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

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

来源：Journal of Experimental Medicine, 2011, 208(7): 1389-1401.

DOI：10.1084/jem.20110921

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.

• 出版日期2011-7-4