Skip to main content
Download PDF

RECQ helicases are deregulated in hematological malignancies in association with a prognostic value

Biomarker Research volume 4, Article number: 3 (2016) Cite this article

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.

Background

The RECQ family of DNA helicases is a family of conserved enzymes that display highly-specialized and vital roles in the maintenance of genome stability [1].

In humans, RECQ helicase family has five members with similar catalytic core: RECQ1, BLM, WRN, RECQ4 and RECQ5 [1]. Mutations in three of the five human RECQ helicases, BLM, WRN and RECQ4, lead to genetic disorders as Bloom, Rothmund-Thompson and Werner’s syndromes that are associated with cancer predisposition, premature ageing and developmental abnormalities [1, 2].

The Bloom’s syndrome helicase, BLM has DNA annealing and unwinding activities. Through its interaction with TOPOIIIα, BLM unwinds the short stretches of naked duplex DNA and processes homologous recombination (HR) intermediates containing a double holiday junction [1, 2]. This helicase appears to prefer specific structures including D-loops and Holliday junctions and promotes Holliday junction branch migration [3]. It may suppress hyper-sister chromatid exchange (SCE) by disruption of D-loop recombination intermediates and also might be involved in the suppression of crossing over during homology-mediated recombination [4]. BLM-mediated crossover suppression may involve synthesis-dependent strand annealing (SDSA) [3]. This helicase facilitates telomere replication by resolving G4 structures [5]. Defects in BLM are also associated with the cancer phenotype [4].

Unlike the other members of the RECQ helicase family, the Werner’s syndrome helicase, WRN contains both the classical helicase activity and 3’-to 5’ exonuclease activity that target multiple DNA or RNA-DNA hybrid structures [1, 2]. As BLM, WRN appears to have robust in vitro G4 unwinding activity [6] and plays a specialized role in telomere replication by disruption of G-quadruplex stretches [7]. Another specific substrate of WRN is D-loop. WRN repress the inappropriate telomeric recombination intermediates through its ability to resolve the D-loops [8]. This helicase was found to be involved in the repair of double strand DNA breaks and studies on Werner’s syndrome fibroblasts have shown defects in recombination intermediate resolution which suggests that WRN is involved in HR [9]. WRN can bind to NBS1 [10], a member of the MRN complex, and to the Ku70/Ku80 heterodimer [11], a core non-homologous end joining DNA repair (NHEJ) complex.

RECQ1 is the shortest of the human RECQ family helicases. RECQ1 displays specific functions in branch migration and restart of reversed DNA replication forks upon DNA topoisomerase I inhibition that is not shared by other human RECQ helicases [12, 13]. Studies have also shown that RECQ1 plays a role in DNA strand breaks repair, mismatch repair and resistance to replication stress [1, 2, 13, 14]. RECQ1 can also contribute to tumor development and progression by regulating the expression of key genes that promote cancer cell migration, invasion and metastasis [15].

The gene encoding for RECQ5 helicase was found to be localized on human chromosome 17q23–25, a region associated with both breast and ovarian cancer [16]. RECQ5 was found to cause a significant increase in the frequency of spontaneous SCE [1, 2]. As BLM, RECQ5 was shown to play an essential role in suppression of crossovers [17]. RECQ5 was identified as a potential proto-oncogene in mouse leukemia [18]. RECQ5 is the only member of RECQ family associated with RNA polymerase II, maintaining genomic stability during transcription [19].

RECQ helicase are at the crossroad between replication, recombination, DNA repair and transcription and could represent potent therapeutic targets for cancer therapy [20]. Hematological malignancies are characterized by genomic instability that is possibly related to underlying defects in DNA repair of genomic stability maintenance. Since these helicases play important roles in the maintenance of chromosomal stability [21], we focused on RECQ helicases expression in hematological cancers compared to their normal counterparts and the association with prognostic impact.

Results and discussion

RECQ helicase gene expression levels were analyzed in different types of hematological malignancies and in their normal counterparts using Oncomine Cancer Microarray database [22] as indicated in Table 1. Abnormal expression of at least one RECQ helicase was identified in all analyzed hematological malignancies (Table 1). RECQ1 was found to be significantly overexpressed in mantle cell lymphoma (P = 0.0025) [23], in unspecified peripheral T-cell lymphoma (P = 0.0038) [24], anaplastic large lymphoma (P = 0.0024) [24] and angioimmunoblastic large cell lymphoma (P = 0.001) [24] (Fig. 1a).

