Abstract
Phosphoinositide-phospholipase C (PI-PLC) beta1 can be considered a specific target for demethylating therapy in high-risk myelodysplastic syndrome (MDS) patients, as azacitidine treatment has been associated with a PI-PLCbeta1-specific promoter demethylation, and induction of PI-PLCbeta1 gene and protein expression. However, little is known about the molecular effect of azacitidine in low-risk MDS or the functional mechanisms linked with azacitidine effect on PI-PLCbeta1 promoter. In the present study, we further investigated the role of epigenetic regulation of PI-PLCbeta1, mainly focusing on the structure of the PI-PLCbeta1 promoter. We first examined the effect of azacitidine on PI-PLCbeta1 promoter methylation and gene expression in low-risk MDS. Moreover, we studied the expression of key molecules associated with the nuclear inositide signaling pathways, such as cyclin D3. By applying a chromatin immunoprecipitation method, we also studied the correlation between the demethylating effect of azacitidine and the degree of recruitment to PI-PLCbeta1 promoter of some transcription factors implicated in hematopoietic stem cell proliferation and differentiation, as well as of the methyl-CpG-binding domain proteins, which specifically interact with methylated DNA. Taken together, our results hint at a specific involvement of PI-PLCbeta1 in epigenetic mechanisms, and are particularly consistent with the hypothesis of a role for PI-PLCbeta1 in azacitidine-induced myeloid differentiation.
| Original language | English |
|---|---|
| Pages (from-to) | 943-950 |
| Number of pages | 8 |
| Journal | Leukemia |
| Volume | 26 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 2012 |
Fingerprint
Keywords
- azacitidine
- methylation
- myelodysplastic syndromes
- nuclear signaling
- PI-PLCbeta1
ASJC Scopus subject areas
- Hematology
- Cancer Research
- Anesthesiology and Pain Medicine
Cite this
Epigenetic regulation of nuclear PI-PLCbeta1 signaling pathway in low-risk MDS patients during azacitidine treatment. / Follo, M. Y.; Russo, D.; Finelli, C.; Mongiorgi, S.; Clissa, C.; Fil, C.; Colombi, C.; Gobbi, M.; Manzoli, L.; Piazzi, M.; Martelli, A. M.; Cocco, L.
In: Leukemia, Vol. 26, No. 5, 05.2012, p. 943-950.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Epigenetic regulation of nuclear PI-PLCbeta1 signaling pathway in low-risk MDS patients during azacitidine treatment
AU - Follo, M. Y.
AU - Russo, D.
AU - Finelli, C.
AU - Mongiorgi, S.
AU - Clissa, C.
AU - Fil, C.
AU - Colombi, C.
AU - Gobbi, M.
AU - Manzoli, L.
AU - Piazzi, M.
AU - Martelli, A. M.
AU - Cocco, L.
PY - 2012/5
Y1 - 2012/5
N2 - Phosphoinositide-phospholipase C (PI-PLC) beta1 can be considered a specific target for demethylating therapy in high-risk myelodysplastic syndrome (MDS) patients, as azacitidine treatment has been associated with a PI-PLCbeta1-specific promoter demethylation, and induction of PI-PLCbeta1 gene and protein expression. However, little is known about the molecular effect of azacitidine in low-risk MDS or the functional mechanisms linked with azacitidine effect on PI-PLCbeta1 promoter. In the present study, we further investigated the role of epigenetic regulation of PI-PLCbeta1, mainly focusing on the structure of the PI-PLCbeta1 promoter. We first examined the effect of azacitidine on PI-PLCbeta1 promoter methylation and gene expression in low-risk MDS. Moreover, we studied the expression of key molecules associated with the nuclear inositide signaling pathways, such as cyclin D3. By applying a chromatin immunoprecipitation method, we also studied the correlation between the demethylating effect of azacitidine and the degree of recruitment to PI-PLCbeta1 promoter of some transcription factors implicated in hematopoietic stem cell proliferation and differentiation, as well as of the methyl-CpG-binding domain proteins, which specifically interact with methylated DNA. Taken together, our results hint at a specific involvement of PI-PLCbeta1 in epigenetic mechanisms, and are particularly consistent with the hypothesis of a role for PI-PLCbeta1 in azacitidine-induced myeloid differentiation.
AB - Phosphoinositide-phospholipase C (PI-PLC) beta1 can be considered a specific target for demethylating therapy in high-risk myelodysplastic syndrome (MDS) patients, as azacitidine treatment has been associated with a PI-PLCbeta1-specific promoter demethylation, and induction of PI-PLCbeta1 gene and protein expression. However, little is known about the molecular effect of azacitidine in low-risk MDS or the functional mechanisms linked with azacitidine effect on PI-PLCbeta1 promoter. In the present study, we further investigated the role of epigenetic regulation of PI-PLCbeta1, mainly focusing on the structure of the PI-PLCbeta1 promoter. We first examined the effect of azacitidine on PI-PLCbeta1 promoter methylation and gene expression in low-risk MDS. Moreover, we studied the expression of key molecules associated with the nuclear inositide signaling pathways, such as cyclin D3. By applying a chromatin immunoprecipitation method, we also studied the correlation between the demethylating effect of azacitidine and the degree of recruitment to PI-PLCbeta1 promoter of some transcription factors implicated in hematopoietic stem cell proliferation and differentiation, as well as of the methyl-CpG-binding domain proteins, which specifically interact with methylated DNA. Taken together, our results hint at a specific involvement of PI-PLCbeta1 in epigenetic mechanisms, and are particularly consistent with the hypothesis of a role for PI-PLCbeta1 in azacitidine-induced myeloid differentiation.
KW - azacitidine
KW - methylation
KW - myelodysplastic syndromes
KW - nuclear signaling
KW - PI-PLCbeta1
UR - http://www.scopus.com/inward/record.url?scp=84860769429&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84860769429&partnerID=8YFLogxK
U2 - 10.1038/leu.2011.300
DO - 10.1038/leu.2011.300
M3 - Article
C2 - 22033492
AN - SCOPUS:84860769429
VL - 26
SP - 943
EP - 950
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 5
ER -