Charalampopoulou Stella, Chapiro Elise, Nadeu Ferran, Zenz Thorsten, Beà Sílvia, Martínez-Farran Ares, Aymerich Marta, Rozman Maria, Roos-Weil Damien, Bernard Olivier, Susin Santos A, Parker Helen, Walewska Renata, Oakes Christopher C, Strefford Jonathan C, Campo Elías, Matutes Estela, Duran-Ferrer Martí, Nguyen-Khac Florence, Martín-Subero José I
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Service d'Hématologie Biologique, Hôpital Pitié-Salpêtrière, Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Paris, France.
Blood Adv. 2024 Dec 24;8(24):6297-6307. doi: 10.1182/bloodadvances.2024013327.
The recognition of B-cell prolymphocytic leukemia (B-PLL) as a separate entity is controversial based on the current classification systems. Here, we analyzed the DNA methylome of a cohort of 20 B-PLL cases diagnosed according to the guidelines of the International Consensus Classification/Fourth revised edition of the World Health Organization Classification, and compared them with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), splenic marginal zone lymphoma (SMZL), and normal B-cell subpopulations. Unsupervised principal component analyses suggest that B-PLL is epigenetically distinct from CLL, MCL, and SMZL, which is further supported by robust differential methylation signatures in B-PLL. We also observe that B-PLL can be segregated into 2 epitypes with differential clinicobiological characteristics. B-PLL epitype 1 carries lower immunoglobulin heavy variable somatic hypermutation and a less profound germinal center-related DNA methylation imprint than epitype 2. Furthermore, epitype 1 is significantly enriched in mutations affecting MYC and SF3B1, and displays DNA hypomethylation and gene upregulation signatures enriched in MYC targets. Despite the low sample size, patients from epitype 1 have an inferior overall survival than those of epitype 2. This study provides relevant insights into the biology and differential diagnosis of B-PLL, and potentially identifies 2 subgroups with distinct biological and clinical features.
根据当前的分类系统，将B细胞原淋巴细胞白血病（B-PLL）识别为一个独立的实体存在争议。在此，我们分析了一组根据国际共识分类/世界卫生组织分类第四修订版指南诊断的20例B-PLL病例的DNA甲基化组，并将它们与慢性淋巴细胞白血病（CLL）、套细胞淋巴瘤（MCL）、脾边缘区淋巴瘤（SMZL）以及正常B细胞亚群进行了比较。无监督主成分分析表明，B-PLL在表观遗传学上与CLL、MCL和SMZL不同，这在B-PLL中强大的差异甲基化特征中得到了进一步支持。我们还观察到，B-PLL可以分为具有不同临床生物学特征的2个表观型。B-PLL表观型1的免疫球蛋白重链可变区体细胞超突变较低，与生发中心相关的DNA甲基化印记比表观型2浅。此外，表观型1在影响MYC和SF3B1的突变中显著富集，并显示出在MYC靶点中富集的DNA低甲基化和基因上调特征。尽管样本量较小，但表观型1的患者总生存期比表观型2的患者差。这项研究为B-PLL的生物学和鉴别诊断提供了相关见解，并可能识别出具有不同生物学和临床特征的2个亚组。