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
Full size table
Fig. 1
figure1

Increased RECQ helicase gene expression in hematological malignancies compared to normal counterparts using Oncomine database (a) and Genomicscape database (b). Data sets in a given panel were from the same study. GEP data are log transformed (Oncomine) or not (Genomicscape) and normalized as previously described [64]

Full size image

WRN is significantly overexpressed in primary effusion lymphoma compared to normal B cells (p = 0.003) [23] (Fig. 1a).

RECQ4 expression was increased in Burkitt Lymphoma (P = 0.001) [23, 25], in diffuse large B cell lymphoma (P = 0.004) [23] and also in primary effusion lymphoma (P = 0.005) [23] compared to normal counterpart (Fig. 1a).

RECQ5 is significantly overexpressed in acute myeloid leukemia (P = 0,001) [26] (Fig. 1a).

Comparing RECQ helicases expression between normal plasma cells (BMPC), premalignant cells from MGUS patients and multiple myeloma cells (MMC) [27], BLM and WRN were found to be significantly downregulated in MMC compared to normal BMPC (P = 0.002 and P = 0.001 respectively) (Fig. 1b). A decreased expression of BLM was also observed in MGUS compared to BMPC (P = 0.01). RECQ1 and RECQ4 are overexpressed in MGUS (P = 0.006 and P = 0.002) and MMC (P < 0.0001 and P = 0.0009) compared to BMPC. Furthermore, a significant increased expression of RECQ1 in MMC compared to MGUS was identified (Fig. 1b).

Furthermore, using the human protein atlas database [28–30], the expression of RECQ1, RECQ4 and RECQ5 could be confirmed at protein level in myeloid and lymphoid cancer cell lines (Additional file 1: Figure S1).

We investigated whether RECQ helicases expression could be associated with tumor progression and prognosis in hematological malignancies (Table 2).

Table 2 Link between RECQ helicase gene expression and prognostic value in hematological malignancies
Full size table

In AML patients with abnormal karyotype (Verhaak cohort, N = 521 patients) [31], a high expression of BLM and RECQ4 is associated with a better overall survival (OS) (P = 0.01 and P = 0.003). At the opposite, high RECQ5 expression was linked with a poor prognosis in the same cohort of patient (P = 0.008) (Fig. 2a). In cox multivariate analysis, only RECQ5 expression kept prognostic value (P = 0.01, hazard ratio (HR) = 1.43).

Fig. 2
figure2

Overall survival related to RECQ helicase gene expression in acute myeloid leukemia with abnormal karyotype (a) and normal karyotype (b). The prognostic value of gene expression was determined using the MaxStat R function in R software. The overall survival of subgroups of patients was compared with the log-rank test and survival curves computed with the Kaplan–Meier method (R software) [66]

Full size image

In AML with normal karyotype, (Metzeler cohort, N = 78) [32], gene expression of four RECQ helicases out of five were identified to predict for OS. High expression of RECQ1 (P = 0.02), BLM (P = 0.01) and RECQ5 (P = 0.03) were found to be associated with poor prognosis. In contrast, high RECQ4 expression was linked with a better outcome (P = 0.03) (Fig. 2b). When tested together in a cox multivariate analysis, only RECQ4 expression remained significant (P = 0.009; HR = 0.4).

Interestingly, RECQ5 overexpression was only identified in myeloid malignancies in association with an adverse prognosis. RECQ5 increased expression was recently reported in JAK2V617F myeloproliferative neoplasms [33]. RECQ5 depletion in JAK2V617F-mutant cells impairs replication after hydroxyurea treatment leading to a significant increased double-stranded breaks and apoptosis [33]. RECQ5 represents a potent regulator of genome stability in myeloproliferative neoplasms in association with drug resistance [33]. RECQ5 overexpression could also be involved in AML pathophysiology and chemoresistance.

Even if RECQ1 mutations have been recently shown to been associated with predisposition to breast cancer [34, 35], no link between RECQ1, BLM, WRN, and RECQ4 deregulation and lymphoid malignancies were previously reported.

In chronic lymphocytic leukemia (CLL), a poor prognosis was linked with high RECQ5 expression (P = 8E-8) and a better outcome was associated with high WRN expression (P = 0.0006) (Fig. 3a).

