Common nonmutational<i>NOTCH1</i>activation in chronic lymphocytic leukemia

Abstract

Activating mutations of <i>NOTCH1</i> (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 <i>NOTCH1</i> 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 <i>NOTCH1</i> mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival, and signal transduction. In particular, we show that NOTCH1 transactivates <i>MYC</i> via binding to B-cell-specific regulatory elements, thus implicating this oncogene in CLL development. These results significantly extend the role of <i>NOTCH1</i> in CLL pathogenesis, and have direct implications for specific therapeutic targeting.