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Chronic lymphocytic leukemia

NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia: link between the NOTCH1 and the NF-κB pathways

Leukemia volume 32, pages 654–662 (2018)Cite this article

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Abstract

In chronic lymphocytic leukemia (CLL), stabilizing mutations of NOTCH1, affecting up to 10–15% of cases, have been associated to poor prognosis, disease progression and refractoriness to chemotherapy. NOTCH1 mutations are significantly overrepresented in trisomy 12 CLL, a disease subset frequently expressing CD49d, the α4 chain of the very-late-activation-4 integrin, a well-known key regulator of microenviromental interactions, and negative prognosticator in CLL. In the present study, by analysing a wide cohort of 1180 CLL, we observed a very strong association between the presence of NOTCH1 mutations and the expression of CD49d (P<0.0001), occurring also outside the trisomy 12 CLL subset. Using both the MEC-1 CLL-like cells stably transfected with the NOTCH1 intracellular domain and primary CLL cells bearing a mutated or wild-type NOTCH1 gene configuration, we provide evidence that triggering of the NOTCH1 pathway resulted in a positive CD49d expression regulation, which was driven by a NOTCH1-dependent activation of nuclear factot-κB (NF-κB). Consistently, pharmacological inhibition of the NOTCH1 and/or of the NF-κB pathways resulted in impaired NF-κB nuclear translocation with consequent down-modulation of CD49d expression. Altogether, our data link for the first time NOTCH1 mutations to CD49d expression regulation through the involvement of the NF-κB pathway in CLL.

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Acknowledgements

This study was supported in part by the Associazione Italiana Ricerca Cancro (AIRC), IG-17622 and Special-Program-Molecular-Clinical-Oncology 5 × 1000 No.10007; RF-2011-02349712, GR-2011-02346826, GR-2011-02347441, GR-2011-02351370, Ministero della Salute, Rome, Italy; Ricerca clinica/traslazionale/di base/epidemiologica/organizzativa, Regione FVG (‘Linfo-Check’ Project), Trieste, Italy; Associazione Italiana contro le Leucemie, linfomi e mielomi (AIL), Venezia Section, Pramaggiore Group, Italy; Fondazione per la Vita di Pordenone, Italy; and 5 × 1000 Intramural Program, Centro di Riferimento Oncologico, Aviano, Italy. We thank our patients for participating and donating samples to make this research possible.

Author contributions

AZ and VG designed the study, coordinated the experiments and wrote the manuscript. DB and ET performed the experiments, analysed the data and contributed to write the manuscript. FP, TB, CC, CP, DM, VB, TD, FMR, RB and MDB performed the experiments and contributed to characterize samples and to data analysis. ES, FZ, GP, FDR, GDP, DR and GG contributed to molecular characterization of samples and provided well characterized biological samples. All the authors commented and contributed to write the manuscript.

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Author notes

  1. D Benedetti and E Tissino: These authors equally contributed as first authors.

  2. V Gattei and A Zucchetto: 1These authors equally contributed as senior authors.

Authors and Affiliations

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

    D Benedetti, E Tissino, F Pozzo, T Bittolo, C Caldana, C Perini, V Bravin, T D’Agaro, F M Rossi, R Bomben, M Dal Bo, V Gattei & A Zucchetto

  2. Cancer Bio-Immunotherapy Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Italy

    D Martorelli

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

    E Santinelli & G Del Poeta

  4. Clinica Ematologica, DIRM, University of Udine, Udine, Italy

    F Zaja

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

    G Pozzato

  6. Division of Hematology, Ferrarotto Hospital, University of Catania, Catania, Italy

    A Chiarenza & F Di Raimondo

  7. Department of Hematology, Institute of Oncology Research and Oncology Institute of Southern Switzerland, Switzerland, Switzerland

    D Rossi

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

    G Gaidano

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  1. D Benedetti
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Correspondence to V Gattei or A Zucchetto.

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Benedetti, D., Tissino, E., Pozzo, F. et al. NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia: link between the NOTCH1 and the NF-κB pathways. Leukemia 32, 654–662 (2018). https://doi.org/10.1038/leu.2017.296

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