Fig. 3
figure3

Overall survival related to RECQ helicase gene expression in chronic lymphocytic leukemia (a), follicular lymphoma (b) and diffuse large B cell lymphoma (c)

Full size image

In a cohort of patients with follicular lymphoma (FL) (Staudt cohort, N = 180) [36], high RECQ1 and RECQ5 expression represented adverse prognostic factors (P = 0.003 and P = 0.0006 respectively) whereas RECQ4 expression was found to be associated with a good prognosis (P = 0.009) (Fig. 3b). Interestingly, RECQ1, RECQ4 and RECQ5 expresison remained independent when tested in cox multivariate analysis (P < 0.0001; HR = 2.8; P = 0.002; HR = 0.49 and P < 0.01; HR = 1.78 respectively).

In diffuse large B cell lymphoma (DLBCL), only RECQ5 expression was associated with a prognostic value. Low RECQ5 expression was a poor prognostic marker in two independent cohorts of patients (P = 0.02 in a cohort of patients treated by combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) therapy (N = 181) and P = 0.01 in a cohort of patients treated by Rituximab combined with CHOP (R-CHOP) regimen (N = 233)) (Fig. 3c) [37].

In MM, high RECQ1, WRN and RECQ4 expression are associated with an adverse prognosis in the UAMS cohort treated with total therapy 2 (Fig. 4) [27].

Fig. 4
figure4

Overall survival related to RECQ helicase gene expression in multiple myeloma

Full size image

These data demonstrate a link between RECQ helicase expression and a prognostic value in different hematological malignancies.

Hematological malignancies are characterized by genomic instability that could be related to defects in DNA repair [21]. The RECQ family of DNA helicases is a family of conserved enzymes that display highly specialized and vital roles in the maintenance of genome stability. Mutations in three of the five human RECQ helicases, BLM, WRN and RECQL4, are associated with genetic disorders characterized by chromosomal instability and increased susceptibility to cancer including leukemia [38, 39]. Mutations in BLM result in a dramatic lowering of BLM mRNA levels and premature termination of protein translation owing to nonsense-mediated mRNA decay [1, 40]. Patients with Bloom syndrome exhibit cancer predisposition including most types of cancers and particularly non-Hodgkin’s lymphoma, leukemias and carcinomas of skin, breast and colon [1]. Interestingly, a low BLM expression is associated with a poor prognosis in AML with complex karyotypes (Fig. 2a). The cancer spectrum observed in patients with Werner’s syndrome is characterized mainly by cancers of mesenchymal origin and some epithelial cancers [1, 41]. RECQ4 mutations are found in Rothmund-Thomson syndrome, RAPADILINO syndrome and Baller-Gerold syndrome [1, 41]. Rothmund-Thomson syndrome are characterized by predisposition to mainly osteosarcoma whereas RAPADILINO syndrome are linked with lymphoma and osteosarcoma predisposition [1].

Specific recurrent chromosomal translocations have been associated with DNA repair deficiencies linked with repression of DDR (DNA damage response) genes in AML [42]. In PML-RARA, PML and BLM are delocalized from the nuclear bodies into microspeckled nuclear regions [43]. All trans retinoic acid (ATRA) treatment of APL patients leads to degradation of PML-RARA and relocalization of BLM to nuclear bodies [43] suggesting that PML-RARA are involved in genomic instability in APL through disruption of BLM and PML localization and activity. Interestingly, we reported that low BLM and RECQ4 expression are associated with a poor prognosis in AML with abnormal karyotype (Fig. 2a), suggesting that downregulation of RECQ helicases could be involved in leukemogenesis and genomic instability. At the opposite, in AML with normal karyotype, RECQ1, BLM and RECQ5 high expression are associated with a poor prognosis (Fig. 2b). As reported in solid cancer, RECQ helicase overexpression could be a marker of chemoresistance and higher proliferation helping AML cells to deal with replication stress [44, 45]. B lymphocytes are continuously produced during adult life and they undergo different genetic alterations associated with DNA breaks, including VDJ recombination, Ig class switch recombination and somatic hypermutation. These mechanisms must be tightly regulated to prevent tumorigenesis and ensure efficient immune response [46]. Collapsed DNA replication forks occurring in rapidly dividing lymphocytes leads to a restart failure and results in an interruption of the normal developmental program [47]. HR is required for lymphoid development [47]. Aberrations affecting HR actors are correlated with genomic instability in B cell cancers [48]. By their involvement in HR and also by their ability to resolve and to continue the normal fork replication after DNA damage or replication fork arrest, WRN [49], BLM [4], RECQ1 [12] and RECQ5 [50] helicases might be crucial in lymphoid development and aberration in their expression or function can lead to cancer genesis. Interestingly, low expression of WRN in CLL and FL, low RECQ4 expression in FL and low RECQ5 in DLBCL are associated with a poor prognosis (Fig. 3). Furthermore, high RECQ5 expression in CLL and FL and high RECQ1 expression in FL are associated with a poor prognosis and could be involved in chemoresistance. In lymphoma, deregulation of DDR is associated with tumorigenesis [51, 52], poor prognosis [53, 54] and could represent a potent therapeutic target [53, 55, 56].

