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Chronic Lymphocytic Leukemia
DNA polymerase ν gene expression influences fludarabine resistance in chronic lymphocytic leukemia independently of p53 status
Haematologica 2018 Volume 103(6):1038-1046
1CRCT, Université de Toulouse, Inserm, CNRS, UPS, France; Equipe Labellisée Ligue Contre le Cancer, Laboratoire d’Excellence Toulouse Cancer, France; 2University of Newcastle, UK; 3Clinical Trials Office - Biostatistics Unit, Institute Claudius Regaud, Institute Universitaire du Cancer Toulouse-Oncopole (IUCT-O), Toulouse, France; 4LAAS, Toulouse, France and 5Department of Hematology, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France
Srdana Grgurevic,1* Patricia Montilla-Perez,1 Alice Bradbury,2 Julia Gilhodes,3 Sophie Queille,1 Sandrine Pelofy,4 Aurélien Bancaud,4 Thomas Filleron,3 Loïc Ysebaert,5 Christian Récher,5 Guy Laurent,5 Jean-Jacques Fournié,1 Christophe Cazaux,1,† Anne Quillet-Mary1 and Jean-Sébastien Hoffmann1*
*SG and J-SH contributed equally to this work † In memoriam
ABSTRACT
Alteration in the DNA replication, repair or recombination process- es is a highly relevant mechanism of genomic instability. Despite genomic aberrations manifested in hematologic malignancies, such a defect as a source of biomarkers has been underexplored. Here, we investigated the prognostic value of expression of 82 genes involved in DNA replication-repair-recombination in a series of 99 patients with chronic lymphocytic leukemia without detectable 17p deletion or TP53 mutation. We found that expression of the POLN gene, encoding the spe- cialized DNA polymerase ν (Pol ν) correlates with time to relapse after first-line therapy with fludarabine. Moreover, we found that POLN was the only gene up-regulated in primary patients’ lymphocytes when exposed in vitro to proliferative and pro-survival stimuli. By using two cell lines that were sequentially established from the same patient during the course of the disease and Pol ν knockout mouse embryonic fibroblasts, we reveal that high relative POLN expression is important for DNA syn- thesis and cell survival upon fludarabine treatment. These findings sug- gest that Pol ν could influence therapeutic resistance in chronic lympho- cytic leukemia. (Patients’ samples were obtained from the CLL 2007 FMP clinical trial registered at: clinicaltrials.gov identifer: 00564512).
Introduction
Chronic lymphocytic leukemia (CLL) is the most common hematologic malig- nancy in the Western hemisphere.1 With a median age at diagnosis of 70 years, CLL is considered to be a disease of the elderly. The malignancy is characterized by the accumulation of mature B lymphocytes that carry B-cell markers, such as CD23, CD19 and CD20, along with a T-cell marker, CD5. Leukemic cells have a defective apoptosis pathway disabled by, among others, overexpression of Bcl-2 protein.2 However, a prolonged life-span of leukemic B cells is not the only cause of disease progression. Several studies have shown that proliferation also plays an important role in the development and clinical course of CLL.3 CLL cells proliferate in so- called proliferation centers (pseudofollicles) of the lymph nodes where they are provided anti-apoptotic and proliferative stimuli from other accessory cells, such as CD40 ligand from helper T lymphocytes or interleukin-2.4 In contrast to the lymph node compartment, the majority of leukemic lymphocytes in the peripheral blood are arrested in the quiescent G0 or G1 phase of the cell cycle.5
CLL is a highly heterogeneous disease in terms of its clinical course and outcome.
Correspondence:
jean-sebastien.hoffmann@inserm.fr or srdana.grgurevic@gmail.com
Received: June 7, 2017. Accepted: March 16, 2018. Pre-published: March 22, 2018.
doi:10.3324/haematol.2017.174243
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/6/1038
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