Transcriptomic profiling of white blood cells reveals new insights into the molecular mechanisms of thalidomide in children with inflammatory bowel disease
Аутори
Lucafò, MariannaPugnetti, Letizia
Curci, Debora
Bidoli, Carlotta
Gerdol, Marco
Celsi, Fulvio
Renzo, Sara
Paci, Monica
Lega, Sara
Lionetti, Paolo
Pallavicin, Alberto
Decorti, Giuliana
Stocco, Gabriele
Bramuzzo, Matteo
Остала ауторства
Morić, IvanaĐorđević, Valentina
Конференцијски прилог (Објављена верзија)
,
© 2023 Institute of Molecular Genetics and Genetic Engineering, University of Belgrade
Метаподаци
Приказ свих података о документуАпстракт
Thalidomide has emerged as an effective immunomodulator in the treatment of pediatric
patients with inflammatory bowel disease (IBD) refractory to standard therapies. Cereblon,
a component of E3 protein ligase complex that mediates ubiquitination and proteasomal
degradation of target proteins, has been identified as the primary target of thalidomide.
Cereblon plays a crucial role in thalidomide teratogenicity, however it is unclear whether it
is also involved in the therapeutic effects in IBD patients. This study aimed at identifying
the mechanisms underpinning thalidomide action in pediatric IBD. Ten IBD pediatric
patients clinically responsive to thalidomide were prospectively enrolled. RNA-sequencing
and functional enrichment analysis was carried out on peripheral blood mononuclear
cells obtained before and after treatment with thalidomide. RNA-sequencing analysis
revealed 378 differentially expressed genes after treatment with thalidomide. The
most deregulated pathways w...ere cytosolic calcium ion concentration, cAMP-mediated
signaling, eicosanoid signaling and inhibition of matrix metalloproteinases. Neuronal
signaling mechanisms such as CREB signaling in neurons and axonal guidance signaling
also emerged. Connectivity Map analysis revealed that thalidomide gene expression
changes were similar to those induced by MLN4924, an inhibitor of NEDD8 activating
enzyme, suggesting that thalidomide exerts its immunomodulatory effects by acting on
the ubiquitin-proteasome pathway.
In vitro experiments on cell lines confirmed the effect of thalidomide on altered candidate
pathways observed in patients. These results represent a unique resource for enhanced
understanding of thalidomide mechanism in patients with IBD, providing novel potential
targets associated with drug response.
Кључне речи:
RNA-sequencing / thalidomide / pediatric / Crohn’s disease / ulcerative colitisИзвор:
4th Belgrade Bioinformatics Conference, 2023, 4, 105-105Издавач:
- Belgrade : Institute of molecular genetics and genetic engineering
Финансирање / пројекти:
- Italian Ministry of Health, through the contribution given to the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy, grant NET-2013-02355002 and RC 10/19.
Напомена:
- Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 2023
Колекције
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - CONF AU - Lucafò, Marianna AU - Pugnetti, Letizia AU - Curci, Debora AU - Bidoli, Carlotta AU - Gerdol, Marco AU - Celsi, Fulvio AU - Renzo, Sara AU - Paci, Monica AU - Lega, Sara AU - Lionetti, Paolo AU - Pallavicin, Alberto AU - Decorti, Giuliana AU - Stocco, Gabriele AU - Bramuzzo, Matteo PY - 2023 UR - https://belbi.bg.ac.rs/ UR - https://imagine.imgge.bg.ac.rs/handle/123456789/2050 AB - Thalidomide has emerged as an effective immunomodulator in the treatment of pediatric patients with inflammatory bowel disease (IBD) refractory to standard therapies. Cereblon, a component of E3 protein ligase complex that mediates ubiquitination and proteasomal degradation of target proteins, has been identified as the primary target of thalidomide. Cereblon plays a crucial role in thalidomide teratogenicity, however it is unclear whether it is also involved in the therapeutic effects in IBD patients. This study aimed at identifying the mechanisms underpinning thalidomide action in pediatric IBD. Ten IBD pediatric patients clinically responsive to thalidomide were prospectively enrolled. RNA-sequencing and functional enrichment analysis was carried out on peripheral blood mononuclear cells obtained before and after treatment with thalidomide. RNA-sequencing analysis revealed 378 differentially expressed genes after treatment with thalidomide. The most deregulated pathways were cytosolic calcium ion concentration, cAMP-mediated signaling, eicosanoid signaling and inhibition of matrix metalloproteinases. Neuronal signaling mechanisms such as CREB signaling in neurons and axonal guidance signaling also emerged. Connectivity Map analysis revealed that thalidomide gene expression changes were similar to those induced by MLN4924, an inhibitor of NEDD8 