In MM, patients with extensive chromosomal instability and replicative stress are associated with an adverse outcome [27, 57–59]. Accordingly, high RECQ1, WRN and RECQ4 expression is associated with a significant poor survival in MM patients (Fig. 4). Although WRN was found to be significantly downregulated in MMC compared to normal BMPC (Fig. 1b), patients with high expression display a poor prognosis. WRN is located on chromosome 8p deleted in 25 % of MM patients without prognostic value [60]. These data could explain the significant downregulation of WRN expression in MM compared to normal BMPC.

Recently, a set of molecule inhibitors of WRN and BLM was characterized [61, 62]. These new molecules could open up new therapeutic strategies for targeting hematological malignancies characterized by RECQ helicase deregulation and a poor prognosis.

Conclusion

The analysis reported here demonstrates that RECQ helicase expression is deregulated in hematological malignancies compared to their normal counterparts in association with a prognostic value in AML, CLL, lymphoma and MM. Deregulation of RECQ helicases appears to play a role in tumorigenesis and could be involved in genomic instability and chemoresistance in hematological malignancies. RECQ helicases represent potent therapeutic targets for synthetic lethal approaches.

Methods

Databases: We used Oncomine Cancer Microarray database (http://www.oncomine.org) [22] and Genomicscape (http://genomicscape.com/) [63] to study gene expression of RECQ family members in nine different human hematological malignancies and their normal tissue counterpart as indicated in Table 1. To compare the gene expression of a tumor type to its normal counterpart, we used gene expression data from a same study with the same methodology. All data were log transformed, median centered per array, and the standard deviation was normalized to one per array [22].

Statistical comparisons were done with Mann–Whitney or Student t-test as previously published [64].

Prognosis values of each member of RECQ family in hematological malignancies were determined by using Maxstat R package based on publicly available data (Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/); accession numbers GSE6891, GSE12417, GSE22762, GSE16131, GSE10846 and GSE4581) analyzed with Genomicscape [63] as previously reported [65].

References

  1. 1.

    Chu WK, Hickson ID. RecQ helicases: multifunctional genome caretakers. Nat Rev Cancer. 2009;9(9):644–54. doi:10.1038/nrc2682.

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Larsen NB, Hickson ID. RecQ Helicases: Conserved Guardians of Genomic Integrity. Adv Exp Med Biol. 2013;767:161–84. doi:10.1007/978-1-4614-5037-5_8.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Weinert BT, Rio DC. DNA strand displacement, strand annealing and strand swapping by the Drosophila Bloom's syndrome helicase. Nucleic Acids Res. 2007;35(4):1367–76. doi:10.1093/nar/gkl831.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  4. 4.

    Sung P, Klein H. Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat Rev Mol Cell Biol. 2006;7(10):739–50. 10. 1038/nrm2008.

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Drosopoulos WC, Kosiyatrakul ST, Schildkraut CL. BLM helicase facilitates telomere replication during leading strand synthesis of telomeres. J Cell Biol. 2015;210(2):191–208. doi:10.1083/jcb.201410061.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  6. 6.

    Kamath-Loeb A, Loeb LA, Fry M. The Werner syndrome protein is distinguished from the Bloom syndrome protein by its capacity to tightly bind diverse DNA structures. PLoS One. 2012;7(1):e30189. doi:10.1371/journal.pone.0030189.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  7. 7.

    Damerla RR, Knickelbein KE, Strutt S, Liu FJ, Wang H, Opresko PL. Werner syndrome protein suppresses the formation of large deletions during the replication of human telomeric sequences. Cell Cycle. 2012;11(16):3036–44. doi:10.4161/cc.21399.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  8. 8.

