An activating intragenic deletion in NOTCH1 in human T-ALL

J. Erika Haydu; Kim De Keersmaecker; Mary Kaye Duff; Elisabeth Paietta; Janis Racevskis; Peter H. Wiernik; Jacob M. Rowe; Adolfo Ferrando

doi:10.1182/blood-2011-10-388504

An activating intragenic deletion in NOTCH1 in human T-ALL

J. Erika Haydu, Kim De Keersmaecker, Mary Kaye Duff, Elisabeth Paietta, Janis Racevskis, Peter H. Wiernik, Jacob M. Rowe, Adolfo Ferrando

Medicine

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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	https://doi.org/10.1182/blood-2011-10-388504
State	Published - Jun 5 2012

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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title = "An activating intragenic deletion in NOTCH1 in human T-ALL",

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.",

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AU - Haydu, J. Erika

AU - De Keersmaecker, Kim

AU - Duff, Mary Kaye

AU - Paietta, Elisabeth

AU - Racevskis, Janis

AU - Wiernik, Peter H.

AU - Rowe, Jacob M.

AU - Ferrando, Adolfo

PY - 2012/6/5

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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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An activating intragenic deletion in NOTCH1 in human T-ALL

Abstract

ASJC Scopus subject areas

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