Landscape of immunoglobulin heavy chain gene repertoire and its clinical relevance to LPL/WM

Abstract

Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) is a heterogeneous disease in which the role of immunoglobulin heavy chain genes (IGH) remains unknown. To determine the clinical relevance of the IGH repertoire in LPL/WM patients, we performed immunoglobulin gene rearrangement and complementarity determining region 3 (CDR3) analysis. The IGH variable gene repertoire was remarkably biased in LPL/WM. IGHV3-23, IGHV4-34, IGHV3-30, IGHV3-7, and IGHV3-74 accounted for half of the cohorts' 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<0.001) and an abnormal karyotype (P=0.004). The IGHV hypermutation rate in patients with the MYD88 L265P mutation was significantly higher than that of wild-type patients (P=0.050). IGHV3-23 and IGHV3-74 segments were more frequently detected in mutated MYD88 LPL/WM patients (P=0.050), while IGHV3-7 presented more frequently in MYD88 wild-type patients (P=0.042). 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.

Single-cell profiles reveal tumor cell heterogeneity and immunosuppressive microenvironment in Waldenström macroglobulinemia

“…Progression from MYD88 L265P to malignant lymphoma may be fundamentally driven by the emergence of cooperating genetic alterations and the tumor microenvironment [35]. Our recent report indicates that MYD88 L265P is a recurrent mutation in WM patients in China [36], and all patients included in present study harbored MYD88 L265P mutation. Here, scRNA-seq analysis provides a comprehensive single-cell transcriptomic atlas to characterize cellular ecosystems in WM BM.…”

“…The clinical onset of WM is often characterized by the development of anemia and progressive tumor infiltration, highlighting the importance of tumor infiltration in disease development and progression [4]. Genetic analyses have demonstrated recurrent mutations of the myeloid differentiation primary response-88 (MYD88) gene in more than 87.5% of WM patients in our lymphoma center of Blood Disease Hospital, CAMS [5]. However, MYD88 mutations are neither specific nor sufficient for the pathogenesis of WM and can be detected in IgM monoclonal gammopathy of undetermined significance (MGUS) as well as in other B cell lymphomas [5][6][7].…”

“…Genetic analyses have demonstrated recurrent mutations of the myeloid differentiation primary response-88 (MYD88) gene in more than 87.5% of WM patients in our lymphoma center of Blood Disease Hospital, CAMS [5]. However, MYD88 mutations are neither specific nor sufficient for the pathogenesis of WM and can be detected in IgM monoclonal gammopathy of undetermined significance (MGUS) as well as in other B cell lymphomas [5][6][7]. The mechanisms underlying the pathogenesis as well as the cellular origin of WM remain poorly understood [8].…”

Secondary light chain amyloidosis with Waldenström’s macroglobulinemia and intermodal marginal zone lymphoma: A case report

“…Due to similar laboratory results, differential diagnosis is particularly difficult between WM and INMZL, which can secrete IgM. Although MYD88 mutations are present in most patients with WM, they are not specific; MYD88 mutations are seen in 5% to 10% of patients with lymph node MZL[ 5 ]. The lymph node biopsy was dominated by small lymphocytes, with abundant cells, small size, visible germinal centre-like structures, and CD20+[ 6 ].…”

Anemia ‐ an initial manifestation of Bing‐Neel syndrome: A case report

“…[ 5 ] However, the presence of particular clinical findings can help to direct additional evaluation. [ 6 ] In addition, we should further investigate any signs, symptoms, or other causes of laboratory or imaging findings to determine their likelihood of being associated with WM. [ 7 ] A careful and systematic history taking can provide information not only on the presence of constitutional symptoms such as fevers, night sweats, or unintentional weight loss, but also for potential alternative causes for these symptoms.…”