Gkoliou Glykeria, Agathangelidis Andreas, Karakatsoulis Georgos, Lalayanni Chrysavgi, Papalexandri Apostolia, Medina Alejandro, Genuardi Elisa, Chlichlia Katerina, Hatjiharissi Evdoxia, Papaioannou Maria, Terpos Evangelos, Jimenez Cristina, Sakellari Ioanna, Ferrero Simone, Ladetto Marco, Sanz Ramon Garcia, Belessi Chrysoula, Stamatopoulos Kostas
Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece.
Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece.
Front Oncol. 2023 Feb 8;13:1123029. doi: 10.3389/fonc.2023.1123029. eCollection 2023.
The analysis of the immunogenetic background of multiple myeloma (MM) has proven key to understanding disease ontogeny. However, limited information is available regarding the immunoglobulin (IG) gene repertoire in MM cases carrying different heavy chain isotypes. Here, we studied the IG gene repertoire in a series of 523 MM patients, of whom 165 and 358 belonged to the IgA and IgG MM groups, respectively. IGHV3 subgroup genes predominated in both groups. However, at the individual gene level, significant (p<0.05) differences were identified regarding IGHV3-21 (frequent in IgG MM) and IGHV5-51 (frequent in IgA MM). Moreover, biased pairings were identified between certain IGHV genes and IGHD genes in IgA versus IgG MM. Turning to the imprints of somatic hypermutation (SHM), the bulk of rearrangements (IgA: 90.9%, IgG: 87.4%) were heavily mutated [exhibiting an IGHV germline identity (GI) <95%]. SHM topology analysis disclosed distinct patterns in IgA MM versus IgG MM cases expressing B cell receptor IG encoded by the same IGHV gene: the most pronounced examples concerned the IGHV3-23, IGHV3-30 and IGHV3-9 genes. Furthermore, differential SHM targeting was also identified between IgA MM versus IgG MM, particularly in cases utilizing certain IGHV genes, alluding to functional selection. Altogether, our detailed immunogenetic evaluation in the largest to-date series of IgA and IgG MM patients reveals certain distinct features in the IGH gene repertoires and SHM. These findings suggest distinct immune trajectories for IgA versus IgG MM, further underlining the role of external drive in the natural history of MM.
多发性骨髓瘤（MM）免疫遗传背景的分析已被证明是理解疾病发生发展的关键。然而，关于携带不同重链同种型的MM病例中免疫球蛋白（IG）基因库的信息有限。在此，我们研究了523例MM患者的IG基因库，其中165例和358例分别属于IgA和IgG MM组。IGHV3亚组基因在两组中均占主导。然而，在个体基因水平上，发现IGHV3 - 21（在IgG MM中常见）和IGHV5 - 51（在IgA MM中常见）存在显著（p<0.05）差异。此外，在IgA与IgG MM中，某些IGHV基因和IGHD基因之间存在偏向性配对。在体细胞超突变（SHM）印记方面，大部分重排（IgA：90.9%，IgG：87.4%）发生了高度突变[IGHV种系同一性（GI）<95%]。SHM拓扑分析揭示了在表达由相同IGHV基因编码的B细胞受体IG的IgA MM与IgG MM病例中存在不同模式：最显著的例子涉及IGHV3 - 23、IGHV3 - 30和IGHV3 - 9基因。此外，在IgA MM与IgG MM之间也发现了不同的SHM靶向，特别是在利用某些IGHV基因的病例中，这暗示了功能选择。总之，我们在迄今为止最大规模的IgA和IgG MM患者系列中进行的详细免疫遗传评估揭示了IGH基因库和SHM中的某些独特特征。这些发现表明IgA与IgG MM存在不同的免疫轨迹，进一步强调了外部驱动在MM自然病程中的作用。