    Opresko PL, Mason PA, Podell ER, Lei M, Hickson ID, Cech TR, et al. POT1 stimulates RecQ helicases WRN and BLM to unwind telomeric DNA substrates. J Biol Chem. 2005;280(37):32069–80. doi:10.1074/jbc.M505211200.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Chen L, Huang S, Lee L, Davalos A, Schiestl RH, Campisi J, et al. WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair. Aging Cell. 2003;2(4):191–9.

    Article  PubMed  Google Scholar 

  10. 10.

    Kobayashi J, Okui M, Asaithamby A, Burma S, Chen BP, Tanimoto K, et al. WRN participates in translesion synthesis pathway through interaction with NBS1. Mech Ageing Dev. 2010;131(6):436–44. doi:10.1016/j.mad.2010.06.005.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  11. 11.

    Karmakar P, Snowden CM, Ramsden DA, Bohr VA. Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus. Nucleic Acids Res. 2002;30(16):3583–91.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  12. 12.

    Berti M, Ray Chaudhuri A, Thangavel S, Gomathinayagam S, Kenig S, Vujanovic M, et al. Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat Struct Mol Biol. 2013;20(3):347–54. doi:10.1038/nsmb.2501.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  13. 13.

    Lu X, Parvathaneni S, Hara T, Lal A, Sharma S. Replication stress induces specific enrichment of RECQ1 at common fragile sites FRA3B and FRA16D. Mol Cancer. 2013;12(1):29. doi:10.1186/1476-4598-12-29.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  14. 14.

    Popuri V, Croteau DL, Brosh Jr RM, Bohr VA. RECQ1 is required for cellular resistance to replication stress and catalyzes strand exchange on stalled replication fork structures. Cell Cycle. 2012;11(22):4252–65. doi:10.4161/cc.22581.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  15. 15.

    Li XL, Lu X, Parvathaneni S, Bilke S, Zhang H, Thangavel S, et al. Identification of RECQ1-regulated transcriptome uncovers a role of RECQ1 in regulation of cancer cell migration and invasion. Cell Cycle. 2014;13(15):2431–45.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  16. 16.

    Sekelsky JJ, Brodsky MH, Rubin GM, Hawley RS. Drosophila and human RecQ5 exist in different isoforms generated by alternative splicing. Nucleic Acids Res. 1999;27(18):3762–9.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  17. 17.

    Hu Y, Lu X, Barnes E, Yan M, Lou H, Luo G. Recql5 and Blm RecQ DNA helicases have nonredundant roles in suppressing crossovers. Mol Cell Biol. 2005;25(9):3431–42. doi:10.1128/MCB.25.9.3431-3442.2005.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  18. 18.

    Hansen GM, Skapura D, Justice MJ. Genetic profile of insertion mutations in mouse leukemias and lymphomas. Genome Res. 2000;10(2):237–43.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  19. 19.

    Saponaro M, Kantidakis T, Mitter R, Kelly GP, Heron M, Williams H, et al. RECQL5 controls transcript elongation and suppresses genome instability associated with transcription stress. Cell. 2014;157(5):1037–49. doi:10.1016/j.cell.2014.03.048.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  20. 20.

    Rezazadeh S. RecQ helicases; at the crossroad of genome replication, repair, and recombination. Mol Biol Rep. 2011. doi:10.1007/s11033-011-1243-y

  21. 21.

    Economopoulou P, Pappa V, Papageorgiou S, Dervenoulas J, Economopoulos T. Abnormalities of DNA repair mechanisms in common hematological malignancies. Leuk Lymphoma. 2011;52(4):567–82. doi:10.3109/10428194.2010.551155.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6(1):1–6.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  23. 23.

    Basso K, Margolin AA, Stolovitzky G, Klein U, Dalla-Favera R, Califano A. Reverse engineering of regulatory networks in human B cells. Nat Genet. 2005;37(4):382–90. doi:10.1038/ng1532.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Piccaluga PP, Agostinelli C, Califano A, Rossi M, Basso K, Zupo S, et al. Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets. J Clin Invest. 2007;117(3):823–34. doi:10.1172/JCI26833.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  25. 25.

    Brune V, Tiacci E, Pfeil I, Doring C, Eckerle S, van Noesel CJ, et al. Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J Exp Med. 2008;205(10):2251–68. doi:10.1084/jem.20080809.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  26. 26.

    Stegmaier K, Ross KN, Colavito SA, O'Malley S, Stockwell BR, Golub TR. Gene expression-based high-throughput screening(GE-HTS) and application to leukemia differentiation. Nat Genet. 2004;36(3):257–63. doi:10.1038/ng1305.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, et al. The molecular classification of multiple myeloma. Blood. 2006;108(6):2020–8.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  28. 28.

    Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. doi:10.1126/science.1260419.

    Article  PubMed  Google Scholar 

  29. 29.

    Ponten F, Jirstrom K, Uhlen M. The Human Protein Atlas--a tool for pathology. J Pathol. 2008;216(4):387–93. doi:10.1002/path.2440.

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Uhlen M, Bjorling E, Agaton C, Szigyarto CA, Amini B, Andersen E, et al. A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteomics. 2005;4(12):1920–32. doi:10.1074/mcp.M500279-MCP200.

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Verhaak RG, Wouters BJ, Erpelinck CA, Abbas S, Beverloo HB, Lugthart S, et al. Prediction of molecular subtypes in acute myeloid leukemia based on gene expression profiling. Haematologica. 2009;94(1):131–4. doi:10.3324/haematol.13299.

    PubMed Central  Article  PubMed  Google Scholar 

  32. 32.

    Metzeler KH, Maharry K, Radmacher MD, Mrozek K, Margeson D, Becker H, et al. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2011;29(10):1373–81. doi:10.1200/JCO.2010.32.7742.

    PubMed Central  Article  PubMed  Google Scholar 

  33. 33.

    Chen E, Ahn JS, Sykes DB, Breyfogle LJ, Godfrey AL, Nangalia J, et al. RECQL5 Suppresses Oncogenic JAK2-Induced Replication Stress and Genomic Instability. Cell reports. 2015;13(11):2345–52. doi:10.1016/j.celrep.2015.11.037.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  34. 34.

    Sun J, Wang Y, Xia Y, Xu Y, Ouyang T, Li J, et al. Mutations in RECQL Gene Are Associated with Predisposition to Breast Cancer. PLoS Genet. 2015;11(5):e1005228. doi:10.1371/journal.pgen.1005228.

    PubMed Central  Article  PubMed  Google Scholar 

  35. 35.

    Cybulski C, Carrot-Zhang J, Kluzniak W, Rivera B, Kashyap A, Wokolorczyk D, et al. Germline RECQL mutations are associated with breast cancer susceptibility. Nat Genet. 2015;47(6):643–6. doi:10.1038/ng.3284.

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Leich E, Salaverria I, Bea S, Zettl A, Wright G, Moreno V, et al. Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations. Blood. 2009;114(4):826–34. doi:10.1182/blood-2009-01-198580.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  37. 37.

    Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008;359(22):2313–23. doi:10.1056/NEJMoa0802885.

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Suhasini AN, Brosh Jr RM. Fanconi anemia and Bloom's syndrome crosstalk through FANCJ-BLM helicase interaction. Trends Genet. 2012;28(1):7–13. doi:10.1016/j.tig.2011.09.003.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  39. 39.

    Poppe B, Van Limbergen H, Van Roy N, Vandecruys E, De Paepe A, Benoit Y, et al. Chromosomal aberrations in Bloom syndrome patients with myeloid malignancies. Cancer Genet Cytogenet. 2001;128(1):39–42.

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    German J, Sanz MM, Ciocci S, Ye TZ, Ellis NA. Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry. Hum Mutat. 2007;28(8):743–53. doi:10.1002/humu.20501.

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Goto M, Miller RW, Ishikawa Y, Sugano H. Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomarkers Prev. 1996;5(4):239–46.

    CAS  PubMed  Google Scholar 

  42. 42.

    Esposito MT, So CW. DNA damage accumulation and repair defects in acute myeloid leukemia: implications for pathogenesis, disease progression, and chemotherapy resistance. Chromosoma. 2014;123(6):545–61. doi:10.1007/s00412-014-0482-9.

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    Zhong S, Hu P, Ye TZ, Stan R, Ellis NA, Pandolfi PP. A role for PML and the nuclear body in genomic stability. Oncogene. 1999;18(56):7941–7. doi:10.1038/sj.onc.1203367.

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Sanada S, Futami K, Terada A, Yonemoto K, Ogasawara S, Akiba J, et al. RECQL1 DNA repair helicase: a potential therapeutic target and a proliferative marker against ovarian cancer. PLoS One. 2013;8(8):e72820. doi:10.1371/journal.pone.0072820.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  45. 45.

