STIM1 at the plasma membrane as a new target in progressive chronic lymphocytic leukemia. Issue 1 (23rd April 2019)

• Record Type: Journal Article
• Authors: Debant, Marjolaine; Burgos, Miguel; Hemon, Patrice; Buscaglia, Paul; Fali, Tinhinane; Melayah, Sarra; Le Goux, Nelig; Vandier, Christophe; Potier-Cartereau, Marie; Pers, Jacques-Olivier; Tempescul, Adrian; Berthou, Christian; Bagacean, Cristina; Mignen, Olivier; Renaudineau, Yves
• Is Part Of: Journal for immunotherapy of cancer. Volume 7:Issue 1(2019)
• Publication Date: 2019-04-23
• Subjects: CLL -- STIM1 -- Constitutive Ca2+ entry -- Disease outcome; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1186/s40425-019-0591-3
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Dysregulation in calcium (Ca 2+ ) signaling is a hallmark of chronic lymphocytic leukemia (CLL). While the role of the B cell receptor (BCR) Ca 2+ pathway has been associated with disease progression, the importance of the newly described constitutive Ca 2+ entry (CE) pathway is less clear. In addition, we hypothesized that these differences reflect modifications of the CE pathway and Ca 2+ actors such as Orai1, transient receptor potential canonical (TRPC) 1, and stromal interaction molecule 1 (STIM1), the latter being the focus of this study. Methods: An extensive analysis of the Ca 2+ entry (CE) pathway in CLL B cells was performed including constitutive Ca 2+ entry, basal Ca 2+ levels, and store operated Ca 2+ entry (SOCE) activated following B cell receptor engagement or using Thapsigargin. The molecular characterization of the calcium channels Orai1 and TRPC1 and to their partner STIM1 was performed by flow cytometry and/or Western blotting. Specific siRNAs for Orai1, TRPC1 and STIM1 plus the Orai1 channel blocker Synta66 were used. CLL B cell viability was tested in the presence of an anti-STIM1 monoclonal antibody (mAb, clone GOK) coupled or not with an anti-CD20 mAb, rituximab. The Cox regression model was used to determine the optimal threshold and to stratify patients. Results: Seeking to explore the CE pathway, we found in untreated CLL patients that an abnormal CE pathway was (i) highly associated with the disease outcome; (ii) positively correlated with basal Ca 2+ concentrations; (iii) independent from the BCR-PLCγ2-InsP3 R (SOCE) Ca 2+ signaling pathway; (iv) supported by Orai1 and TRPC1 channels; (v) regulated by the pool of STIM1 located in the plasma membrane (STIM1PM ); and (vi) blocked when using a mAb targeting STIM1PM . Next, we further established an association between an elevated expression of STIM1PM and clinical outcome. In addition, combining an anti-STIM1 mAb with rituximab significantly reduced in vitro CLL B cell viability within the high STIM1PM CLL subgroup. Conclusions: These data establish the critical role of a newly discovered BCR independent Ca 2+ entry in CLL evolution, provide new insights into CLL pathophysiology, and support innovative therapeutic perspectives such as targeting STIM1 located at the plasma membrane.