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 (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.

Graphical abstract

Figure 1.

Distribution of IGHV gene segments in patients with LPL/WM. (A) IGHV gene usage in patients with LPL/WM. (B) Top 31 IGHV genes expressed in our series are shown along the x-axis. (C) IGHV distribution in LPL/WM and normal B cells. *P < .05, **P < .01, ***P < .001.

Figure 2.

Distribution and associations of IGH gene segments in patients with LPL/WM. (A) Distribution of IGHD gene repertoire in patients with LPL/WM. (B). Distribution of IGHJ gene repertoire in patients with LPL/WM. Circular graphs of the associations between (C) IGHV and IGHD segments and (D) IGHV and IGHJ segments in patients with LPL/WM. The Comprehensive R Archive Network software package (https://mirrors.tuna.tsinghua.edu.cn/CRAN/) was used analyze IGHV segment combinations with IGHD and IGHJ segments.

Figure 3.

Distinct mutation rates and CDR3 lengths of patients with IGHV4-34, IGHV3-23, IGHV3-30, IGHV3-7, and IGHV3-74 genes. (A) IGHV mutation rate in patients with different IGHV segments. (B) Correlation between CDR3 amino acid length and IGHV mutation rate. Linear regression fit for all data is shown by the blue line. (C) Those with the IGHV3-30 gene had longer V_H CDR3 lengths than other subgroups. (D) Distribution of CDR3 lengths in patients with IGHV3-23 and IGHV3-30 segments. *P < .05.

Figure 4.

Links between cytogenetic aberrations and IGH segments. (A) Distribution of major IGHV gene segments in patients with normal or abnormal karyotypes. (B) Distribution of IGHV3-7 gene segments in patients with and without 6q deletion karyotype. *P < .05, **P < .01, ***P < .001.

Figure 5.

Mutations in MYD88 L265P with IGH segments. (A) MYD88 L265P patients had higher SHM rate than wild-type MYD88 patients. (B) Chart showing CDR3 amino acid lengths in patients with either mutated or wild-type MYD88.

Figure 6.

Survival analysis of patients with IGHV4 gene. (A) PFS and (B) OS estimates for patients with LPL/WM according to IGHV4 gene usage.