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Chronic lymphocytic leukemia

Mutations in NOTCH1 PEST domain orchestrate CCL19-driven homing of chronic lymphocytic leukemia cells by modulating the tumor suppressor gene DUSP22

Leukemia volume 31, pages 1882–1893 (2017)Cite this article

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Abstract

Even if NOTCH1 is commonly mutated in chronic lymphocytic leukemia (CLL), its functional impact in the disease remains unclear. Using CRISPR/Cas9-generated Mec-1 cell line models, we show that NOTCH1 regulates growth and homing of CLL cells by dictating expression levels of the tumor suppressor gene DUSP22. Specifically, NOTCH1 affects the methylation of DUSP22 promoter by modulating a nuclear complex, which tunes the activity of DNA methyltransferase 3A (DNMT3A). These effects are enhanced by PEST-domain mutations, which stabilize the molecule and prolong signaling. CLL patients with a NOTCH1-mutated clone showed low levels of DUSP22 and active chemotaxis to CCL19. Lastly, in xenograft models, NOTCH1-mutated cells displayed a unique homing behavior, localizing preferentially to the spleen and brain. These findings connect NOTCH1, DUSP22, and CCL19-driven chemotaxis within a single functional network, suggesting that modulation of the homing process may provide a relevant contribution to the unfavorable prognosis associated with NOTCH1 mutations in CLL.

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Acknowledgements

Supported by the Associazione Italiana per la Ricerca sul Cancro AIRC (IG-17314 to SD, IG-15217 to SO and 5x1000 #100007 to GG), by the Human Genetics Foundation Institutional funds, by the Italian Ministries of Education, University and Research (Futuro in Ricerca 2012 # RBFR12D1CB), the Italian Ministry of Health (Bando Giovani Ricercatori GR-2011-02346826 and Bando Ricerca Finalizzata RF-2011-02349712), the Fondazione Cariplo, grant #2012-0689 and local university funds (ex-60%).

Author contributions

FA: designed the study, performed experiments, analyzed and interpreted data and together with SD wrote the paper; BG, CB, SC, RB, SS, TV, KG, NV, GGar, EM, FD and FN performed experiments; MC, JA, RRF, DR and GGai: provided patient samples and relevant clinical information and contributed to data interpretation; RP and SO: discussed results and contributed to data interpretation; SD: designed the study, interpreted data and together with FA wrote the paper.

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Authors and Affiliations

  1. Human Genetics Foundation, Turin, Italy

    F Arruga, B Gizdic, C Bologna, S Cignetto, R Buonincontri, S Serra, T Vaisitti, K Gizzi, F Neri, D Incarnato, S Oliviero & S Deaglio

  2. Department of Medical Sciences, University of Turin, Turin, Italy

    F Arruga, B Gizdic, C Bologna, S Cignetto, R Buonincontri, S Serra, T Vaisitti & S Deaglio

  3. Department of Molecular Biotechnologies and Health Science, University of Turin, Turin, Italy

    N Vitale, G Garaffo, E Mereu, M Coscia & R Piva

  4. Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy

    F Diop, D Rossi & G Gaidano

  5. Department of Hematology, Weill Cornell Medicine, New York, NY, USA

    J Allan & R R Furman

  6. Department of Life Sciences and Systems Biology, University of Turin, Turin, Italy

    S Oliviero

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Correspondence to F Arruga or S Deaglio.

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Arruga, F., Gizdic, B., Bologna, C. et al. Mutations in NOTCH1 PEST domain orchestrate CCL19-driven homing of chronic lymphocytic leukemia cells by modulating the tumor suppressor gene DUSP22. Leukemia 31, 1882–1893 (2017). https://doi.org/10.1038/leu.2016.383

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