Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia

V. Kumar, R. Palermo, C. Talora, A. F. Campese, S. Checquolo, D. Bellavia, L. Tottone, G. Testa, E. Miele, S. Indraccolo, A. Amadori, E. Ferretti, A. Gulino, A. Vacca, I. Screpanti

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Notch signaling deregulation is linked to the onset of several tumors including T-cell acute lymphoblastic leukemia (T-ALL). Deregulated microRNA (miRNA) expression is also associated with several cancers, including leukemias. However, the transcriptional regulators of miRNAs, as well as the relationships between Notch signaling and miRNA deregulation, are poorly understood. To identify miRNAs regulated by Notch pathway, we performed microarray-based miRNA profiling of several Notch-expressing T-ALL models. Among seven miRNAs, consistently regulated by overexpressing or silencing Notch3, we focused our attention on miR-223, whose putative promoter analysis revealed a conserved RBPjk binding site, which was nested to an NF-kB consensus. Luciferase and chromatin immunoprecipitation assays on the promoter region of miR-223 show that both Notch and NF-kB are novel coregulatory signals of miR-223 expression, being able to activate cooperatively the transcriptional activity of miR-223 promoter. Notably, the Notch-mediated activation of miR-223 represses the tumor suppressor FBXW7 in T-ALL cell lines. Moreover, we observed the inverse correlation of miR-223 and FBXW7 expression in a panel of T-ALL patient-derived xenografts. Finally, we show that miR-223 inhibition prevents T-ALL resistance to γ-secretase inhibitor (GSI) treatment, suggesting that miR-223 could be involved in GSI sensitivity and its inhibition may be exploited in target therapy protocols.

Original languageEnglish
Pages (from-to)2324-2335
Number of pages12
JournalLeukemia
Volume28
Issue number12
DOIs
Publication statusPublished - Dec 11 2014

Fingerprint

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
NF-kappa B
MicroRNAs
Neoplasms
Amyloid Precursor Protein Secretases
Chromatin Immunoprecipitation
Luciferases
Heterografts
Genetic Promoter Regions
Leukemia
Binding Sites
Cell Line
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine
  • Medicine(all)

Cite this

Kumar, V., Palermo, R., Talora, C., Campese, A. F., Checquolo, S., Bellavia, D., ... Screpanti, I. (2014). Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia. Leukemia, 28(12), 2324-2335. https://doi.org/10.1038/leu.2014.133

Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia. / Kumar, V.; Palermo, R.; Talora, C.; Campese, A. F.; Checquolo, S.; Bellavia, D.; Tottone, L.; Testa, G.; Miele, E.; Indraccolo, S.; Amadori, A.; Ferretti, E.; Gulino, A.; Vacca, A.; Screpanti, I.

In: Leukemia, Vol. 28, No. 12, 11.12.2014, p. 2324-2335.

Research output: Contribution to journalArticle

Kumar, V, Palermo, R, Talora, C, Campese, AF, Checquolo, S, Bellavia, D, Tottone, L, Testa, G, Miele, E, Indraccolo, S, Amadori, A, Ferretti, E, Gulino, A, Vacca, A & Screpanti, I 2014, 'Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia', Leukemia, vol. 28, no. 12, pp. 2324-2335. https://doi.org/10.1038/leu.2014.133
Kumar V, Palermo R, Talora C, Campese AF, Checquolo S, Bellavia D et al. Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia. Leukemia. 2014 Dec 11;28(12):2324-2335. https://doi.org/10.1038/leu.2014.133
Kumar, V. ; Palermo, R. ; Talora, C. ; Campese, A. F. ; Checquolo, S. ; Bellavia, D. ; Tottone, L. ; Testa, G. ; Miele, E. ; Indraccolo, S. ; Amadori, A. ; Ferretti, E. ; Gulino, A. ; Vacca, A. ; Screpanti, I. / Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia. In: Leukemia. 2014 ; Vol. 28, No. 12. pp. 2324-2335.
@article{92279c0064b44c47890733346f2d934e,
title = "Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia",
abstract = "Notch signaling deregulation is linked to the onset of several tumors including T-cell acute lymphoblastic leukemia (T-ALL). Deregulated microRNA (miRNA) expression is also associated with several cancers, including leukemias. However, the transcriptional regulators of miRNAs, as well as the relationships between Notch signaling and miRNA deregulation, are poorly understood. To identify miRNAs regulated by Notch pathway, we performed microarray-based miRNA profiling of several Notch-expressing T-ALL models. Among seven miRNAs, consistently regulated by overexpressing or silencing Notch3, we focused our attention on miR-223, whose putative promoter analysis revealed a conserved RBPjk binding site, which was nested to an NF-kB consensus. Luciferase and chromatin immunoprecipitation assays on the promoter region of miR-223 show that both Notch and NF-kB are novel coregulatory signals of miR-223 expression, being able to activate cooperatively the transcriptional activity of miR-223 promoter. Notably, the Notch-mediated activation of miR-223 represses the tumor suppressor FBXW7 in T-ALL cell lines. Moreover, we observed the inverse correlation of miR-223 and FBXW7 expression in a panel of T-ALL patient-derived xenografts. Finally, we show that miR-223 inhibition prevents T-ALL resistance to γ-secretase inhibitor (GSI) treatment, suggesting that miR-223 could be involved in GSI sensitivity and its inhibition may be exploited in target therapy protocols.",
author = "V. Kumar and R. Palermo and C. Talora and Campese, {A. F.} and S. Checquolo and D. Bellavia and L. Tottone and G. Testa and E. Miele and S. Indraccolo and A. Amadori and E. Ferretti and A. Gulino and A. Vacca and I. Screpanti",
year = "2014",
month = "12",
day = "11",
doi = "10.1038/leu.2014.133",
language = "English",
volume = "28",
pages = "2324--2335",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia

