State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Blood Adv. 2022 Jul 12;6(13):4049-4059. doi: 10.1182/bloodadvances.2022007279.
Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) is a heterogeneous disease in which the role of immunoglobulin heavy-chain genes (IGHs) remains unknown. To determine the clinical relevance of the IGH repertoire in patients with LPL/WM, we performed immunoglobulin gene rearrangement and complementarity determining region 3 (CDR3) analysis. The IGH variable gene (IGHV) repertoire was remarkably biased in LPL/WM. IGHV3-23, IGHV4-34, IGHV3-30, IGHV3-7, and IGHV3-74 accounted for one-half of the cohort's repertoire. Most cases (97.1%) were found to carry mutated IGHV genes, based on a 98% IGHV germline homology cutoff. IGHV3-30 was associated with long heavy chain CDR3, indicating there was specific antigen selection in LPL/WM. Patients with IGHV3-7 were significantly more likely to harbor the 6q deletion (P < .001) and an abnormal karyotype (P = .004). The IGHV hypermutation rate in patients with the MYD88 L265P mutation was significantly higher than that of wild-type patients (P = .050). IGHV3-23 and IGHV3-74 segments were more frequently detected in patients with MYD88-mutated LPL/WM (P = .050), whereas IGHV3-7 presented more frequently in MYD88 wild-type patients (P = .042). Patients with IGHV4, especially IGHV4-34, had higher levels of lactate dehydrogenase, and IGHV4 was a predictive marker of shorter progression-free survival. These results showed for the first time that the IGHV repertoire has clinical relevance in LPL/WM.
淋巴浆细胞淋巴瘤/华氏巨球蛋白血症（Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia，LPL/WM）是一种异质性疾病，其中免疫球蛋白重链基因（Immunoglobulin heavy-chain genes，IGHs）的作用尚不清楚。为了确定IGH 重排谱在 LPL/WM 患者中的临床意义，我们进行了免疫球蛋白基因重排和互补决定区 3（Complementarity determining region 3，CDR3）分析。LPL/WM 中 IGHV 重排谱明显偏向。IGHV3-23、IGHV4-34、IGHV3-30、IGHV3-7 和 IGHV3-74 占队列的一半。根据 98%IGHV 种系同源性截断值，大多数病例（97.1%）发现携带突变的 IGHV 基因。IGHV3-30 与长重链 CDR3 相关，表明在 LPL/WM 中有特定的抗原选择。IGHV3-7 患者更有可能携带 6q 缺失（P <.001）和异常核型（P =.004）。MYD88 L265P 突变患者的 IGHV 高频突变率明显高于野生型患者（P =.050）。IGHV3-23 和 IGHV3-74 段在 MYD88 突变型 LPL/WM 患者中更频繁检测到（P =.050），而 IGHV3-7 在 MYD88 野生型患者中更频繁出现（P =.042）。IGHV4 尤其是 IGHV4-34 患者的乳酸脱氢酶水平较高，IGHV4 是无进展生存时间较短的预测标志物。这些结果首次表明，IGHV 重排谱在 LPL/WM 中具有临床意义。
