Analysis of the chronic lymphocytic leukemia coding genome: Role of NOTCH1 mutational activation

Giulia Fabbri, Silvia Rasi, Davide Rossi, Vladimir Trifonov, Hossein Khiabanian, Jing Ma, Adina Grunn, Marco Fangazio, Daniela Capello, Sara Monti, Stefania Cresta, Ernesto Gargiulo, Francesco Forconi, Anna Guarini, Luca Arcaini, Marco Paulli, Luca Laurenti, Luigi M. Larocca, Roberto Marasca, Valter GatteiDavid Oscier, Francesco Bertoni, Charles G. Mullighan, Robin Foà, Laura Pasqualucci, Raul Rabadan, Riccardo Dalla-Favera*, Gianluca Gaidano

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

533 Citations (Scopus)


The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown. The full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next-generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains <20 clonally represented gene alterations/case, including predominantly nonsilent mutations, and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. Although most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%), as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance.

Original languageEnglish
Pages (from-to)1389-1401
Number of pages13
JournalJournal of Experimental Medicine
Issue number7
Publication statusPublished - 4 Jul 2011
Externally publishedYes


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