Araujo-Ayala Ferran, Béguelin Wendy
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Weill Cornell Medicine, New York, New York, United States.
Blood. 2025 Mar 16. doi: 10.1182/blood.2024026020.
Follicular lymphoma (FL) represents a heterogeneous group of B-cell neoplasms with distinct genetic, epigenetic, microenvironmental, and clinical features. It is the most prevalent indolent non-Hodgkin lymphoma, characterized by a relapsing course and risk of transformation to aggressive diffuse large B-cell lymphoma. Recent advances in high-throughput sequencing, spatial transcriptomics, and imaging technologies uncovered genetic, epigenetic, and immunogenetic features underpinning FL, offering insights into its biology and potential therapeutic vulnerabilities. While FL is primarily driven by the hallmark t(14;18) translocation involving BCL2, its pathogenesis requires additional oncogenic mutations, particularly in genes regulating chromatin and histone modifications. These early genetic and epigenetic alterations promote the persistence and evolution of cancer precursor cells, setting the stage for lymphomagenesis. The tumor microenvironment is also crucial in FL progression and patient prognosis, with T-cells, stromal cells, and macrophages playing pivotal roles in facilitating tumor immune escape. Targeted therapies, including BCL2 inhibitors, epigenetic modulators, and immunotherapies, have emerged from this deeper understanding of FL biology. Achieving a cure for FL will require targeted therapies that selectively eliminate cancer precursor cells with minimal impact on normal cells, thus preventing relapse and avoiding harmful side effects. Eradicating minimal-residual-disease should be a primary objective rather than waiting for clinical relapse. Future research must prioritize the development of accurate experimental models, the elucidation of FL precursors, and a deeper understanding of its heterogeneity, dependencies, progression, and mechanisms driving transformation. Implementing targeted therapies at FL early stages, instead of the current "watch and wait" approach, will be essential to improve patient outcomes.
滤泡性淋巴瘤（FL）是一组异质性的B细胞肿瘤，具有独特的遗传、表观遗传、微环境和临床特征。它是最常见的惰性非霍奇金淋巴瘤，其特点是病程易复发且有转化为侵袭性弥漫性大B细胞淋巴瘤的风险。高通量测序、空间转录组学和成像技术的最新进展揭示了FL的遗传、表观遗传和免疫遗传特征，为其生物学特性和潜在的治疗弱点提供了深入了解。虽然FL主要由涉及BCL2的标志性t(14;18)易位驱动，但其发病机制还需要其他致癌突变，特别是在调节染色质和组蛋白修饰的基因中。这些早期的遗传和表观遗传改变促进了癌症前体细胞的持续存在和进化，为淋巴瘤的发生奠定了基础。肿瘤微环境在FL的进展和患者预后中也至关重要，T细胞、基质细胞和巨噬细胞在促进肿瘤免疫逃逸中起关键作用。基于对FL生物学的更深入理解，包括BCL2抑制剂、表观遗传调节剂和免疫疗法在内的靶向治疗已经出现。要治愈FL，需要有针对性的治疗方法，以选择性地消除癌症前体细胞，同时对正常细胞的影响最小，从而防止复发并避免有害的副作用。根除微小残留病应该是主要目标，而不是等待临床复发。未来的研究必须优先开发准确的实验模型，阐明FL的前体，并更深入地了解其异质性、依赖性、进展以及驱动转化的机制。在FL早期实施靶向治疗，而不是目前的“观察等待”方法，对于改善患者预后至关重要。
