Journal
LEUKEMIA
Volume 30, Issue 10, Pages 2011-2018Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2016.88
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Funding
- Associazione Italiana Ricerca Cancro (AIRC) [IG-13227, IG-17622]
- Special Program Molecular Clinical Oncology 5 x 1000 [10007]
- Ministero della Salute, Rome, Italy [GR-2010-2317594, GR-2011-02347441, GR-2011-02346826, GR-2011-02351370, RF-2010-2307262, RF-2011-02349712]
- Associazione Italiana contro le Leucemie, linfomi e mielomi (AIL), Venezia Section, Pramaggiore Group, Italy
- Fondazione per la Vita di Pordenone, Italy
- Ricerca Scientifica Applicata, Regione Friuli Venezia Giulia ('Linfonet' Project), Trieste, Italy
- '5x1000 Intramural Program', Centro di Riferimento Oncologico, Aviano, Italy
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CD49d, the alpha-chain of the integrin heterodimer alpha 4 beta 1, was identified among the strongest predictors of overall survival (OS) in chronic lymphocytic leukemia (CLL), along with IGHV mutational status and deletion of the 17p chromosome involving TP53. In addition to TP53, the clinical relevance of NOTCH1, SF3B1 and BIRC3 gene mutations has been recently emphasized. By analyzing a cohort of 778 unselected CLL patients, we assessed the clinical relevance of CD49d as an OS predictor in subgroups defined by mutation/deletion of the TP53, NOTCH1, SF3B1 and BIRC3 genes. In this context, CD49d emerged as an independent predictor of OS in multivariate Cox analysis (Hazard ratio = 1.88, P<0.0001). Consistently, high CD49d expression identified CLL subsets with inferior OS in the context of each category of a previously reported hierarchical risk stratification model. Moreover, by evaluating the relative importance of biological prognosticators by random survival forests, CD49d was selected among the top-ranked OS predictor (variable importance = 0.0410), along with IGHV mutational status and TP53 abnormalities. These results confirmed CD49d as an independent negative OS prognosticator in CLL also in comprehensive models comprising the novel recurrent mutations. In this context, TP53 disruption and NOTCH1 mutations retained prognostic relevance, in keeping with their roles in CLL cell immuno-chemoresistance.
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