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

G Fabbri, S Rasi, D Rossi, V Trifonov, H Khiabanian, J Ma, A Grunn, M Fangazio, D Capello, Stefano Monti, S Cresta, E Gargiulo, F Forconi, A Guarini, L Arcaini, M Paulli, Luca Laurenti, Luigi Maria Larocca, R Marasca, V GatteiD Oscier, Francesco Bertoni, Cg Mullighan, Robin Foa, L Pasqualucci, R Rabadan, R Dalla-Favera, G Gaidano

Risultato della ricerca: Contributo in rivistaArticolo in rivista

470 Citazioni (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.
Lingua originaleEnglish
pagine (da-a)1389-1401
Numero di pagine13
Stato di pubblicazionePubblicato - 2011


  • Adult
  • Aged
  • Disease Progression
  • Drug Resistance, Neoplasm
  • Female
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic
  • Genes, Immunoglobulin Heavy Chain
  • Genome, Human
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Male
  • Middle Aged
  • Mutation
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Receptor, Notch1
  • Treatment Failure


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