MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation

Martina Pigazzi, Elena Manara, Silvia Bresolin, Claudia Tregnago, Alessandra Beghin, Emma Baron, Emanuela Giarin, Er Chieh Cho, Riccardo Masetti, Dinesh S. Rao, Kathleen M. Sakamoto

研究成果: 雜誌貢獻文章

33 引文 (Scopus)

摘要

MicroRNA-34b down-regulation in acute myeloid leukemia was previously shown to induce CREB overexpression, thereby causing leukemia proliferation in vitro and in vivo. The role of microRNA-34b and CREB in patients with myeloid malignancies has never been evaluated. We examined microRNA-34b expression and the methylation status of its promoter in cells from patients diagnosed with myeloid malignancies. We used gene expression profiling to identify signatures of myeloid transformation. We established that microRNA-34b has suppressor ability and that CREB has oncogenic potential in primary bone marrow cell cultures and in vivo. MicroRNA-34b was found to be up-regulated in pediatric patients with juvenile myelomonocytic leukemia (n=17) and myelodysplastic syndromes (n=28), but was down-regulated in acute myeloid leukemia patients at diagnosis (n=112). Our results showed that hypermethylation of the microRNA-34b promoter occurred in 66% of cases of acute myeloid leukemia explaining the low microRNA-34b levels and CREB overexpression, whereas preleukemic myelodysplastic syndromes and juvenile myelomonocytic leukemia were not associated with hypermethylation or CREB overexpression. In paired samples taken from the same patients when they had myelodysplastic syndrome and again during the subsequent acute myeloid leukemia, we confirmed microRNA-34b promoter hypermethylation at leukemia onset, with 103 CREB target genes differentially expressed between the two disease stages. This subset of CREB targets was confirmed to associate with high-risk myelodysplastic syndromes in a separate cohort of patients (n=20). Seventy-eight of these 103 CREB targets were also differentially expressed between healthy samples (n=11) and de novo acute myeloid leukemia (n=72). Further, low microRNA-34b and high CREB expression levels induced aberrant myelopoiesis through CREB-dependent pathways in vitro and in vivo. In conclusion, we suggest that microRNA-34b controls CREB expression and contributes to myeloid transformation from both healthy bone marrow and myelodysplastic syndromes. We identified a subset of CREB target genes that represents a novel transcriptional network that may control myeloid transformation.

原文英語
頁(從 - 到)602-610
頁數9
期刊Haematologica
98
發行號4
DOIs
出版狀態已發佈 - 四月 2013
對外發佈Yes

指紋

MicroRNAs
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Juvenile Myelomonocytic Leukemia
Leukemia
Myelopoiesis
Gene Regulatory Networks
Gene Expression Profiling
Bone Marrow Cells
Methylation
Genes
Neoplasms
Down-Regulation
Cell Culture Techniques
Bone Marrow
Pediatrics

ASJC Scopus subject areas

  • Hematology

引用此文

Pigazzi, M., Manara, E., Bresolin, S., Tregnago, C., Beghin, A., Baron, E., ... Sakamoto, K. M. (2013). MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation. Haematologica, 98(4), 602-610. https://doi.org/10.3324/haematol.2012.070664

MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation. / Pigazzi, Martina; Manara, Elena; Bresolin, Silvia; Tregnago, Claudia; Beghin, Alessandra; Baron, Emma; Giarin, Emanuela; Cho, Er Chieh; Masetti, Riccardo; Rao, Dinesh S.; Sakamoto, Kathleen M.

於: Haematologica, 卷 98, 編號 4, 04.2013, p. 602-610.

