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Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia.
Fabbri, Giulia; Holmes, Antony B; Viganotti, Mara; Scuoppo, Claudio; Belver, Laura; Herranz, Daniel; Yan, Xiao-Jie; Kieso, Yasmine; Rossi, Davide; Gaidano, Gianluca; Chiorazzi, Nicholas; Ferrando, Adolfo A; Dalla-Favera, Riccardo.
Afiliación
  • Fabbri G; Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
  • Holmes AB; Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
  • Viganotti M; Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
  • Scuoppo C; Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
  • Belver L; Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
  • Herranz D; Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
  • Yan XJ; The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, NY 11030.
  • Kieso Y; The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, NY 11030.
  • Rossi D; Division of Hematology, Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland.
  • Gaidano G; Lymphoma and Genomics Research Program, Institute of Oncology Research, 6500 Bellinzona, Switzerland.
  • Chiorazzi N; Division of Haematology, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy.
  • Ferrando AA; The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, NY 11030.
  • Dalla-Favera R; Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
Proc Natl Acad Sci U S A ; 114(14): E2911-E2919, 2017 04 04.
Article en En | MEDLINE | ID: mdl-28314854
Activating mutations of NOTCH1 (a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in ∼4-13% of chronic lymphocytic leukemia (CLL) cases, where they are associated with disease progression and chemorefractoriness. However, the specific role of NOTCH1 in leukemogenesis remains to be established. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ∼50% of peripheral blood CLL cases lacking gene mutations. We identify a "NOTCH1 gene-expression signature" in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival, and signal transduction. In particular, we show that NOTCH1 transactivates MYC via binding to B-cell-specific regulatory elements, thus implicating this oncogene in CLL development. These results significantly extend the role of NOTCH1 in CLL pathogenesis, and have direct implications for specific therapeutic targeting.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos B / Leucemia Linfocítica Crónica de Células B / Receptor Notch1 Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos B / Leucemia Linfocítica Crónica de Células B / Receptor Notch1 Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos