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The whole genome landscape of Burkitt lymphoma subtypes

ABSTRACT: Burkitt lymphoma (BL) is an aggressive, MYC-driven lymphoma comprising three distinct clinical subtypes, including sporadic BLs that occur worldwide, endemic BLs that occur predominantly in sub-Saharan Africa, and immunodeficiency-associated BLs that occur primarily in the setting of HIV. In this study, we comprehensively delineated the genomic basis of BL through whole genome sequencing of 101 tumors representing all 3 subtypes of BL to identify 72 driver genes. These data were additionally informed by CRISPR screens in BL cell lines to functionally annotate the role of oncogenic drivers. Nearly every driver gene was found to have both coding and non-coding mutations highlighting the importance of whole genome sequencing for identifying driver events. Our data implicate coding and non-coding mutations in IGLL5, BACH2, SIN3A and DNMT1. EBV infection was associated with higher mutation load, with EBV type 1 showing a higher mutational burdens than type 2 EBV. While sporadic and immunodeficiency-associated BLs had similar genetic profiles, endemic BLs manifested more frequent mutations in BCL7A and BCL6, and fewer genetic alterations in DNMT1, SNTB2, CTCF. Silencing mutations in ID3 were a common feature of all three subtypes of BL. In vitro, mass spectrometry-based proteomics demonstrated that the ID3 protein binds primarily to TCF3 and TCF4. In vivo knockout of ID3 potentiated the effects of MYC, leading to rapid tumorigenesis and tumor phenotypes consistent with those observed in the human disease.

PROVIDER: EGAS00001003778 | EGA |

REPOSITORIES: EGA

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Project description:Sporadic Burkitt lymphoma (sBL) can be delineated from diffuse large B-cell lymphoma (DLBCL) by a very homogeneous mRNA expression signature. However, it remained unclear whether all three BL variants – sBL, endemic BL (eBL) and immunodeficiency-associated BL (HIV-BL) – represent a uniform biological entity despite their differences in geographical occurrence, association with immunodeficiency and/or incidence of EBV infection. To address this issue, we generated micro RNA (miRNA) profiles from 18 eBL, 31 sBL and 15 HIV-BL cases. In addition, we analyzed the miRNA expression of 86 DLBCL to determine whether miRNA profiles recapitulate the molecular differences between BL and DLBCL evidenced by mRNA profiling. A signature of 38 miRNAs enriched in MYC regulated and NF-kB pathway associated miRNAs was obtained that differentiated BL from DLBCL. The miRNA profiles of sBL and eBL displayed only 6 differentially expressed miRNAs, whereas HIV and EBV infection had no impact on the miRNA profile of BL. In conclusion, miRNA profiling confirms that BL and DLBCL represent distinct lymphoma categories and demonstrates that the three BL variants are representatives of the same biological entity with only marginal miRNA expression differences between eBL and sBL. Archival tumor specimens of 86 diffuse large B-cell lymphoma (DLBCL) and 64 Burkitt lymphoma (BL) patients were obtained. The DLBCL samples have previously been reviewed by a panel of expert hematopathologists and their clinical data were published as part of the RiCOVER-60 trial. The diagnosis of all BL cases was confirmed by histopathology review according to the criteria of the WHO classification. Based on their geographical origin, 31 BL samples were designated as sporadic BL (sBL) and 18 samples as endemic BL (eBL). Fifteen BL cases were diagnosed as immunodeficiency-associated BL (HIV-BL). Of the 18 eBL 14 cases were EBV+ (87.5%), 2 samples were EBV- (12.5%) and for 2 eBL cases the EBV status was unknown. Of the sBL samples 26 were EBV- (86.7%), 4 cases were EBV+ (13.3%) and for 1 case the EBV status was not evaluable. Among the HIV-BL 5 (33.3%) were EBV+, whereas 10 (66.7%) were EBV-.

Project description:Burkitt lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL (eBL) in developing countries, necessitating new strategies. The normal germinal center B cell is the presumed cell of origin for both BL and diffuse large B cell lymphoma (DLBCL), yet gene expression analysis suggests that these malignancies may utilize different oncogenic pathways. BL is subdivided into a sporadic subtype (sBL) that is diagnosed in developed countries, the EBV-associated eBL subtype, and an HIV-associated subtype (hivBL), but it is unclear whether these subtypes employ similar or divergent oncogenic mechanisms. Here we used high throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways that cooperate with MYC, the defining oncogene of this cancer. In 70% of sBL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival PI(3) kinase pathway in BL, in part by augmenting tonic B cell receptor signaling. In 38% of sBL cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. These findings suggest opportunities to improve therapy for patients with BL. Gene expression was analyzed using Agilent human 4X44K oligo gene expression arrays. Cell lines (Namalwa, BL41, Daudi, Defauw, and THOMAS) were infected with control (empty vector, Cy3) paired with ID3 (Cy5) or control (shControl, Cy3) paired with shTCF3 (Cy5) constructs, and changes in gene expression were monitored over time after induction of the constructs with doxycyclin. In Namalwa (n=8) and THOMAS (n=4) cell lines, a four timepoint series (24, 48, 72, 96 hours) of construct induction was analyzed, for a total of 12 arrays. In BL41 (n=4), Daudi (n=4) and Defauw (n=4) cell lines, a two timepoint series (24 and 48 hours) of construct induction was analyzed, for a total of 12 arrays. In addition, two cell lines (Daudi and THOMAS) were treated with Rapamycin (100 pM) and paired with a DMSO control in a four timepoint series (3, 6, 12 and 24 hours) for a total of 8 arrays.

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The whole genome landscape of Burkitt lymphoma subtypes

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