AI Article Synopsis
- NOTCH1 mutations are found in 4-13% of chronic lymphocytic leukemia (CLL) cases and are linked to disease progression and resistance to chemotherapy.
- Approximately 50% of CLL patients without NOTCH1 mutations still have detectable active NOTCH1 (ICN1) in their blood.
- A “NOTCH1 gene-expression signature” in CLL cells is associated with key B-cell regulatory functions, indicating NOTCH1’s involvement in CLL development and suggesting potential targeted therapy options.
Article Abstract
Activating mutations of (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 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 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival, and signal transduction. In particular, we show that NOTCH1 transactivates via binding to B-cell-specific regulatory elements, thus implicating this oncogene in CLL development. These results significantly extend the role of in CLL pathogenesis, and have direct implications for specific therapeutic targeting.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389283 | PMC |
| http://dx.doi.org/10.1073/pnas.1702564114 | DOI Listing |
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