    Matsushita Y, Yokoyama Y, Yoshida H, Osawa Y, Mizunuma M, Shigeto T, et al. The level of RECQL1 expression is a prognostic factor for epithelial ovarian cancer. J Ovarian Res. 2014;7:107. doi:10.1186/s13048-014-0107-1.

    PubMed Central  Article  PubMed  Google Scholar 

  46. 46.

    Gennery AR, Cant AJ, Jeggo PA. Immunodeficiency associated with DNA repair defects. Clin Exp Immunol. 2000;121(1):1–7.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  47. 47.

    Caddle LB, Hasham MG, Schott WH, Shirley BJ, Mills KD. Homologous recombination is necessary for normal lymphocyte development. Mol Cell Biol. 2008;28(7):2295–303. doi:10.1128/MCB.02139-07.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  48. 48.

    Hasham MG, Donghia NM, Coffey E, Maynard J, Snow KJ, Ames J, et al. Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination. Nat Immunol. 2010;11(9):820–6. doi:10.1038/ni.1909.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  49. 49.

    Sidorova JM, Li N, Folch A, Monnat Jr RJ. The RecQ helicase WRN is required for normal replication fork progression after DNA damage or replication fork arrest. Cell Cycle. 2008;7(6):796–807.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  50. 50.

    Yin L. Chondroitin synthase 1 is a key molecule in myeloma cell-osteoclast interactions. J Biol Chem. 2005;280(16):15666–72.

    Article  CAS  PubMed  Google Scholar 

  51. 51.

    Gu X, Booth CJ, Liu Z, Strout MP. AID-associated DNA repair pathways regulate malignant transformation in a murine model of BCL6-driven diffuse large B cell lymphoma. Blood. 2015. doi:10.1182/blood-2015-02-628164

  52. 52.

    Hathcock KS, Padilla-Nash HM, Camps J, Shin DM, Triner D, Shaffer AL, 3rd et al. ATM deficiency in absence of T cells promotes development of NF-kB-dependent murine B cell lymphomas that resemble human ABC DLBCL. Blood. 2015. doi:10.1182/blood-2015-06-654749

  53. 53.

    Bret C, Klein B, Cartron G, Schved JF, Constantinou A, Pasero P et al. DNA repair in diffuse large B-cell lymphoma: a molecular portrait. Br J Haematol. 2014. doi:10.1111/bjh.13206

  54. 54.

    Bret C, Klein B, Moreaux J. Gene expression-based risk score in diffuse large B-cell lymphoma. Oncotarget. 2012;3(12):1700–10.

    PubMed Central  Article  PubMed  Google Scholar 

  55. 55.

    Kwok M, Davies N, Agathanggelou A, Smith E, Petermann E, Yates E, et al. Synthetic lethality in chronic lymphocytic leukaemia with DNA damage response defects by targeting the ATR pathway. Lancet. 2015;385 Suppl 1:S58. doi:10.1016/S0140-6736(15)60373-7.

    Article  PubMed  Google Scholar 

  56. 56.

    Bret C, Klein B, Moreaux J. Nucleotide excision DNA repair pathway as a therapeutic target in patients with high-risk diffuse large B cell lymphoma. Cell Cycle. 2013;12(12):1811–2. doi:10.4161/cc.25115.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  57. 57.

    Cottini F, Hideshima T, Suzuki R, Tai YT, Bianchini G, Richardson PG, et al. Synthetic Lethal Approaches Exploiting DNA Damage in Aggressive Myeloma. Cancer Discov. 2015;5(9):972–87. doi:10.1158/2159-8290.CD-14-0943.

    Article  CAS  PubMed  Google Scholar 

  58. 58.

    Hose D, Reme T, Hielscher T, Moreaux J, Messner T, Seckinger A, et al. Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma. Haematologica. 2011;96(1):87–95. doi:10.3324/haematol.2010.030296.

    PubMed Central  Article  PubMed  Google Scholar 

  59. 59.

    Kassambara A, Gourzones-Dmitriev C, Sahota S, Reme T, Moreaux J, Goldschmidt H, et al. A DNA repair pathway score predicts survival in human multiple myeloma: the potential for therapeutic strategy. Oncotarget. 2014;5(9):2487–98.

    PubMed Central  Article  PubMed  Google Scholar 

  60. 60.

