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RECQ Helicases Are Deregulated in Hematological Malignancies In RECQ helicases are deregulated in hematological malignancies in association with a prognostic value Elena Viziteu, Alboukadel Kassambara, Philippe Pasero, Bernard Klein, Jerome Moreaux To cite this version: Elena Viziteu, Alboukadel Kassambara, Philippe Pasero, Bernard Klein, Jerome Moreaux. RECQ he- licases are deregulated in hematological malignancies in association with a prognostic value. Biomarker Research, BioMed Central, 2016, 4, pp.3. 10.1186/s40364-016-0057-4. inserm-01322505 HAL Id: inserm-01322505 https://www.hal.inserm.fr/inserm-01322505 Submitted on 27 May 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Viziteu et al. Biomarker Research (2016) 4:3 DOI 10.1186/s40364-016-0057-4 RESEARCH Open Access RECQ helicases are deregulated in hematological malignancies in association with a prognostic value Elena Viziteu2, Alboukadel Kassambara1,2, Philippe Pasero2, Bernard Klein1,2,3 and Jerome Moreaux1,2,3* Abstract Background: RECQ helicase family members act as guardians of the genome to assure proper DNA metabolism in response to genotoxic stress. Hematological malignancies are characterized by genomic instability that is possibly related to underlying defects in DNA repair of genomic stability maintenance. Methods: We have investigated the expression of RECQ helicases in different hematological malignancies and in their normal counterparts using publicly available gene expression data. Furthermore, we explored whether RECQ helicases expression could be associated with tumor progression and prognosis. Results: Expression of at least one RECQ helicase family member was found significantly deregulated in all hematological malignancies investigated when compared to their normal counterparts. In addition, RECQ helicase expression was associated with a prognostic value in acute myeloid leukemia, chronic lymphocytic leukemia, lymphoma and multiple myeloma. Conclusion: RECQ helicase expression is deregulated in hematological malignancies compared to their normal counterparts in association with a prognostic value. Deregulation of RECQ helicases appears to play a role in tumorigenesis and represent potent therapeutic targets for synthetic lethal approaches in hematological malignancies. Keywords: RECQ helicases, Gene expression, Hematological malignancies, Prognostic markers, Therapeutic targets Background duplex DNA and processes homologous recombination The RECQ family of DNA helicases is a family of con- (HR) intermediates containing a double holiday junction served enzymes that display highly-specialized and vital [1, 2]. This helicase appears to prefer specific structures roles in the maintenance of genome stability [1]. including D-loops and Holliday junctions and promotes In humans, RECQ helicase family has five members Holliday junction branch migration [3]. It may suppress with similar catalytic core: RECQ1, BLM, WRN, RECQ4 hyper-sister chromatid exchange (SCE) by disruption of and RECQ5 [1]. Mutations in three of the five human D-loop recombination intermediates and also might be RECQ helicases, BLM, WRN and RECQ4, lead to genetic involved in the suppression of crossing over during disorders as Bloom, Rothmund-Thompson and Werner’s homology-mediated recombination [4]. BLM-mediated syndromes that are associated with cancer predisposition, crossover suppression may involve synthesis-dependent premature ageing and developmental abnormalities [1, 2]. strand annealing (SDSA) [3]. This helicase facilitates The Bloom’s syndrome helicase, BLM has DNA anneal- telomere replication by resolving G4 structures [5]. De- ing and unwinding activities. Through its interaction with fects in BLM are also associated with the cancer pheno- TOPOIIIα, BLM unwinds the short stretches of naked type [4]. Unlike the other members of the RECQ helicase family, * Correspondence: [email protected] the Werner’s syndrome helicase, WRN contains both the 1Laboratory for Monitoring Innovative Therapies, Department of Biological classical helicase activity and 3’-to 5’ exonuclease activity Hematology, Hôpital Saint-Eloi - CHRU de Montpellier, 80, av. Augustin Fliche, 34295 Montpellier, Cedex 5, France that target multiple DNA or RNA-DNA hybrid structures 2Institute of Human