Abstract
BackgroundIGHV 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.MethodsThe 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.Results2 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.ConclusionsThe 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.
Highlights
Immunoglobulin heavy-chain variable region (IGHV) mutation status is a crucial prognostic biomarker for Chronic lymphocytic leukemia (CLL)
Our work revealed the transcriptomic signature characterized by co-expression modules, and provided insights and rationales to utilize Helicase POLQlike (HELQ)/Early growth response protein 3 (EGR3) expression as prognostic markers for CLL
The median age at diagnosis was 61 years old, and the majority of the cohort were in early stages (104 Binet stage A and 8 Binet stage B patients) and untreated (78 untreated vs 34 treated patients) [7]
Summary
IGHV mutation status is a crucial prognostic biomarker for CLL. We investigated the transcriptomic signatures associating with IGHV mutation status and CLL prognosis. CLL (chronic lymphocytic leukemia) is characterized by uncontrolled proliferation of monoclonal B cells, and resistance to cell apoptosis. CLL is the most prevalent adult leukemia in Europe and America. The disease course of CLL is heterogenous, and the treatment was initiated only in patients with advancing or symptomatic disease. The immunochemotherapy, including anti-CD20 monoclonal antibody and cytotoxic agents (fludarabine and cyclophosphamide, etc.) was the traditional choice. While novel agents, including BTK (Bruton’s Tyrosine Kinase) inhibitor (ibrutinib, zanubrutinib) and BCL2 (B cell lymphoma 2) inhibitor (venetoclax), have greatly improved the survival of CLL patients
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