Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics

摘要

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 pathways2. 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 MYQ 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 cydin D3 isoforms that drive cell cycle progression. These findings suggest opportunities to improve therapy for patients with BL.%虽然高强度化疗能治愈Burkitt's淋巴瘤，但与治疗相关的毒性意味着，这种治疗不适合比较脆弱的患者，如老年人或这种病已成为一种地方病的发展中国家的患者。这项研究在很高比例的Burkitt's淋巴瘤零星病例中识别出转录因子TCF3或其负调控因子ID3的突变，并且提出几个新的药物治疗目标，其中包括PI(3)激酶及其下游通道、B-细胞受体信号作用和周期蛋白D3／CDK6。