Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia

Authors: Giulia Fabbri, Antony B. Holmes, Mara Viganotti, Claudio Scuoppo, Laura Belver, Daniel Herranz, Xiao‐Jie Yan, Yasmine Kieso, Davide Rossi, Gianluca Gaïdano, Nicholas Chiorazzi, Adolfo A. Ferrando, Riccardo Dalla‐Favera - Proceedings of the National Academy of Sciences, PNAS 2017 cited by 127

Significance A pathogenetic role of NOTCH1 in chronic lymphocytic leukemia (CLL) has been implied by the presence of deregulating mutations in a relatively small fraction of cases. Our results now indicate that ∼50% of CLL cases devoid of mutations express the active form of NOTCH1 ICN1 (intracellular portion of NOTCH1), thus implicating a much broader role of this transcription factor in the disease. ICN1 + CLL cases display equivalent NOTCH1-dependent transcriptional responses regardless of the gene mutation status, indicating that the detection of ICN1 represents a reliable biomarker of NOTCH1 activation for diagnostic and therapeutic targeting. Finally, our results identify the NOTCH1-dependent transcriptional program in CLL cells, thus providing direct insights into the pathogenesis of a large fraction of CLL cases.