Structure of the Notch1 Negative Regulatory Region: Implications for Normal Activation and Pathogenic Signaling in TALL (original) (raw)

An activating intragenic deletion in NOTCH1 in human T-ALL

Blood, 2012

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.

Identification of a Conserved Negative Regulatory Sequence That Influences the Leukemogenic Activity of NOTCH1

Molecular and Cellular Biology, 2006

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Notch 1 signalling in human T-cell development and leukemia

Inmunología, 2009

Los receptores Notch regulan diferentes aspectos del desarrollo de los metazoos y de la renovación tisular, que incluyen decisiones binarias de destino celular, supervivencia, proliferación o diferenciación, en diferentes tipos celulares y tejidos y en diferentes contextos celulares. En hematopoyesis, la señalización por Notch contribuye activamente al desarrollo de los linfocitos T, induciendo un programa madurativo específico en los progenitores que llegan al timo procedentes de las células madre hematopoyéticas (HSC) de la médula ósea y bloqueando, simultáneamente, la generación de linajes celulares alternativos. Conforme a esta importante función, la desregulación de la señalización por Notch tiene consecuencias críticas para la supervivencia y proliferación de las células T y contribuye significativamente a la generación de la leucemia T linfoblástica aguda (T-ALL). Por tanto, el estudio de las vías moleculares inducidas por Notch que determinan la maduración de los progenitores T, así como su transformación oncogénica durante el desarrollo intratímico, constituye una importante área de investigación en la actualidad. Se ha demostrado la participación de varios genes y rutas de señalización, tales como c-myc, NF-κB y PI3K, en la oncogénesis de las células T inducida por Notch y más recientemente se ha sugerido la implicación del receptor de la interleucina 7 (IL-7R) en el proceso. En esta revisión discutiremos recientes estudios moleculares que revelan cómo Notch determina la generación de linfocitos T a partir de los inmigrantes intratímicos y cómo su desregulación puede contribuir a la generación de leucemias T-ALL, en parte debido a la regulación directa de la expresión del IL-7R.

Two Distinct Notch1 Mutant Alleles Are Involved in the Induction of T-Cell Leukemia in c-myc Transgenic Mice

Molecular and Cellular Biology, 2000

We have previously characterized a large panel of provirus insertion Notch1 mutant alleles and their products arising in thymomas of MMTV D /myc transgenic mice. Here, we show that these Notch1 mutations represent two clearly distinct classes. In the first class (type I), proviral integrations were clustered just upstream of sequences encoding the transmembrane domain. Type I Notch1 alleles produced two types of mutant Notch1 RNA, one of which encoded the entire Notch1 cytoplasmic domain [N(IC)] and the other of which encoded a soluble ectodomain [N(EC) Mut ] which, in contrast to the processed wild-type ectodomain [N(EC) WT ], did not reside at the cell surface and became secreted in a temperature-dependent manner. A second, novel class of mutant Notch1 allele (

Investigation of deregulated genes of Notch signaling pathway in human T cell acute lymphoblastic leukemia cell lines and clinical samples

Molecular Biology Reports, 2013

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