淋巴浆细胞淋巴瘤/华氏巨球蛋白血症 (LPL/WM) 患者偶尔会发展为弥漫性大 B 细胞淋巴瘤 (DLBCL)。这主要是由 LPL/WM 转化引起的，尽管也可能出现克隆无关的 DLBCL。 LPL/WM 的特点是激活 MYD88L265P (>95%) 和 CXCR4 突变 (~30%)，但转化的遗传驱动因素仍有待确定。在此，在 13 名发展为 DLBCL 的 LPL/WM 患者中，研究了 LPL 和 DLBCL 的克隆关系以及导致转化的突变。在 2 名 LPL/WM 患者 (15%) 中，免疫球蛋白基因重排的高通量测序显示 LPL 组织活检中存在 >1 个克隆 B 细胞群。在大多数 LPL/WM 患者中，DLBCL 表现与 LPL 中的显性克隆有克隆相关性，这提供了转化的证据。然而，在 3 名患者 (23%) 中，DLBCL 与 LPL 中的主要恶性 B 细胞克隆无关，其中 2 名患者从头发展为 DLBCL。在该研究队列中，分析的 11 名患者中有 8 名 (73%) 出现 LPL 突变，而 6 例 (55%) 则观察到 CXCR4 突变。 3 名患者 (27%) 的 MYD88WT LPL 活检具有 CD79B 和 TNFAIP3 突变的特征。转化后，DLBCL 获得了针对 BTG1、BTG2、CD79B、CARD11、TP53 和 PIM1 的新突变。我们共同证明了发展为 DLBCL 的 LPL/WM 患者中可变的克隆 B 细胞动力学，以及大约四分之一的 LPL/WM 患者中发生克隆无关的 DLBCL。此外，我们还确定了 DLBCL 转化时常见的突变基因，这些基因与 LPL 中已存在的保留突变共同表征了 LPL/WM 患者中 DLBCL 发生的突变情况。版权所有 © 2023 作者。由 Wolters Kluwer Health, Inc. 代表欧洲血液学协会出版。

Patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) occasionally develop diffuse large B-cell lymphoma (DLBCL). This mostly results from LPL/WM transformation, although clonally unrelated DLBCL can also arise. LPL/WM is characterized by activating MYD88L265P (>95%) and CXCR4 mutations (~30%), but the genetic drivers of transformation remain to be identified. Here, in thirteen LPL/WM patients who developed DLBCL, the clonal relationship of LPL and DLBCL together with mutations contributing to transformation were investigated. In 2 LPL/WM patients (15%), high-throughput sequencing of immunoglobulin gene rearrangements showed evidence of >1 clonal B-cell population in LPL tissue biopsies. In the majority of LPL/WM patients, DLBCL presentations were clonally related to the dominant clone in LPL, providing evidence of transformation. However, in 3 patients (23%), DLBCL was clonally unrelated to the major malignant B-cell clone in LPL, of which 2 patients developed de novo DLBCL. In this study cohort, LPL displayed MYD88L265P mutation in 8 out of eleven patients analyzed (73%), while CXCR4 mutations were observed in 6 cases (55%). MYD88WT LPL biopsies present in 3 patients (27%) were characterized by CD79B and TNFAIP3 mutations. Upon transformation, DLBCL acquired novel mutations targeting BTG1, BTG2, CD79B, CARD11, TP53, and PIM1. Together, we demonstrate variable clonal B-cell dynamics in LPL/WM patients developing DLBCL, and the occurrence of clonally unrelated DLBCL in about one-quarter of LPL/WM patients. Moreover, we identified commonly mutated genes upon DLBCL transformation, which together with preserved mutations already present in LPL characterize the mutational landscape of DLBCL occurrences in LPL/WM patients.Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.