AU - Kumar, V.

AU - Palermo, R.

AU - Talora, C.

AU - Campese, A. F.

AU - Checquolo, S.

AU - Bellavia, D.

AU - Tottone, L.

AU - Testa, G.

AU - Miele, E.

AU - Indraccolo, S.

AU - Amadori, A.

AU - Ferretti, E.

AU - Gulino, A.

AU - Vacca, A.

AU - Screpanti, I.

PY - 2014/12/11

Y1 - 2014/12/11

N2 - Notch signaling deregulation is linked to the onset of several tumors including T-cell acute lymphoblastic leukemia (T-ALL). Deregulated microRNA (miRNA) expression is also associated with several cancers, including leukemias. However, the transcriptional regulators of miRNAs, as well as the relationships between Notch signaling and miRNA deregulation, are poorly understood. To identify miRNAs regulated by Notch pathway, we performed microarray-based miRNA profiling of several Notch-expressing T-ALL models. Among seven miRNAs, consistently regulated by overexpressing or silencing Notch3, we focused our attention on miR-223, whose putative promoter analysis revealed a conserved RBPjk binding site, which was nested to an NF-kB consensus. Luciferase and chromatin immunoprecipitation assays on the promoter region of miR-223 show that both Notch and NF-kB are novel coregulatory signals of miR-223 expression, being able to activate cooperatively the transcriptional activity of miR-223 promoter. Notably, the Notch-mediated activation of miR-223 represses the tumor suppressor FBXW7 in T-ALL cell lines. Moreover, we observed the inverse correlation of miR-223 and FBXW7 expression in a panel of T-ALL patient-derived xenografts. Finally, we show that miR-223 inhibition prevents T-ALL resistance to γ-secretase inhibitor (GSI) treatment, suggesting that miR-223 could be involved in GSI sensitivity and its inhibition may be exploited in target therapy protocols.

AB - Notch signaling deregulation is linked to the onset of several tumors including T-cell acute lymphoblastic leukemia (T-ALL). Deregulated microRNA (miRNA) expression is also associated with several cancers, including leukemias. However, the transcriptional regulators of miRNAs, as well as the relationships between Notch signaling and miRNA deregulation, are poorly understood. To identify miRNAs regulated by Notch pathway, we performed microarray-based miRNA profiling of several Notch-expressing T-ALL models. Among seven miRNAs, consistently regulated by overexpressing or silencing Notch3, we focused our attention on miR-223, whose putative promoter analysis revealed a conserved RBPjk binding site, which was nested to an NF-kB consensus. Luciferase and chromatin immunoprecipitation assays on the promoter region of miR-223 show that both Notch and NF-kB are novel coregulatory signals of miR-223 expression, being able to activate cooperatively the transcriptional activity of miR-223 promoter. Notably, the Notch-mediated activation of miR-223 represses the tumor suppressor FBXW7 in T-ALL cell lines. Moreover, we observed the inverse correlation of miR-223 and FBXW7 expression in a panel of T-ALL patient-derived xenografts. Finally, we show that miR-223 inhibition prevents T-ALL resistance to γ-secretase inhibitor (GSI) treatment, suggesting that miR-223 could be involved in GSI sensitivity and its inhibition may be exploited in target therapy protocols.

UR - http://www.scopus.com/inward/record.url?scp=84925282873&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925282873&partnerID=8YFLogxK

U2 - 10.1038/leu.2014.133

DO - 10.1038/leu.2014.133

M3 - Article

C2 - 24727676

AN - SCOPUS:84925282873

VL - 28

SP - 2324

EP - 2335

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 12

ER -