HELQ 和 EGR3 的表达与慢性淋巴细胞白血病中的 IGHV 突变状态和预后相关。
HELQ and EGR3 expression correlate with IGHV mutation status and prognosis in chronic lymphocytic leukemia.
机构信息
Department of Hematology, China-Japan Friendship Hospital, Yinghua East Street, Beijing, 100029, China.
出版信息
J Transl Med. 2021 Jan 23;19(1):42. doi: 10.1186/s12967-021-02708-6.
BACKGROUND
IGHV mutation status is a crucial prognostic biomarker for CLL. In the present study, we investigated the transcriptomic signatures associating with IGHV mutation status and CLL prognosis.
METHODS
The co-expression modules and hub genes correlating with IGHV status, were identified using the GSE28654, by 'WGCNA' package and R software (version 4.0.2). The over-representation analysis was performed to reveal enriched cell pathways for genes of correlating modules. Then 9 external cohorts were used to validate the correlation of hub genes expression with IGHV status or clinical features (treatment response, transformation to Richter syndrome, etc.). Moreover, to elucidate the significance of hub genes on disease course and prognosis of CLL patients, the Kaplan-Meier analysis for the OS and TTFT of were performed between subgroups dichotomized by the median expression value of individual hub genes.
RESULTS
2 co-expression modules and 9 hub genes ((FCRL1/FCRL2/HELQ/EGR3LPL/LDOC1/ZNF667/SOWAHC/SEPTIN10) correlating with IGHV status were identified by WGCNA, and validated by external datasets. The modules were found to be enriched in NF-kappaB, HIF-1 and other important pathways, involving cell proliferation and apoptosis. The expression of hub genes was revealed to be significantly different, not only between CLL and normal B cell, but also between various types of lymphoid neoplasms. HELQ expression was found to be related with response of immunochemotherapy treatment significantly (p = 0.0413), while HELQ and ZNF667 were expressed differently between stable CLL and Richter syndrome patients (p < 0.0001 and p = 0.0278, respectively). By survival analysis of subgroups, EGR3 expression was indicated to be significantly associated with TTFT by 2 independent cohorts (GSE39671, p = 0.0311; GSE22762, p = 0.0135). While the expression of HELQ and EGR3 was found to be associated with OS (p = 0.0291 and 0.0114 respectively).The Kras, Hedgehog and IL6-JAK-STAT3 pathways were found to be associating with the expression of hub genes, resulting from GSEA.
CONCLUSIONS
The expression of HELQ and EGR3 were correlated with IGHV mutation status in CLL patients. Additionally, the expression of HELQ/EGR3 were prognostic markers for CLL associating with targetable cell signaling pathways.
背景
IGHV 突变状态是 CLL 的一个关键预后生物标志物。在本研究中，我们研究了与 IGHV 突变状态和 CLL 预后相关的转录组特征。
方法
使用“WGCNA”包和 R 软件（版本 4.0.2），通过 GSE28654 识别与 IGHV 状态相关的共表达模块和枢纽基因。进行过表达分析以揭示与相关模块基因相关的富含细胞途径。然后，使用 9 个外部队列验证枢纽基因表达与 IGHV 状态或临床特征（治疗反应、转化为 Richter 综合征等）的相关性。此外，为了阐明枢纽基因对 CLL 患者疾病过程和预后的意义，通过 Kaplan-Meier 分析对个体枢纽基因中位数表达值划分的亚组进行 OS 和 TTFT 分析。
结果
通过 WGCNA 鉴定了与 IGHV 状态相关的 2 个共表达模块和 9 个枢纽基因（FCRL1/FCRL2/HELQ/EGR3LPL/LDOC1/ZNF667/SOWAHC/SEPTIN10），并通过外部数据集进行了验证。这些模块被发现富含 NF-kappaB、HIF-1 和其他重要途径，涉及细胞增殖和凋亡。枢纽基因的表达不仅在 CLL 和正常 B 细胞之间存在显著差异，而且在各种类型的淋巴肿瘤之间也存在显著差异。HELQ 表达与免疫化学治疗反应显著相关（p=0.0413），而 HELQ 和 ZNF667 在稳定的 CLL 和 Richter 综合征患者之间的表达不同（p<0.0001 和 p=0.0278）。通过两个独立队列的生存亚组分析（GSE39671，p=0.0311；GSE22762，p=0.0135），EGR3 表达被表明与 TTFT 显著相关。而 HELQ 和 EGR3 的表达与 OS 相关（p=0.0291 和 0.0114）。GSEA 显示，Kras、Hedgehog 和 IL6-JAK-STAT3 途径与枢纽基因的表达相关。
结论
HELQ 和 EGR3 的表达与 CLL 患者的 IGHV 突变状态相关。此外，HELQ/EGR3 的表达与 CLL 的预后相关，与可靶向的细胞信号通路相关。
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