Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
Department of Internal Medicine, Haematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Semin Oncol. 2018 Oct;45(5-6):291-302. doi: 10.1053/j.seminoncol.2018.07.005. Epub 2018 Oct 23.
The molecular pathogenesis of follicular lymphoma (FL) was partially revealed 3 decades ago, with the discovery of the translocation that brings BCL2 under the influence of immunoglobulin heavy chain enhancers in a vast majority of cases. Despite the importance of this seminal observation, it has become increasingly clear that additional genetic alterations need to occur to trigger neoplastic transformation and disease progression. The evolution of FL involves developmental arrest and disruption of the normal function of one or more of epigenetic regulators including KMT2D/MLL2, EZH2, CBP/CREBBP, p300/EP300, and HIST1H1 in >95% of cases. B-cells "arrested" in germinal centers acquire dozens of additional genetic aberrations that influence key pathways controlling their physiological development including B Cell Receptor (BCR) signaling, PI3K/AKT, TLR, mTOR, NF-κB, JAK/STAT, MAPK, CD40/CD40L, chemokine, and interleukin signaling. Additionally, most cases of FL do not result from linear accumulation of genomic aberrations, but rather evolve from a common progenitor cell population by diverse evolution, creating multiple FL subclones in one patient. Moreover, one of the subclones might acquire a combination of aberrations involving genes controlling cell survival and proliferation including MDM2, CDKN2A/B, BCL6, MYC, TP53, β2M, FOXO1, MYD88, STAT3, or miR-17-92, and this can lead to the transformation of an initially indolent FL to an aggressive lymphoma (2%-3% risk per year). The complexity of the disease is also underscored by the importance of its interactions with the microenvironment that can substantially influence disease development and prognosis. Interpreting individual aberrations in relation to their impact on normal processes, their frequency, position in the disease evolution, and the consequences of their (co)occurrence, are the basis for understanding FL pathogenesis. This is necessary for the identification of patients with risk of early progression or transformation, for the development of novel targeted therapies, and for personalized treatment approaches. In this review, we summarize recent knowledge of molecular pathways and microenvironmental components involved in FL biology, and discuss them in the context of physiological B-cell development, FL evolution, and targeted therapies.
滤泡性淋巴瘤（FL）的分子发病机制在 30 年前部分被揭示，当时发现了绝大多数病例中 BCL2 受免疫球蛋白重链增强子影响的易位。尽管这一开创性观察具有重要意义，但越来越明显的是，需要发生额外的遗传改变才能引发肿瘤转化和疾病进展。FL 的演变涉及发育停滞和正常功能的破坏，包括表观遗传调节剂中的 KMT2D/MLL2、EZH2、CBP/CREBBP、p300/EP300 和 HIST1H1，在>95%的病例中均有发生。在生发中心“停滞”的 B 细胞获得数十种额外的遗传异常，这些异常影响控制其生理发育的关键途径，包括 B 细胞受体（BCR）信号、PI3K/AKT、TLR、mTOR、NF-κB、JAK/STAT、MAPK、CD40/CD40L、趋化因子和白细胞介素信号。此外，大多数 FL 病例并非源于基因组异常的线性积累，而是通过不同的进化从一个共同的祖细胞群体演变而来，在一个患者中产生多个 FL 亚克隆。此外，一个亚克隆可能获得涉及控制细胞存活和增殖的基因的异常组合，包括 MDM2、CDKN2A/B、BCL6、MYC、TP53、β2M、FOXO1、MYD88、STAT3 或 miR-17-92，这可能导致最初惰性的 FL 转化为侵袭性淋巴瘤（每年 2%-3%的风险）。疾病的复杂性还体现在其与微环境的相互作用的重要性上，这些相互作用可以极大地影响疾病的发展和预后。解释个体异常与其对正常过程的影响、其频率、在疾病演变中的位置以及它们（共同）发生的后果，是理解 FL 发病机制的基础。这对于识别具有早期进展或转化风险的患者、开发新型靶向治疗方法以及实施个性化治疗方法是必要的。在这篇综述中，我们总结了 FL 生物学中涉及的分子途径和微环境成分的最新知识，并在生理 B 细胞发育、FL 演变和靶向治疗的背景下讨论了这些知识。
