Abstract
Oncogenic activating mutations in NOTCH1 occur in more than 50% of T-cell acute lymphoblastic leukemias (T-ALLs). In the present study, we describe a novel mechanism of NOTCH1 activation in T-ALL in which a deletion removing the 5′ portion of NOTCH1 abolishes the negative regulatory control of the extracellular domain and leads to constitutively active NOTCH1 signaling. Polypeptides translated from truncated transcripts encoded by the NOTCH1 deletion allele retain the transmembrane domain of the receptor and are constitutively cleaved by the γ-secretase complex, resulting in high levels of NOTCH1 signaling that can be effectively blocked by γ-secretase inhibitors. Our results expand the spectrum of oncogenic lesions activating NOTCH1 signaling in human T-ALL.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5211-5214 |
| Number of pages | 4 |
| Journal | Blood |
| Volume | 119 |
| Issue number | 22 |
| DOIs | |
| State | Published - Jun 5 2012 |
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ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
An activating intragenic deletion in NOTCH1 in human T-ALL. / Haydu, J. Erika; De Keersmaecker, Kim; Duff, Mary Kaye; Paietta, Elisabeth M.; Racevskis, Janis; Wiernik, Peter H.; Rowe, Jacob M.; Ferrando, Adolfo.
In: Blood, Vol. 119, No. 22, 05.06.2012, p. 5211-5214.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - An activating intragenic deletion in NOTCH1 in human T-ALL
AU - Haydu, J. Erika
AU - De Keersmaecker, Kim
AU - Duff, Mary Kaye
AU - Paietta, Elisabeth M.
AU - Racevskis, Janis
AU - Wiernik, Peter H.
AU - Rowe, Jacob M.
AU - Ferrando, Adolfo
PY - 2012/6/5
Y1 - 2012/6/5
N2 - Oncogenic activating mutations in NOTCH1 occur in more than 50% of T-cell acute lymphoblastic leukemias (T-ALLs). In the present study, we describe a novel mechanism of NOTCH1 activation in T-ALL in which a deletion removing the 5′ portion of NOTCH1 abolishes the negative regulatory control of the extracellular domain and leads to constitutively active NOTCH1 signaling. Polypeptides translated from truncated transcripts encoded by the NOTCH1 deletion allele retain the transmembrane domain of the receptor and are constitutively cleaved by the γ-secretase complex, resulting in high levels of NOTCH1 signaling that can be effectively blocked by γ-secretase inhibitors. Our results expand the spectrum of oncogenic lesions activating NOTCH1 signaling in human T-ALL.
AB - Oncogenic activating mutations in NOTCH1 occur in more than 50% of T-cell acute lymphoblastic leukemias (T-ALLs). In the present study, we describe a novel mechanism of NOTCH1 activation in T-ALL in which a deletion removing the 5′ portion of NOTCH1 abolishes the negative regulatory control of the extracellular domain and leads to constitutively active NOTCH1 signaling. Polypeptides translated from truncated transcripts encoded by the NOTCH1 deletion allele retain the transmembrane domain of the receptor and are constitutively cleaved by the γ-secretase complex, resulting in high levels of NOTCH1 signaling that can be effectively blocked by γ-secretase inhibitors. Our results expand the spectrum of oncogenic lesions activating NOTCH1 signaling in human T-ALL.
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UR - http://www.scopus.com/inward/citedby.url?scp=84861842411&partnerID=8YFLogxK
U2 - 10.1182/blood-2011-10-388504
DO - 10.1182/blood-2011-10-388504
M3 - Article
VL - 119
SP - 5211
EP - 5214
JO - Blood
JF - Blood
SN - 0006-4971
IS - 22
ER -