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Ferrata Storti Foundation
Haematologica 2019 Volume 104(10):2040-2052
Chronic Lymphocytic Leukemia
p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape
Laura Patrussi,1 Nagaja Capitani,1,2 Cristina Ulivieri,1 Noemi Manganaro,1 Massimo Granai,3 Francesca Cattaneo,1 Anna Kabanova,1 Lucia Mundo,3 Stefania Gobessi,4 Federica Frezzato,5,6 Andrea Visentin,5,6 Francesca Finetti,1 Pier Giuseppe Pelicci,7 Mario M. D'Elios,2 Livio Trentin,5,6 Gianpietro Semenzato,5,6 Lorenzo Leoncini,3 Dimitar G. Efremov4 and Cosima T. Baldari1
1Department of Life Sciences, University of Siena, Siena; 2Department of Clinical and Experimental Medicine, University of Florence, Florence; 3Department of Human Biotechnologies, University of Siena, Siena; 4International Center for Genetic Engineering and Biotechnology, Trieste; 5Venetian Institute of Molecular Medicine, Padua; 6Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua and 7European Institute of Oncology, Milan, Italy
ABSTRACT
The Shc family adaptor p66Shc acts as a negative regulator of prolifer- ative and survival signals triggered by the B-cell receptor and, by enhancing the production of reactive oxygen species, promotes oxidative stress-dependent apoptosis. Additionally, p66Shc controls the expression and function of chemokine receptors that regulate lymphocyte traffic. Chronic lymphocytic leukemia cells have a p66Shc expression defect which contributes to their extended survival and correlates with poor prog- nosis. We analyzed the impact of p66Shc ablation on disease severity and progression in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia. We showed that Eμ-TCL1/p66Shc-/- mice developed an aggres- sive disease that had an earlier onset, occurred at a higher incidence and led to earlier death compared to that in Eμ-TCL1 mice. Eμ-TCL1/p66Shc-/- mice displayed substantial leukemic cell accumulation in both nodal and extra- nodal sites. The target organ selectivity correlated with upregulation of chemokine receptors whose ligands are expressed therein. This also applied to chronic lymphocytic leukemia cells, where chemokine receptor expres- sion and extent of organ infiltration were found to correlate inversely with these cells’ level of p66Shc expression. p66Shc expression declined with dis- ease progression in Eμ-TCL1 mice and could be restored by treatment with the Bruton tyrosine kinase inhibitor ibrutinib. Our results highlight p66Shc deficiency as an important factor in the progression and severity of chronic lymphocytic leukemia and underscore p66Shc expression as a relevant ther- apeutic target.
Introduction
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of long-lived mature CD5+ B cells in peripheral blood, bone marrow and secondary lymphoid organs.1 Leukemic cell survival is associated with defective apoptosis2 and, moreover, is promoted by stromal cell-derived chemokines during their transit through secondary lymphoid organs,3 where they also undergo proliferation within pseudofollicles.1 Imbalanced expression of chemokine receptors regulating homing to (CCR7, CXCR4, CXCR5) and egress from (S1PR1) secondary lymphoid organs concurs to retain CLL cells in the lymphoid niche.3
The adaptor p66Shc participates in signaling pathways linking oxidative stress to apoptosis.4 p66Shc promotes the production of reactive oxygen species (ROS) by interrupting the mitochondrial respiratory chain through cytochrome c binding and oxidation, causing activation of the apoptotic cascade. Additionally, it negatively
Correspondence:
COSIMA T. BALDARI
baldari@unisi.it
LAURA PATRUSSI
patrussi2@unisi.it
Received: October 22, 2018. Accepted: February 22, 2019. Pre-published: February 28, 2019.
doi:10.3324/haematol.2018.209981
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/10/2040
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