Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia.
Proc Natl Acad Sci U S A
; 114(14): E2911-E2919, 2017 04 04.
Article
em En
| MEDLINE
| ID: mdl-28314854
ABSTRACT
Activating mutations of NOTCH1 (a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in â¼4-13% 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 â¼50% 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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Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
/
Leucemia Linfocítica Crônica de Células B
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Receptor Notch1
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article