molecular level, ZRF1 controls the RA-regulated gene network through its interaction with the RA receptor α (RARα) and its binding to RA target genes. Our genomewide expression study reveals that ZRF1 regulates the transcription of nearly half of RA target genes. Consistent with our in vitro observations that ZRF1 regulates proliferation, apoptosis, and differentiation, ZRF1 depletion strongly inhibits leukemia progression in xenograft mouse models. Finally, ZRF1 knockdown cooperate with RA treatment in leukemia suppression in vivo. Taken together, our results show that ZRF1 is a key transcriptional regulator in leukemia progression and suggest that ZRF1 inhibition could be a novel strategy to be explored for AML treatment. |
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