Constitutive activation of the DNA damage response pathway as a novel therapeutic target in diffuse large B-cell lymphoma
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Enrico Derenzini1, Claudio Agostinelli2, Enrica Imbrogno1, Ilaria Iacobucci1, Beatrice Casadei1, Elisa Brighenti1, Simona Righi2, Fabio Fuligni2, Andrea Ghelli Luserna Di Rorà1, Anna Ferrari1, Giovanni Martinelli1, Stefano Pileri2, Pier Luigi Zinzani1
1Institute of Hematology and Medical Oncology L.A. Seragnoli, Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Italy
2Haematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Italy
Enrico Derenzini, e-mail: firstname.lastname@example.org
Keywords: Diffuse Large B-cell Lymphoma, genomic instability, CHK1, CHK2, gamma-H2AX, MYC
Received: August 23, 2014 Accepted: November 08, 2014 Published: January 07, 2015
The recent finding that MYC-driven cancers are sensitive to inhibition of the DNA damage response (DDR) pathway, prompted us to investigate the role of DDR pathway as therapeutic target in diffuse large B-cell lymphoma (DLBCL), which frequently overexpresses the MYC oncogene. In a preliminary immunohistochemical study conducted on 99 consecutive DLBCL patients, we found that about half of DLBCLs showed constitutive expression of the phosphorylated forms of checkpoint kinases (CHK) and CDC25c, markers of DDR activation, and of phosphorylated histone H2AX (γH2AX), marker of DNA damage and genomic instability. Constitutive γH2AX expression correlated with c-MYC levels and DDR activation, and defined a subset of tumors characterised by poor outcome. Next, we used the CHK inhibitor PF-0477736 as a tool to investigate whether the inhibition of the DDR pathway might represent a novel therapeutic approach in DLBCL. Submicromolar concentrations of PF-0477736 hindered proliferation in DLBCL cell lines with activated DDR pathway. These results were fully recapitulated with a different CHK inhibitor (AZD-7762). Inhibition of checkpoint kinases induced rapid DNA damage accumulation and apoptosis in DLBCL cell lines and primary cells. These data suggest that pharmacologic inhibition of DDR through targeting of CHK kinases may represent a novel therapeutic strategy in DLBCL.
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