[雙語翻譯]--外文翻譯--惡性瘧原蟲感染易致染色體組不穩(wěn)定和活化誘導(dǎo)胞苷脫氨酶依賴的b細(xì)胞淋巴瘤（英文）

1、Plasmodium Infection Promotes Genomic Instability and AID Dependent B Cell LymphomaDavide F. Robbiani1,*, Stephanie Deroubaix1, Niklas Feldhahn1,4, Thiago Y. Oliveira1, Elsa Callen2, Qiao Wang1, Mila Jankovic1, Israel T.

2、 Silva1,5, Philipp C. Rommel1, David Bosque1, Tom Eisenreich1, André Nussenzweig2, and Michel C. Nussenzweig1,3,*1Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA2Laborat

3、ory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA3Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USASummaryChronic in

4、fection with Plasmodium falciparum was epidemiologically associated with endemic Burkitt’s lymphoma, a mature B cell cancer characterized by chromosome translocation between the c-myc oncogene and Igh, over 50 years ago.

5、 Whether infection promotes B cell lymphoma, and if so by what mechanism remains unknown. To investigate the relationship between parasitic disease and lymphomagenesis we used Plasmodium chabaudi (Pc) to produce chronic

6、malaria infection in mice. Pc induces prolonged expansion of germinal centers (GCs), unique compartments where B cells undergo rapid clonal expansion and express activation-induced cytidine deaminase (AID), a DNA mutator

7、. GC B cells elicited during Pc infection suffer widespread DNA damage leading to chromosome translocations. Although infection does not change the overall rate, it modifies lymphomagenesis to favor mature B cell lymphom

8、as that are AID dependent and show chromosome translocations. Thus, malaria infection favors mature B cell cancers by eliciting protracted AID expression in GC B cells.IntroductionMany pathogens have been implicated as e

9、tiologic agents in the development of human cancer. For example, individuals infected with Epstein Barr Virus (EBV), Hepatitis C Virus, Human Immunodeficiency Virus, Helicobacter pylori, or Plasmodium falciparum are all

10、at higher than average risk of developing B cell lymphoma (de Martel et al., 2012; Epeldegui et al., 2010; Kutok and Wang, 2006; Marcucci and Mele, 2011; Molyneux et al., 2012; Zucca et al., 2000; Zur Hausen, 2009). Alth

11、ough viruses can promote neoplasia directly, by *corresponding authors. Contact: drobbiani@rockefeller.edu and nussen@rockefeller.edu. 4present address: Centre for Haematology, Division of Experimental Medicine, Imperial

12、 College London, W12 0NN London, UK 5present address: Laboratory of Bioinformatics and Computational Biology, CIPE/A.C. Camargo Cancer Center, São Paulo 01509-010, BrazilExtended Supplemental Procedures are provide

13、d in the Supplemental Information section available online.The authors declare no competing financial interests.HHS Public Access Author manuscript Cell. Author manuscript; available in PMC 2015 November 13.Published in

14、final edited form as: Cell. 2015 August 13; 162(4): 727–737. doi:10.1016/j.cell.2015.07.019.Author Manuscript Author Manuscript Author Manuscript Author Manuscript1B). We conclude that Plasmodium infection induces a robu

15、st and long-lasting expansion of GC B cells.Ig somatic mutation and class switch recombination are initiated by AID, a cytidine deaminase (Muramatsu et al., 2000; Petersen-Mahrt et al., 2002; Revy et al., 2000). This enz

16、yme is typically restricted to activated B cells in GCs, but malaria infection produces widespread B cell activation (Scholzen and Sauerwein, 2013). To determine if AID is restricted to GCs during Pc infection, we examin

17、ed AIDGFP reporter mice (Crouch et al., 2007). We found that AID expression was restricted to GC B cells and was sustained over a period of at least 10 weeks (Figures 1C and S1B). To confirm AID protein expression, we so

18、rted GC B cells into dark and light zone cells and performed western blot analysis. As expected AID was found mainly in dark zone cells, which contained three times more AID than light zone cells or in vitro activated B

19、cells (Figure 1D). We conclude that AID is primarily expressed in Plasmodium-induced GC B cells.Widespread chromosome translocations in malaria germinal centersAID and replication associated stress can independently prod

20、uce DNA breaks and translocations in cultured B cells (Barlow et al., 2013; Hakim et al., 2012; Klein et al., 2011). To map the DNA damage caused by Plasmodium infection in vivo, we adapted a previously described next-ge

21、neration translocation capture and sequencing method (TC-Seq; (Klein et al., 2011)). Mice with an I-SceI recognition site at c-myc (MycI) were bred to a ROSAerISCEI transgene (encoding for I-SceI fused to the estrogen re

22、ceptor ligand binding domain, er) and to either AID deficient or AID overexpressing mice (ROSAAIDer, see Experimental Procedures and Figure S2). Compound MycI/IROSAerISCEI/erISCEIAID?/? and MycI/IROSAerISCEI/AIDer mice w

23、ere infected with Plasmodium and treated with Tamoxifen at the peak of the GC response, to induce the nuclear shuttling of erISCEI in the absence or presence of AID, and translocations between the DNA break at MycI on ch

24、romosome 15 and lesions in the rest of the genome were captured by TC-Seq (Figure 2A). We recovered 191150 and 65905 unique rearrangements to the I-SceI site in MycI from 105 million AID deficient or proficient malaria G

25、C B cells, respectively (see Experimental Procedures). In agreement with previous in vitro experiments (Klein et al., 2011), malaria rearrangements were preferentially intrachromosomal (95.2% vs. 94.3% of all rearrangeme

26、nt-associated reads, in the absence or presence of AID respectively; Figure 2B), and enriched at the I-SceI site (Figure 2C). Irrespective of AID expression, rearrangements were significantly increased in genic regions o

27、ver the predicted random distribution of 40.1% (Figure 2D), and favored more actively transcribed genes (Figure 2E). Consistent with this, the asymmetric distribution of events in the direction of transcription at the I-

28、SceI site was less pronounced in malaria GCs than in vitro stimulated B cells, which express higher levels of c-myc (Figures 2C and S2E; (Klein et al., 2011; Shaffer et al., 2001; Thomas and Rothstein, 1989)). We conclud

29、e that the overall distribution of chromosome rearrangements induced by Plasmodium in vivo is similar to the one observed in retrovirally-infected cells in vitro.AID-independent damage involves sites of DNA replication-a

30、ssociated fragilityEarly replication fragile sites (ERFS) are a set of genomic regions prone to breakage during DNA replication (Barlow et al., 2013). To assess the contribution of DNA replication to Robbiani et al. Page