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Chronic lymphocytic leukemia

CD49d prevails over the novel recurrent mutations as independent prognosticator of overall survival in chronic lymphocytic leukemia

Leukemia volume 30, pages 2011–2018 (2016)Cite this article

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Abstract

CD49d, the alpha-chain of the integrin heterodimer α4β1, 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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Acknowledgements

Supported in part by the Associazione Italiana Ricerca Cancro (AIRC), Investigator Grants IG-13227 and IG-17622, and Special Program Molecular Clinical Oncology 5 × 1000 No. 10007; Progetto Ricerca Finalizzata I.R.C.C.S. no. RF-2010-2307262, RF-2011-02349712, Progetto Giovani Ricercatori no. GR-2010-2317594, no. GR-2011-02347441, no. GR-2011-02346826, no. GR-2011-02351370, Ministero della Salute, Rome, Italy; 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.

Author contributions

MDB analyzed the data and wrote the manuscript, PB analyzed the data and contributed to writing the manuscript, RB contributed to analyzing the data and performed molecular studies, FP, TB, EZ, IC and MD performed molecular studies, FMR performed FISH analysis, AZ, ET, DB, PN and HC performed cytofluorimetric studies, FZ, GP, AC, FDR and GDP provided well-characterized biological samples and clinical data, DR and GG provided well-characterized biological samples, clinical data and contributed to writing the manuscript and VG designed the study, contributed to analyzing the data and wrote the manuscript.

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  1. M Dal Bo and P Bulian: These authors equally contributed as first authors.

Authors and Affiliations

  1. Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy

    M Dal Bo, P Bulian, R Bomben, A Zucchetto, F M Rossi, F Pozzo, E Tissino, D Benedetti, T Bittolo, P Nanni, I Cattarossi, E Zaina, H Chivilò, M Degan & V Gattei

  2. Clinica Ematologica, Centro Trapianti e Terapie Cellulari 'Carlo Melzi' DISM, Azienda Ospedaliera Universitaria S. Maria Misericordia, Udine, Italy

    F Zaja

  3. Department of Internal Medicine and Hematology, Maggiore General Hospital, University of Trieste, Trieste, Italy

    G Pozzato

  4. Division of Hematology, Ferrarotto Hospital, Catania, Italy

    A Chiarenza & F Di Raimondo

  5. Division of Hematology, S. Eugenio Hospital, University of Tor Vergata, Rome, Italy

    M I Del Principe & G Del Poeta

  6. Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    D Rossi & G Gaidano

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  1. M Dal Bo
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Dal Bo, M., Bulian, P., Bomben, R. et al. CD49d prevails over the novel recurrent mutations as independent prognosticator of overall survival in chronic lymphocytic leukemia. Leukemia 30, 2011–2018 (2016). https://doi.org/10.1038/leu.2016.88

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