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EZH2 upregulates th...
EZH2 upregulates the PI3K/AKT pathway through IGF1R and MYC in clinically aggressive chronic lymphocytic leukaemia
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- Kosalai, Subazini Thankaswamy, 1980 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
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Morsy, Mohammad Hamdy Abdelrazak, 1986 (författare)
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Papakonstantinou, N. (författare)
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- Mansouri, L. (författare)
- Karolinska Institutet
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Stavroyianni, N. (författare)
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- Kanduri, Chandrasekhar, 1967 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
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Stamatopoulos, K. (författare)
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- Rosenquist, R. (författare)
- Karolinska Institutet
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Kanduri, Meena, 1974 (författare)
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(creator_code:org_t)
- 2019-06-26
- 2019
- Engelska.
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Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 14:11, s. 1125-1140
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Abstract
Ämnesord
Stäng
- EZH2 is overexpressed in poor-prognostic chronic lymphocytic leukaemia (CLL) cases, acting as an oncogene; however, thus far, the EZH2 target genes in CLL have not been disclosed. In this study, using ChIP-sequencing, we identified EZH2 and H3K27me3 target genes in two prognostic subgroups of CLL with distinct prognosis and outcome, i.e., cases with unmutated (U-CLL, n = 6) or mutated IGHV genes (M-CLL, n = 6). While the majority of oncogenic pathways were equally enriched for EZH2 target genes in both prognostic subgroups, PI3K pathway genes were differentially bound by EZH2 in U-CLL versus M-CLL. The occupancy of EZH2 for selected PI3K pathway target genes was validated in additional CLL samples (n = 16) and CLL cell lines using siRNA-mediated EZH2 downregulation and ChIP assays. Intriguingly, we found that EZH2 directly binds to the IGF1R promoter along with MYC and upregulates IGF1R expression in U-CLL, leading to downstream PI3K activation. By investigating an independent CLL cohort (n = 96), a positive correlation was observed between EZH2 and IGF1R expression with higher levels in U-CLL compared to M-CLL. Accordingly, siRNA-mediated downregulation of either EZH2, MYC or IGF1R and treatment with EZH2 and MYC pharmacological inhibitors in the HG3 CLL cell line induced a significant reduction in PI3K pathway activation. In conclusion, we characterize for the first time EZH2 target genes in CLL revealing a hitherto unknown implication of EZH2 in modulating the PI3K pathway in a non-canonical, PRC2-independent way, with potential therapeutic implications considering that PI3K inhibitors are effective therapeutic agents for CLL.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- Chronic lymphocytic leukemia
- EZH2
- ChIP sequencing
- PI3K pathway
- IGFR1
- group protein ezh2
- breast-cancer
- overexpression
- lymphoma
- target
- expression
- proliferation
- methylation
- inhibition
- idelalisib
- Biochemistry & Molecular Biology
- Genetics & Heredity
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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