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Csa Can Induce DNA Double-Strand Breaks: Implications for BMT Regimens Particularly for Individuals with Defective DNA Repair

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Csa Can Induce DNA Double-Strand Breaks: Implications for BMT Regimens Particularly for Individuals with Defective DNA Repair Bone Marrow Transplantation (2008) 41, 983–989 & 2008 Nature Publishing Group All rights reserved 0268-3369/08 $30.00 www.nature.com/bmt ORIGINAL ARTICLE CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair M O’Driscoll and PA Jeggo Genome Damage and Stability Centre, University of Sussex, Brighton, East Sussex, UK Several human disorders mutated in core components of myelo-ablative haematopoietic stem cell transplantation the major DNA double-strand break (DSB) repair path- (NHSCT) using reduced doses of DNA damaging agents way, non-homologous end joining (NHEJ), have been has improved the success rate for transplantation in this described. Cell lines from these patients are characterized context.1,3 Several human disorders have now been by sensitivity to DSB-inducing agents. DNA ligase IV described that are defective in non-homologous end-joining syndrome (LIG4) patients specifically, for unknown (NHEJ), the principal pathway by which human cells repair reasons, respond particularly badly following treatment DNA double-strand breaks (DSBs).4,5 These include DNA for malignancy or BMT. We report the first systematic ligase IV syndrome (LIG4), which is caused by hypo- evaluation of the response of LIG4 syndrome to morphic mutations in DNA ligase IV, Artemis-dependent compounds routinely employed for BMT conditioning. SCID (ART-SCID), caused by mutations in the Artemis We found human pre-B lymphocytes, a key target endonuclease and XRCC4-like factor (XLF)/Cernunnos- population for BMT conditioning, when deficient for dependent SCID, caused by mutations in an XLF/ DNA ligase IV, unexpectedly exhibit significant sensitiv- Cernunnos.5–8 Increased cellular and clinical radiosensitivity ity to CsA the principal prophylaxis for GVHD. is a feature of these conditions due to their failure to repair Furthermore, we found that CsA treatment alone or in ionizing radiation-induced DSBs.6 Because of the central combination with BU and fludarabine resulted in increased role played by NHEJ in V(D)J recombination all of these levels of DSBs specifically in LIG4 syndrome cells disorders initially present with moderate-to-severe com- compared to wild-type or Artemis-deficient cells. Our bined immunodeficiency necessitating clinical intervention study shows that CsA can induce DSBs and that LIG4 often culminating in BMT.9 But, anecdotal (unpublished syndrome patient’s fail to adequately repair this damage. data) and evidence from other studies suggest that LIG4 These DSBs likely arise as a consequence of DNA syndrome patients are particularly poorly following BMT replication in the presence of CsA. This work has (Table 1). Indeed, there is only one detailed report of a implications for BMT and GVHD management in general successful BMT in LIG4 syndrome using NHSCT with a and specifically for LIG4 syndrome. modified conditioning regimen.12 This is in marked contrast Bone Marrow Transplantation (2008) 41, 983–989; to that of ART-SCID where NHSCT has been used doi:10.1038/bmt.2008.18; published online 18 February 2008 successfully in these patients even before the underlying Keywords: CsA; DNA double-strand breaks; LIG4 causative genetic defect was identified.9,13,14 The reason for syndrome the difference in response in these two patient groups that display similar levels of radiosensitivity is unclear. To date, there has not been a report of BMT in XLF/Cernunnos- dependent SCID. The agents commonly employed as part of the con- Introduction ditioning regimen prior to NHSCT include BU (Myerlan), a bi-functional DNA crosslinking agent, fludarabine BMT remains one of the only curative options available to (FluD) (Fludara), a nucleoside analogue and MTX treat progressive anaemia, combined immunodeficiency (Amethopterin), a dihydrofolate reductase inhibitor. All of and/or lymphoma development in the context of DNA these compounds can induce DSBs either directly or damage response-defective disorders, such as Fanconi indirectly. CsA is a widely used prophylaxis for GVHD, anaemia and Nijmegen breakage syndrome.1,2 Non- which represents a significant post transplantation compli- cation.15,16 CsA binds to the cyclophilin class of proteins that can then function as an inhibitor of calcineurin, a Correspondence: Dr M O’Driscoll, Genome Damage and Stability serine-threonine phosphatase (also called PP2B). CsA’s Centre, University of Sussex, Science Park Road, Falmer, Brighton, utility as an immunosuppressive agent is thought to derive East Sussex, BN1 9RQ, UK. E-mail: [email protected] from its ability to prevent nuclear localization of transcrip- Received 1 November 2007; revised 