Burkitt Lymphoma Pathogenesis and Therapeutic Targets from Structural and Functional Genomics
By R. Schmitz, R. Young, M. Ceribelli, S. Jhavar, Wenming Xiao, Meili Zhang, George W. Wright, A. Shaffer, D. Hodson, Eric D. Buras and 32 more. Nature, 2012
975 citations recorded by the source corpus.
Burkitt’s 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 in developing countries, necessitating new strategies. The normal germinal centre 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 use different oncogenic pathways. BL is subdivided into a sporadic subtype that is diagnosed in developed countries, the Epstein–Barr-virus-associated endemic subtype, and an HIV-associated subtype, but it is unclear whether these subtypes use similar or divergent oncogenic mechanisms. Here we used high-throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways in BL that cooperate with MYC, the defining oncogene of this cancer. In 70% of sporadic BL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival phosphatidylinositol-3-OH kinase pathway in BL, in part by augmenting tonic B-cell receptor signalling. In 38% of sporadic BL 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.
Subfields: Immunology, Oncology, Pathology and Forensic Medicine
View Paper: https://www.semanticscholar.org/paper/1e1948b2e11532a1a693738850baa559fb2c0c7a
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Citations in the corpus
- Revisiting Global Gene Expression Analysis (2012, neutral): “What are the implications for classifying cell states in disease? Significant effort is being devoted to expression profiling cancer cells and these studies use standard normalization methods (Alizadeh et al., 2000; Beer et al., 2002; Berger et al., 2010; Bhattacharjee et al., 2001; Bittner et al., ”
- MYC, Metabolism, and Cancer. (2015, background): “Indeed, human Burkitt lymphoma loses TP53 in up to 40% of cases (44, 45).”
- A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications (2020, background): “CCND3 mutations likely foster vigorous proliferation in BN2, as in Burkitt’s lymphoma (BL) (Schmitz et al., 2012).”
- A compendium of mutational cancer driver genes (2020, neutral): “Nature reviews | CanCer a PTPN11 (multiple myeloma) b NFE2L2 (lung squamous) RB1 (bladder adenocarcinoma) e EGFR (glioblastoma) f EGFR (lung adenocarcinoma) M ut at ed s am pl es in m ul ti pl e m ye lo m a SH2 0 4 8 12 E76 SH2 Excess rate Missense Nonsense Splice 0.0 0.5 1.0 N = 23 N = 0 N = 0 M ut”