Genetics, CNRS-UPR1142, Montpellier F-34396, France [1, 2]. As BLM, WRN appears to have robust in vitro G4 Full list of author information is available at the end of the article © 2016 Viziteu et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Viziteu et al. Biomarker Research (2016) 4:3 Page 2 of 9 unwinding activity [6] and plays a specialized role in telo- could represent potent therapeutic targets for cancer mere replication by disruption of G-quadruplex stretches therapy [20]. Hematological malignancies are character- [7]. Another specific substrate of WRN is D-loop. WRN ized by genomic instability that is possibly related to repress the inappropriate telomeric recombination inter- underlying defects in DNA repair of genomic stability mediates through its ability to resolve the D-loops [8]. maintenance. Since these helicases play important roles This helicase was found to be involved in the repair of in the maintenance of chromosomal stability [21], we fo- double strand DNA breaks and studies on Werner’ssyn- cused on RECQ helicases expression in hematological drome fibroblasts have shown defects in recombination cancers compared to their normal counterparts and the intermediate resolution which suggests that WRN is in- association with prognostic impact. volved in HR [9]. WRN can bind to NBS1 [10], a member of the MRN complex, and to the Ku70/Ku80 heterodimer Results and discussion [11], a core non-homologous end joining DNA repair RECQ helicase gene expression levels were analyzed in (NHEJ) complex. different types of hematological malignancies and in RECQ1 is the shortest of the human RECQ family heli- their normal counterparts using Oncomine Cancer cases. RECQ1 displays specific functions in branch migra- Microarray database [22] as indicated in Table 1. Abnor- tion and restart of reversed DNA replication forks upon mal expression of at least one RECQ helicase was identi- DNA topoisomerase I inhibition that is not shared by fied in all analyzed hematological malignancies (Table 1). other human RECQ helicases [12, 13]. Studies have also RECQ1 was found to be significantly overexpressed in shown that RECQ1 plays a role in DNA strand breaks re- mantle cell lymphoma (P = 0.0025) [23], in unspecified pair, mismatch repair and resistance to replication stress peripheral T-cell lymphoma (P = 0.0038) [24], anaplastic [1, 2, 13, 14]. RECQ1 can also contribute to tumor devel- large lymphoma (P = 0.0024) [24] and angioimmunoblas- opment and progression by regulating the expression of tic large cell lymphoma (P = 0.001) [24] (Fig. 1a). key genes that promote cancer cell migration, invasion WRN is significantly overexpressed in primary effusion and metastasis [15]. lymphoma compared to normal B cells (p = 0.003) [23] The gene encoding for RECQ5 helicase was found to (Fig. 1a). be localized on human chromosome 17q23–25, a region RECQ4 expression was increased in Burkitt Lymph- associated with both breast and ovarian cancer [16]. oma (P = 0.001) [23, 25], in diffuse large B cell lymph- RECQ5 was found to cause a significant increase in the oma (P = 0.004) [23] and also in primary effusion frequency of spontaneous SCE [1, 2]. As BLM, RECQ5 lymphoma (P =0.005)[23]comparedtonormalcoun- was shown to play an essential role in suppression of terpart (Fig. 1a). crossovers [17]. RECQ5 was identified as a potential RECQ5 is significantly overexpressed in acute myeloid proto-oncogene in mouse leukemia [18]. RECQ5 is the leukemia (P = 0,001) [26] (Fig. 1a). only member of RECQ family associated with RNA poly- Comparing RECQ helicases expression between normal merase II, maintaining genomic stability during tran- plasma cells (BMPC), premalignant cells from MGUS pa- scription [19]. tients and multiple myeloma cells (MMC) [27], BLM and RECQ helicase are at the crossroad between replica- WRN were found to be significantly downregulated in tion, recombination, DNA repair and transcription and MMC compared to normal BMPC (P = 0.002 and P = Table 1 RECQ family member expression in hematological malignancies compared to that of their normal tissue counterparts using publicly available gene expression data, including the Oncomine Cancer Microarray and Genomicscape databases Hematological Malignancies Datasets Gene overexpression compared to normal tissue counterpart
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