9 January 2008; accepted 10 January tion factor NFAT (nuclear transcription factor in activated 2008; published online 18 February 2008 T cells).17 NFAT is involved in the transcription of various CsA, DSBs and LIG4 syndrome M O’Driscoll and PA Jeggo 984 Table 1 A summary of the outcome of clinical management of BMT on ART-SCID and LIG4 syndrome patients Publication Details ART-SCID O’Marcaigh et al.9 420 Patients successfully transplanted using NHSCT. Treated five patients with CsA only 3 mg/kg per day. For GVHD prophylaxis CsA (3 mg/kg per day) and MTX, initially at 0.5 mg/kg, and the remaining three at 0.33 mg/kg given on days 1, 3, 6 and 11 post transplant LIG4 Buck et al.5 Patient no. 1: BU, EDX, ATG Â 2. The donor was her mother (3/6 identical). Patient developed moderate VOD and eventually an EBV-induced lymphoproliferation and died Patient no. 2: Transplanted at 2.5 months of age receiving 5 days of ATG 5 mg/kg per day from day À14 to À10, then BU 2 mg/kg for 12 h p.o. during 4 days, followed by EDX 50 mg/kg per day from day À5 to day À2. Patient received CD34-positive selected marrow from her mother (3/6 identical). Patient developed severe VOD and died of complications Enders et al.10 Patient no. 1: Transplanted at 4 months of age with Thiotepa 3 Â 5 mg/kg (day À8 to day À6), Fludarabine 4 Â 1.43 mg/kg (day À5 to day À2), ATG 3 Â 20 mg/kg (day À3 to day À1), MUD, 1.87 Â 107 CD 34 per kg. For GVHD prophylaxis CsA from day À1 (3 mg/kg per day) and MTX (10 mg/kg) day +1, 3, 6, 11. Patient developed hemolytic-uremia (anemia and renal failure) 3 months post transplantation assumed to have been as an overresponse to the GVHD treatment Patient no. 2: Died following treatment for EBV-NHL using the NHL-BFM-95 protocol with modifications (1 g instead of 5 g MTX, no ifosphamid) with additional CSF therapy due to blasts in the CSF (MTX and prednisone) van der Burg et al.11 This patient died of possible VOD following treatment with BU (50 mg per day) and cyclophosphamide (500 mg per day) Gruhn et al.12 This patient was diagnosed as LIG4 prior to transplantation hence a NHSCT protocol was applied.6 This patient was transplanted at 10.5 years of age for pancytopenia, Fludara 4 Â 30 mg/m2 per day, EDX 4 Â 10 mg/kg per day, ATG 4 Â 15 mg/m2 per day donor: HLA-identical brother. For GVHD prophylaxis CsA (3 mg/kg per day) from day À1 to d+64, G-CSF from day +5 Abbreviations: EBV-NHL ¼ Epstein–Barr virus-positive non-Hodgkin lymphoma; EDX ¼ endoxan (cyclophosphamide); MUD ¼ matched unrelated donor; NHSCT ¼ non-myeloablative haematopoietic SCT; VOD ¼ veno-occlusive disease. cytokines (for example IL-2) that are required to activate described elsewhere.6,19 The LIG4 syndrome fibroblast was T cells. Inhibition of NFAT nuclear localization by CsA derived from a 9-year-old patient with three homozygous results in profound systemic immunosuppression. alterations in LigIVÀ/À (8C4T(A3V), 26C4T(T9I) and Because of the poor clinical outcome of LIG4 syndrome 833G4A(R278H)).6 The ART-SCID fibroblast (CJ179) patients to BMT we set out to investigate whether the was derived from an immuno-deficient child and fails to failure to repair DSBs induced by the agents used during express a detectable Artemis transcript due to a genomic NHSCT could have a disproportionately adverse impact in deletion.19 the context of LigIVÀ/À deficiency. Using the methylthia- zolyldiphenyl-tetrazolium bromide (MTT) assay, we eval- Drugs uated the sensitivity of human pre-B lymphocytes either All drugs/chemicals were obtained from Sigma-Aldrich UK proficient or engineered by gene targeting to be deficient for Ltd (Poole, UK) and made up fresh prior to each survival. À/À LigIV to the components employed clinically as part of BU was dissolved in DMSO and made up to 5 mM in PBS the conditioning regimen prior to BMT and for GVHD (p2% v/v DMSO). FluD and CsA were dissolved in prophylaxis. These included BU, FluD, MTX and CsA. DMSO. Methyl methane sulphonate (MMS) was diluted in Furthermore, using an indirect immunofluorescence assay complete medium. based on 53BP1 foci formation as a sensitive marker for DSBs, we evaluated the impact of BMT conditioning regimens on DSB formation and repair in NHEJ-defective Antibodies human cells. Anti-53BP1 (BL181) antibody was obtained from Uni- versal Biologicals (Cambridge, UK). Anti-bromodeoxyur- idine (BrdU; Bu20A) antibody was obtained from Autogen BioClear (Wiltshire, UK). Materials and methods Immunofluorescence-based DNA DSB repair assay Cell lines Immunofluorescence-based detection of 53BP1 foci forma- Wild-type (WT; Nalm 6) and LigIVÀ/À (N114-P2) pre-B tion using an anti-53BP1-specific antibody was used as an human lymphocyte cells have been described previously.18 indirect highly sensitive assay for monitoring DNA DSB These cells were cultured in RPMI-1640 supplemented with formation and repair, as previously characterized.19 53BP1 L-glutamine and 15% FCS.
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