    Walker BA, Leone PE, Chiecchio L, Dickens NJ, Jenner MW, Boyd KD, et al. A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value. Blood. 2010;116(15):e56–65. doi:10.1182/blood-2010-04-279596.

    Article  CAS  PubMed  Google Scholar 

  61. 61.

    Aggarwal M, Banerjee T, Sommers JA, Brosh Jr RM. Targeting an Achilles' heel of cancer with a WRN helicase inhibitor. Cell Cycle. 2013;12(20):3329–35. doi:10.4161/cc.26320.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  62. 62.

    Nguyen GH, Dexheimer TS, Rosenthal AS, Chu WK, Singh DK, Mosedale G, et al. A small molecule inhibitor of the BLM helicase modulates chromosome stability in human cells. Chem Biol. 2013;20(1):55–62. doi:10.1016/j.chembiol.2012.10.016.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  63. 63.

    Kassambara A, Reme T, Jourdan M, Fest T, Hose D, Tarte K, et al. GenomicScape: an easy-to-use web tool for gene expression data analysis. Application to investigate the molecular events in the differentiation of B cells into plasma cells. PLoS Comput Biol. 2015;11(1):e1004077. doi:10.1371/journal.pcbi.1004077.

    PubMed Central  Article  PubMed  Google Scholar 

  64. 64.

    Kassambara A, Klein B, Moreaux J. MMSET is overexpressed in cancers: link with tumor aggressiveness. Biochem Biophys Res Commun. 2009;379(4):840–5. doi:10.1016/j.bbrc.2008.12.093.

    Article  CAS  PubMed  Google Scholar 

  65. 65.

    Kassambara A, Hose D, Moreaux J, Walker BA, Protopopov A, Reme T, et al. Genes with a spike expression are clustered in chromosome (sub)bands and spike (sub)bands have a powerful prognostic value in patients with multiple myeloma. Haematologica. 2012;97(4):622–30. doi:10.3324/haematol.2011.046821.

    PubMed Central  Article  PubMed  Google Scholar 

  66. 66.

    Moreaux J, Kassambara A, Hose D, Klein B. STEAP1 is overexpressed in cancers: A promising therapeutic target. Biochem Biophys Res Commun. 2012;429(3-4):148–55. doi:10.1016/j.bbrc.2012.10.123.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from French INCA (Institut National du Cancer) Institute (2012-109/087437), Languedoc Roussillon CRLR (R14026FF), Fondation de France (201400047510), ITMO Cancer (MM&TT) and AXLR SATT (30041633). EV is supported by a grant from Guillaume Espoir association (Saint- Genis-Laval, France).

Author information

Affiliations

  1. Laboratory for Monitoring Innovative Therapies, Department of Biological Hematology, Hôpital Saint-Eloi - CHRU de Montpellier, 80, av. Augustin Fliche, 34295, Montpellier, Cedex 5, France

    Alboukadel Kassambara, Bernard Klein & Jerome Moreaux

  2. Institute of Human Genetics, CNRS-UPR1142, Montpellier, F-34396, France

    Elena Viziteu, Alboukadel Kassambara, Philippe Pasero, Bernard Klein & Jerome Moreaux

  3. University of Montpellier 1, UFR de Médecine, Montpellier, France

    Bernard Klein & Jerome Moreaux

Authors
  1. Elena Viziteu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alboukadel Kassambara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philippe Pasero
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bernard Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jerome Moreaux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jerome Moreaux.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

EV performed research, bioinformatics, and participated in the writing of the paper. AK participated in the bioinformatics. PP participated in the writing of the paper. BK participated in the research and in the writing of the paper. JM supervised the research, bioinformatics, and the writing of the paper. All authors read and approved the final manuscript.

Additional file

Additional file 1: Figure S1.

RECQ helicase gene and protein expression in myeloid and lymphoid cell lines using using the human protein atlas database. RECQ1, RECQ4 and RECQ5 expression could be confirmed at protein level in myeloid and lymphoid cancer cell lines. (PDF 599 kb)

Rights and permissions

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.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Viziteu, E., Kassambara, A., Pasero, P. et al. RECQ helicases are deregulated in hematological malignancies in association with a prognostic value. Biomark Res 4, 3 (2016). https://doi.org/10.1186/s40364-016-0057-4

Download citation

Keywords

  • RECQ helicases
  • Gene expression
  • Hematological malignancies
  • Prognostic markers
  • Therapeutic targets

Biomarker Research

ISSN: 2050-7771

Contact us

\