Abstract
Deregulated Notch signaling has been extensively linked to T-cell acute lymphoblastic leukemia (T-ALL). Here, we show a direct relationship between Notch3 receptor and Jagged1 ligand in human cell lines and in a mouse model of T-ALL. We provide evidence that Notch-specific ligand Jagged1 is a new Notch3 signaling target gene. This essential event justifies an aberrant Notch3/Jagged1 cis-expression inside the same cell. Moreover, we demonstrate in Notch3-IC-overexpressing T lymphoma cells that Jagged1 undergoes a raft-associated constitutive processing. The proteolytic cleavage allows the Jagged1 intracellular domain to empower Notch signaling activity and to increase the transcriptional activation of Jagged1 itself (autocrine effect). On the other hand, the release of the soluble Jagged1 extracellular domain has a positive impact on activating Notch signaling in adjacent cells (paracrine effect), finally giving rise to a Notch3/Jagged1 auto-sustaining loop that supports the survival, proliferation, and invasion of lymphoma cells and contributes to the development and progression of Notch-dependent T-ALL. These observations are also supported by a study conducted on a cohort of patients in which Jagged1 expression is associated to adverse prognosis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1007-1017 |
| Number of pages | 11 |
| Journal | Neoplasia (United States) |
| Volume | 16 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2014 |
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ASJC Scopus subject areas
- Cancer Research
Cite this
Notch3/Jagged1 circuitry reinforces notch signaling and sustains T-ALL. / Pelullo, Maria; Quaranta, Roberta; Talora, Claudio; Checquolo, Saula; Cialfi, Samantha; Felli, Maria P ia; te Kronnie, Geertruy; Borga, Chiara; Besharat, Zein M ersini; Palermo, Rocco; Di Marcotullio, Lucia; Capobianco, Anthony J; Gulino, Alberto; Screpanti, Isabella; Bellavia, Diana.
In: Neoplasia (United States), Vol. 16, No. 12, 01.12.2014, p. 1007-1017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Notch3/Jagged1 circuitry reinforces notch signaling and sustains T-ALL
AU - Pelullo, Maria
AU - Quaranta, Roberta
AU - Talora, Claudio
AU - Checquolo, Saula
AU - Cialfi, Samantha
AU - Felli, Maria P ia
AU - te Kronnie, Geertruy
AU - Borga, Chiara
AU - Besharat, Zein M ersini
AU - Palermo, Rocco
AU - Di Marcotullio, Lucia
AU - Capobianco, Anthony J
AU - Gulino, Alberto
AU - Screpanti, Isabella
AU - Bellavia, Diana
PY - 2014/12/1
Y1 - 2014/12/1
N2 - Deregulated Notch signaling has been extensively linked to T-cell acute lymphoblastic leukemia (T-ALL). Here, we show a direct relationship between Notch3 receptor and Jagged1 ligand in human cell lines and in a mouse model of T-ALL. We provide evidence that Notch-specific ligand Jagged1 is a new Notch3 signaling target gene. This essential event justifies an aberrant Notch3/Jagged1 cis-expression inside the same cell. Moreover, we demonstrate in Notch3-IC-overexpressing T lymphoma cells that Jagged1 undergoes a raft-associated constitutive processing. The proteolytic cleavage allows the Jagged1 intracellular domain to empower Notch signaling activity and to increase the transcriptional activation of Jagged1 itself (autocrine effect). On the other hand, the release of the soluble Jagged1 extracellular domain has a positive impact on activating Notch signaling in adjacent cells (paracrine effect), finally giving rise to a Notch3/Jagged1 auto-sustaining loop that supports the survival, proliferation, and invasion of lymphoma cells and contributes to the development and progression of Notch-dependent T-ALL. These observations are also supported by a study conducted on a cohort of patients in which Jagged1 expression is associated to adverse prognosis.
AB - Deregulated Notch signaling has been extensively linked to T-cell acute lymphoblastic leukemia (T-ALL). Here, we show a direct relationship between Notch3 receptor and Jagged1 ligand in human cell lines and in a mouse model of T-ALL. We provide evidence that Notch-specific ligand Jagged1 is a new Notch3 signaling target gene. This essential event justifies an aberrant Notch3/Jagged1 cis-expression inside the same cell. Moreover, we demonstrate in Notch3-IC-overexpressing T lymphoma cells that Jagged1 undergoes a raft-associated constitutive processing. The proteolytic cleavage allows the Jagged1 intracellular domain to empower Notch signaling activity and to increase the transcriptional activation of Jagged1 itself (autocrine effect). On the other hand, the release of the soluble Jagged1 extracellular domain has a positive impact on activating Notch signaling in adjacent cells (paracrine effect), finally giving rise to a Notch3/Jagged1 auto-sustaining loop that supports the survival, proliferation, and invasion of lymphoma cells and contributes to the development and progression of Notch-dependent T-ALL. These observations are also supported by a study conducted on a cohort of patients in which Jagged1 expression is associated to adverse prognosis.
UR - http://www.scopus.com/inward/record.url?scp=85003322506&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85003322506&partnerID=8YFLogxK
U2 - 10.1016/j.neo.2014.10.004
DO - 10.1016/j.neo.2014.10.004
M3 - Article
C2 - 25499214
AN - SCOPUS:85003322506
VL - 16
SP - 1007
EP - 1017
JO - Neoplasia (United States)
JF - Neoplasia (United States)
SN - 1522-8002
IS - 12
ER -