Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by a block of differentiation at the promyelocytic stage. APL patients respond to pharmacological concentrations of all-trans retinoic acid ( RA) and disease remission correlates with terminal differentiation of leukemic blasts. The PML/RAR oncogenic transcription factor is responsible for both the pathogenesis of APL and for its sensitivity to RA. In order to identify physiological targets of RA therapy, we analysed gene expression profiles of RA-treated APL blasts and found 1056 common target genes. Comparing these results to those obtained in RA-treated U937 cell lines revealed that transcriptional response to RA is largely dependent on the expression of PML/RAR. Several genes involved in the control of differentiation and stem cell renewal are early targets of RA regulation, and may be important effectors of RA response. Modulation of chromatin modifying genes was also observed, suggesting that specific structural changes in local chromatin domains may be required to promote RA-mediated differentiation. Computational analysis of upstream genomic regions in RA target genes revealed nonrandom distribution of transcription factor binding sites, indicating that specific transcriptional regulatory complexes may be involved in determining RA response.

Meani, N., Minardi, S., Licciulli, S., Gelmetti, V., Lo Coco, F., Nervi, C., et al. (2005). Molecular signature of retinoic acid treatment in acute promyelocytic leukemia. ONCOGENE, 24(20), 3358-3368 [10.1038/sj.onc.1208498].

Molecular signature of retinoic acid treatment in acute promyelocytic leukemia

LO COCO, FRANCESCO;
2005

Abstract

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by a block of differentiation at the promyelocytic stage. APL patients respond to pharmacological concentrations of all-trans retinoic acid ( RA) and disease remission correlates with terminal differentiation of leukemic blasts. The PML/RAR oncogenic transcription factor is responsible for both the pathogenesis of APL and for its sensitivity to RA. In order to identify physiological targets of RA therapy, we analysed gene expression profiles of RA-treated APL blasts and found 1056 common target genes. Comparing these results to those obtained in RA-treated U937 cell lines revealed that transcriptional response to RA is largely dependent on the expression of PML/RAR. Several genes involved in the control of differentiation and stem cell renewal are early targets of RA regulation, and may be important effectors of RA response. Modulation of chromatin modifying genes was also observed, suggesting that specific structural changes in local chromatin domains may be required to promote RA-mediated differentiation. Computational analysis of upstream genomic regions in RA target genes revealed nonrandom distribution of transcription factor binding sites, indicating that specific transcriptional regulatory complexes may be involved in determining RA response.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/15 - Malattie del Sangue
eng
Con Impact Factor ISI
acute myeloid leukemia; differentiation therapy; expression profiling; transcription factor binding sites; transcriptional regulation; retinoic acid; DNA modification; effector cell; human cell; pathogenesis; stem cell; leukemia; neoplastic; U937 cells
http://www.nature.com/onc/journal/v24/n20/pdf/1208498a.pdf
Meani, N., Minardi, S., Licciulli, S., Gelmetti, V., Lo Coco, F., Nervi, C., et al. (2005). Molecular signature of retinoic acid treatment in acute promyelocytic leukemia. ONCOGENE, 24(20), 3358-3368 [10.1038/sj.onc.1208498].
Meani, N; Minardi, S; Licciulli, S; Gelmetti, V; LO COCO, F; Nervi, C; Pelicci, P; Muller, H; Alcalay, M
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/8022
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