All authors: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute; and Harvard Medical School, Boston, MA.
J Clin Oncol. 2017 Mar 20;35(9):994-1001. doi: 10.1200/JCO.2016.71.0814. Epub 2017 Feb 13.
Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM). Commonly recurring mutations include MYD88 (95% to 97%), CXCR4 (30% to 40%), ARID1A (17%), and CD79B (8% to 15%). Diagnostic discrimination of WM from overlapping B-cell malignancies is aided by MYD88 mutation status. Transcription is affected by MYD88 and CXCR4 mutations and includes overexpression of genes involved in VDJ recombination, CXCR4 pathway signaling, and BCL2 family members. Among patients with MYD88 mutations, those with CXCR4 mutations show transcriptional silencing of tumor suppressors associated with acquisition of mutated MYD88. Deletions involving chromosome 6q are common and include genes that modulate nuclear factor-κB, BCL2, BTK, apoptosis, differentiation, and ARID1B. Non-chromosome 6q genes are also frequently deleted and include LYN, a regulator of B-cell receptor signaling. MYD88 and CXCR4 mutations affect WM disease presentation and treatment outcome. Patients with wild-type MYD88 show lower bone marrow disease burden and serum immunoglobulin M levels but show an increased risk of death. Patients with CXCR4 mutations have higher bone marrow disease burden, and those with nonsense CXCR4 mutations have higher serum immunoglobulin M levels and incidence of symptomatic hyperviscosity. Mutated MYD88 triggers BTK, IRAK1/IRAK4, and HCK growth and survival signaling, whereas CXCR4 mutations promote AKT and extracellular regulated kinase-1/2 signaling and drug resistance in the presence of its ligand CXCL12. Ibrutinib is active in patients with WM and is affected by MYD88 and CXCR4 mutation status. Patients with mutated MYD88 and wild-type CXCR4 mutation status exhibit best responses to ibrutinib. Lower response rates and delayed responses to ibrutinib are associated with mutated CXCR4 in patients with WM. MYD88 and CXCR4 mutation status may be helpful in treatment selection for symptomatic patients. Novel therapeutic approaches under investigation include therapeutics targeting MYD88, CXCR4, and BCL2 signaling.
下一代测序技术揭示了瓦尔登斯特伦巨球蛋白血症（WM）中经常出现的体细胞突变。常见的反复出现的突变包括 MYD88（95%至 97%）、CXCR4（30%至 40%）、ARID1A（17%）和 CD79B（8%至 15%）。通过 MYD88 突变状态可以帮助从重叠的 B 细胞恶性肿瘤中诊断 WM。转录受 MYD88 和 CXCR4 突变的影响，包括参与 VDJ 重组、CXCR4 途径信号传导和 BCL2 家族成员的基因过度表达。在 MYD88 突变的患者中，那些具有 CXCR4 突变的患者表现出与获得突变 MYD88 相关的肿瘤抑制基因转录沉默。涉及 6q 染色体的缺失很常见，包括调节核因子-κB、BCL2、BTK、凋亡、分化和 ARID1B 的基因。非 6q 染色体基因也经常缺失，包括 B 细胞受体信号传导的调节剂 LYN。MYD88 和 CXCR4 突变影响 WM 疾病表现和治疗结果。具有野生型 MYD88 的患者骨髓疾病负担和血清免疫球蛋白 M 水平较低，但死亡风险增加。具有 CXCR4 突变的患者骨髓疾病负担较高，具有无意义 CXCR4 突变的患者血清免疫球蛋白 M 水平较高，症状性高粘血症的发生率较高。突变的 MYD88 触发 BTK、IRAK1/IRAK4 和 HCK 生长和存活信号，而 CXCR4 突变在其配体 CXCL12 存在的情况下促进 AKT 和细胞外调节激酶-1/2 信号传导和耐药性。依鲁替尼在 WM 患者中有效，并受 MYD88 和 CXCR4 突变状态的影响。具有突变型 MYD88 和野生型 CXCR4 突变状态的患者对依鲁替尼表现出最佳反应。WM 患者中 CXCR4 突变与依鲁替尼的较低反应率和延迟反应相关。MYD88 和 CXCR4 突变状态可能有助于对有症状患者的治疗选择。正在研究的新的治疗方法包括针对 MYD88、CXCR4 和 BCL2 信号传导的治疗方法。