activating enzyme, suggesting that thalidomide exerts its immunomodulatory effects by acting on the ubiquitin-proteasome pathway. In vitro experiments on cell lines confirmed the effect of thalidomide on altered candidate pathways observed in patients. These results represent a unique resource for enhanced understanding of thalidomide mechanism in patients with IBD, providing novel potential targets associated with drug response. PB - Belgrade : Institute of molecular genetics and genetic engineering C3 - 4th Belgrade Bioinformatics Conference T1 - Transcriptomic profiling of white blood cells reveals new insights into the molecular mechanisms of thalidomide in children with inflammatory bowel disease EP - 105 SP - 105 VL - 4 UR - https://hdl.handle.net/21.15107/rcub_imagine_2050 ER -
@conference{ author = "Lucafò, Marianna and Pugnetti, Letizia and Curci, Debora and Bidoli, Carlotta and Gerdol, Marco and Celsi, Fulvio and Renzo, Sara and Paci, Monica and Lega, Sara and Lionetti, Paolo and Pallavicin, Alberto and Decorti, Giuliana and Stocco, Gabriele and Bramuzzo, Matteo", year = "2023", abstract = "Thalidomide has emerged as an effective immunomodulator in the treatment of pediatric patients with inflammatory bowel disease (IBD) refractory to standard therapies. Cereblon, a component of E3 protein ligase complex that mediates ubiquitination and proteasomal degradation of target proteins, has been identified as the primary target of thalidomide. Cereblon plays a crucial role in thalidomide teratogenicity, however it is unclear whether it is also involved in the therapeutic effects in IBD patients. This study aimed at identifying the mechanisms underpinning thalidomide action in pediatric IBD. Ten IBD pediatric patients clinically responsive to thalidomide were prospectively enrolled. RNA-sequencing and functional enrichment analysis was carried out on peripheral blood mononuclear cells obtained before and after treatment with thalidomide. RNA-sequencing analysis revealed 378 differentially expressed genes after treatment with thalidomide. The most deregulated pathways were cytosolic calcium ion concentration, cAMP-mediated signaling, eicosanoid signaling and inhibition of matrix metalloproteinases. Neuronal signaling mechanisms such as CREB signaling in neurons and axonal guidance signaling also emerged. Connectivity Map analysis revealed that thalidomide gene expression changes were similar to those induced by MLN4924, an inhibitor of NEDD8 activating enzyme, suggesting that thalidomide exerts its immunomodulatory effects by acting on the ubiquitin-proteasome pathway. In vitro experiments on cell lines confirmed the effect of thalidomide on altered candidate pathways observed in patients. These results represent a unique resource for enhanced understanding of thalidomide mechanism in patients with IBD, providing novel potential targets associated with drug response.", publisher = "Belgrade : Institute of molecular genetics and genetic engineering", journal = "4th Belgrade Bioinformatics Conference", title = "Transcriptomic profiling of white blood cells reveals new insights into the molecular mechanisms of thalidomide in children with inflammatory bowel disease", pages = "105-105", volume = "4", url = "https://hdl.handle.net/21.15107/rcub_imagine_2050" }
Lucafò, M., Pugnetti, L., Curci, D., Bidoli, C., Gerdol, M., Celsi, F., Renzo, S., Paci, M., Lega, S., Lionetti, P., Pallavicin, A., Decorti, G., Stocco, G.,& Bramuzzo, M.. (2023). Transcriptomic profiling of white blood cells reveals new insights into the molecular mechanisms of thalidomide in children with inflammatory bowel disease. in 4th Belgrade Bioinformatics Conference Belgrade : Institute of molecular genetics and genetic engineering., 4, 105-105. https://hdl.handle.net/21.15107/rcub_imagine_2050
Lucafò M, Pugnetti L, Curci D, Bidoli C, Gerdol M, Celsi F, Renzo S, Paci M, Lega S, Lionetti P, Pallavicin A, Decorti G, Stocco G, Bramuzzo M. Transcriptomic profiling of white blood cells reveals new insights into the molecular mechanisms of thalidomide in children with inflammatory bowel disease. in 4th Belgrade Bioinformatics Conference. 2023;4:105-105. https://hdl.handle.net/21.15107/rcub_imagine_2050 .
Lucafò, Marianna, Pugnetti, Letizia, Curci, Debora, Bidoli, Carlotta, Gerdol, Marco, Celsi, Fulvio, Renzo, Sara, Paci, Monica, Lega, Sara, Lionetti, Paolo, Pallavicin, Alberto, Decorti, Giuliana, Stocco, Gabriele, Bramuzzo, Matteo, "Transcriptomic profiling of white blood cells reveals new insights into the molecular mechanisms of thalidomide in children with inflammatory bowel disease" in 4th Belgrade Bioinformatics Conference, 4 (2023):105-105, https://hdl.handle.net/21.15107/rcub_imagine_2050 .