Abstract:
Follicular helper T-cell (TFH) lymphoma harbors recurrent mutations of RHOAG17V, IDH2R172, TET2, and DNMT3A. TET2 and DNMT3A mutations are the most frequently affected genes in clonal hematopoiesis (CH). The aim of our study was to investigate the frequency of CH in bone marrow biopsies (BMB) of TFH/angioimmunoblastic T-cell lymphoma (TFH-AITL) patients and its association with myeloid neoplasms. A total of 29 BMB from 22 patients with a diagnosis of TFH-AITL were analyzed by next-generation sequencing (NGS) with a custom panel. Morphologically, 5 BMB revealed that TFH-AITL infiltrates of >5% of bone marrow (BM) cellularity confirmed in 4 cases by NGS-based T-cell clonality. IDH2R172 was demonstrated only in 1 (3%) of 29, and RHOAG17V in 2 (7%) of 29 samples. TET2 and DNMT3A were identified in 24 (83%) of 29 and 17 (59%) of 29 BMB, respectively. In the parallel lymph node the frequencies of mutations were 27% (IDH2R172), 64% (RHOAG17V), 86% (TET2), and 50% (DNMT3A). TET2 and/or DNMT3A mutations identical in lymph node and BMB were present in 18 (82%) of 22 patients, regardless of BM infiltration. In 3 cases the CH mutations were detected 13, 41, and 145 months before TFH-AITL diagnosis. Cases with TET2/DNMT3A mutations and BM variant allele frequencies >40% (7/18, 39%) showed lower blood counts. However, only low platelet count was statistically significant (P = .024). Myeloid neoplasms and/or myelodysplastic syndrome-related mutations were identified in 4 cases (4/22; 18%); all with high TET2 variant allele frequencies (>40%; P = .0114). In conclusion, CH is present in 82% of TFH-AITL and can be demonstrated up to 145 months before TFH-AITL diagnosis. NGS T-cell clonality analysis is an excellent tool to confirm TFH-AITL BM infiltration. Concurrent myeloid neoplasms were identified in 18% of the cases and were associated with TET2 mutations with high allelic burden (>40%). We demonstrated that myeloid neoplasms might occur simultaneously or precede the diagnosis of TFH lymphoma.
摘要:
滤泡辅助性T细胞(TFH)淋巴瘤具有RHOAG17V的复发性突变,IDH2R172、TET2和DNMT3A。TET2和DNMT3A突变是克隆造血(CH)中最常受影响的基因。我们研究的目的是调查TFH/血管免疫母细胞性T细胞淋巴瘤(TFH-AITL)患者的骨髓活检(BMB)中CH的频率及其与髓样肿瘤的关系。通过具有定制面板的下一代测序(NGS)分析了来自22名诊断为TFH-AITL的患者的总共29个BMB。形态学上,5BMB揭示TFH-AITL浸润>5%的BM细胞性,在4个病例中通过基于NGS的T细胞克隆性证实。IDH2R172仅在1/29(3%)中显示,和RHOAG17V在2/29(7%)样品中。TET2和DNMT3A在24/29(83%)和17/29(59%)BMB中被鉴定,分别。在平行淋巴结(LN)中,突变频率为27%(IDH2R172),64%(RHOAG17V),86%(TET2),和50%(DNMT3A)。18/22(82%)患者存在LN和BMB中相同的TET2和/或DNMT3A突变,不管BM渗透。在3例中,在TFH-AITL诊断前13、41和145个月检测到CH突变。TET2/DNMT3A突变和BM变异等位基因频率(VAF)>40%(7/18,39%)的病例显示较低的血细胞计数。然而,只有低血小板计数有统计学意义(p=0.024).在4例(4/22;18%)中发现了髓系肿瘤和/或MDS相关突变;所有患者均具有高TET2VAF(>40%;p=0.0114)。总之,在TFH-AITL的82%中存在CH,可以在TFH-AITL诊断前145个月内证实。NGST细胞克隆性分析是确认TFH-AITLBM浸润的极好工具。在18%的病例中发现并发骨髓性肿瘤,并与具有高等位基因负荷(>40%)的TET2突变相关。我们证明髓系肿瘤可能同时发生或先于TFH淋巴瘤的诊断。