研究成果: 雜誌貢獻文章

Pigazzi, M, Manara, E, Bresolin, S, Tregnago, C, Beghin, A, Baron, E, Giarin, E, Cho, EC, Masetti, R, Rao, DS & Sakamoto, KM 2013, 'MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation', Haematologica, 卷 98, 編號 4, 頁 602-610. https://doi.org/10.3324/haematol.2012.070664
Pigazzi, Martina ; Manara, Elena ; Bresolin, Silvia ; Tregnago, Claudia ; Beghin, Alessandra ; Baron, Emma ; Giarin, Emanuela ; Cho, Er Chieh ; Masetti, Riccardo ; Rao, Dinesh S. ; Sakamoto, Kathleen M. / MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation. 於: Haematologica. 2013 ; 卷 98, 編號 4. 頁 602-610.
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abstract = "MicroRNA-34b down-regulation in acute myeloid leukemia was previously shown to induce CREB overexpression, thereby causing leukemia proliferation in vitro and in vivo. The role of microRNA-34b and CREB in patients with myeloid malignancies has never been evaluated. We examined microRNA-34b expression and the methylation status of its promoter in cells from patients diagnosed with myeloid malignancies. We used gene expression profiling to identify signatures of myeloid transformation. We established that microRNA-34b has suppressor ability and that CREB has oncogenic potential in primary bone marrow cell cultures and in vivo. MicroRNA-34b was found to be up-regulated in pediatric patients with juvenile myelomonocytic leukemia (n=17) and myelodysplastic syndromes (n=28), but was down-regulated in acute myeloid leukemia patients at diagnosis (n=112). Our results showed that hypermethylation of the microRNA-34b promoter occurred in 66{\%} of cases of acute myeloid leukemia explaining the low microRNA-34b levels and CREB overexpression, whereas preleukemic myelodysplastic syndromes and juvenile myelomonocytic leukemia were not associated with hypermethylation or CREB overexpression. In paired samples taken from the same patients when they had myelodysplastic syndrome and again during the subsequent acute myeloid leukemia, we confirmed microRNA-34b promoter hypermethylation at leukemia onset, with 103 CREB target genes differentially expressed between the two disease stages. This subset of CREB targets was confirmed to associate with high-risk myelodysplastic syndromes in a separate cohort of patients (n=20). Seventy-eight of these 103 CREB targets were also differentially expressed between healthy samples (n=11) and de novo acute myeloid leukemia (n=72). Further, low microRNA-34b and high CREB expression levels induced aberrant myelopoiesis through CREB-dependent pathways in vitro and in vivo. In conclusion, we suggest that microRNA-34b controls CREB expression and contributes to myeloid transformation from both healthy bone marrow and myelodysplastic syndromes. We identified a subset of CREB target genes that represents a novel transcriptional network that may control myeloid transformation.",
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AU - Manara, Elena

AU - Bresolin, Silvia

AU - Tregnago, Claudia

AU - Beghin, Alessandra

AU - Baron, Emma

AU - Giarin, Emanuela

AU - Cho, Er Chieh

AU - Masetti, Riccardo

AU - Rao, Dinesh S.

AU - Sakamoto, Kathleen M.

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N2 - MicroRNA-34b down-regulation in acute myeloid leukemia was previously shown to induce CREB overexpression, thereby causing leukemia proliferation in vitro and in vivo. The role of microRNA-34b and CREB in patients with myeloid malignancies has never been evaluated. We examined microRNA-34b expression and the methylation status of its promoter in cells from patients diagnosed with myeloid malignancies. We used gene expression profiling to identify signatures of myeloid transformation. We established that microRNA-34b has suppressor ability and that CREB has oncogenic potential in primary bone marrow cell cultures and in vivo. MicroRNA-34b was found to be up-regulated in pediatric patients with juvenile myelomonocytic leukemia (n=17) and myelodysplastic syndromes (n=28), but was down-regulated in acute myeloid leukemia patients at diagnosis (n=112). Our results showed that hypermethylation of the microRNA-34b promoter occurred in 66% of cases of acute myeloid leukemia explaining the low microRNA-34b levels and CREB overexpression, whereas preleukemic myelodysplastic syndromes and juvenile myelomonocytic leukemia were not associated with hypermethylation or CREB overexpression. In paired samples taken from the same patients when they had myelodysplastic syndrome and again during the subsequent acute myeloid leukemia, we confirmed microRNA-34b promoter hypermethylation at leukemia onset, with 103 CREB target genes differentially expressed between the two disease stages. This subset of CREB targets was confirmed to associate with high-risk myelodysplastic syndromes in a separate cohort of patients (n=20). Seventy-eight of these 103 CREB targets were also differentially expressed between healthy samples (n=11) and de novo acute myeloid leukemia (n=72). Further, low microRNA-34b and high CREB expression levels induced aberrant myelopoiesis through CREB-dependent pathways in vitro and in vivo. In conclusion, we suggest that microRNA-34b controls CREB expression and contributes to myeloid transformation from both healthy bone marrow and myelodysplastic syndromes. We identified a subset of CREB target genes that represents a novel transcriptional network that may control myeloid transformation.

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