Abstract
Next-generation whole-exome sequencing has revealed two novel genes, namely NOTCH1 and SF3B1, whose mutations predict poor outcome and preferentially associate with chemorefractory chronic lymphocytic leukemia (CLL). Analysis of 539 CLL cases documents that NOTCH1 mutations i) represent one of the most frequent cancer gene mutations involved at presentation; ii) cluster with cases harboring trisomy 12 and tend to be mutually exclusive with TP53 disruption among genetic subgroups; iii) identify high-risk patients showing poor survival similar to that associated with TP53 abnormalities; and iv) exert a prognostic role independent of widely accepted clinical and genetic risk factors. Mutations of SF3B1, a splicing factor that is a critical component of the spliceosome, recurrently associate with fludarabine-refractory CLL, occur at a low rate at CLL presentation and have a minor role in Richter transformation, corroborating the notion that CLL histological shift is molecularly distinct from chemorefractory progression without the Richter transformation.
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GG has received consulting fees from Onyx Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline and F. Hoffmann-La Roche Ltd. GG has also received lecture fees from F. Hoffmann-La Roche Ltd and GlaxoSmithKline. RF has received consulting fees from F. Hoffmann-La Roche Ltd, Bristol-Myers Squibb, GlaxoSmithKline, Mundipharma and Celgene. RF has also received lecture fees from F. Hoffmann-La Roche Ltd, Mundipharma, Janssen and Novartis. The remaining authors declare no conflict of interest.
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This article was published as part of a supplement that was supported by Novartis, MSD Italia, Roche, Celgene, GlaxoSmithKline, Sanofi, Gilead, Adienne, Italfarmaco, Pierre Fabre Pharmaceuticals with an unrestricted educational contribution to AREO—Associazione Ricerche Emato-Oncologiche (Genoa) and AMS—Associazione Malattie del Sangue (Milan) for the purpose of advancing research in acute and chronic leukemia.
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Rossi, D., Rasi, S., Spina, V. et al. The genome of chemorefractory chronic lymphocytic leukemia reveals frequent mutations of NOTCH1 and SF3B1. Leukemia Suppl 1 (Suppl 2), S26–S28 (2012). https://doi.org/10.1038/leusup.2012.16
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DOI: https://doi.org/10.1038/leusup.2012.16
