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A Three-Gene Expression Signature Identifies a Cluster of Patients with Short Survival in Chronic Lymphocytic Leukemia.

ABSTRACT: Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by its heterogeneous clinical evolution. Despite the discovery of the most frequent cytogenomic drivers of disease during the last decade, new efforts are needed in order to improve prognostication. In this study, we used gene expression data of CLL samples in order to discover novel transcriptomic patterns associated with patient survival. We observed that a 3-gene expression signature composed of SCGB2A1, KLF4, and PPP1R14B differentiate a group of circa 5% of cases with short survival. This effect was independent of the main cytogenetic markers of adverse prognosis. Finally, this finding was reproduced in an independent retrospective cohort. We believe that this small gene expression pattern will be useful for CLL prognostication and its association with CLL response to novel drugs should be explored in the future.

SUBMITTER: Mosquera Orgueira A

PROVIDER: S-EPMC6885206 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A Three-Gene Expression Signature Identifies a Cluster of Patients with Short Survival in Chronic Lymphocytic Leukemia.

Mosquera Orgueira Adrián A Antelo Rodríguez Beatriz B Díaz Arias José Ángel JÁ Díaz Varela Nicolás N Bello López José Luis JL

Journal of oncology 20191107

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by its heterogeneous clinical evolution. Despite the discovery of the most frequent cytogenomic drivers of disease during the last decade, new efforts are needed in order to improve prognostication. In this study, we used gene expression data of CLL samples in order to discover novel transcriptomic patterns associated with patient survival. We observed that a 3-gene expression signature composed of <i>SCGB2A1</i>, ...[more]

PMID: 31827514

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Project description:BackgroundChronic lymphocytic leukemia (CLL) is an indolent heme malignancy characterized by the accumulation of CD5+ CD19+ B cells and episodes of relapse. The biological signaling that influence episodes of relapse in CLL are not fully described. Here, we identify gene networks associated with CLL relapse and survival risk.MethodsNetworks were investigated by using a novel weighted gene network co-expression analysis method and examining overrepresentation of upstream regulators and signaling pathways within co-expressed transcriptome modules across clinically annotated transcriptomes from CLL patients (N = 203). Gene Ontology analysis was used to identify biological functions overrepresented in each module. Differential Expression of modules and individual genes was assessed using an ANOVA (Binet Stage A and B relapsed patients) or T-test (SF3B1 mutations). The clinical relevance of biomarker candidates was evaluated using log-rank Kaplan Meier (survival and relapse interval) and ROC tests.ResultsEight distinct modules (M2, M3, M4, M7, M9, M10, M11, M13) were significantly correlated with relapse and differentially expressed between relapsed and non-relapsed Binet Stage A CLL patients. The biological functions of modules positively correlated with relapse were carbohydrate and mRNA metabolism, whereas negatively correlated modules to relapse were protein translation associated. Additionally, M1, M3, M7, and M13 modules negatively correlated with overall survival. CLL biomarkers BTK, BCL2, and TP53 were co-expressed, while unmutated IGHV biomarker ZAP70 and cell survival-associated NOTCH1 were co-expressed in modules positively correlated with relapse and negatively correlated with survival days.ConclusionsThis study provides novel insights into CLL relapse biology and pathways associated with known and novel biomarkers for relapse and overall survival. The modules associated with relapse and overall survival represented both known and novel pathways associated with CLL pathogenesis and can be a resource for the CLL research community. The hub genes of these modules, e.g., ARHGAP27P2, C1S, CASC2, CLEC3B, CRY1, CXCR5, FUT5, MID1IP1, and URAHP, can be studied further as new therapeutic targets or clinical markers to predict CLL patient outcomes.

Project description:Several studies in chronic lymphocytic leukemia (CLL) patients have reported impaired immune cell functions, which contribute to tumor evasion and disease progression. However, studies on CLL-like monoclonal B-cell lymphocytosis (MBL) are scarce. In the study described here, we characterized the immune environment in 62 individuals with clinical MBL, 56 patients with early-stage CLL, and 31 healthy controls. Gene expression arrays and quantitative reverse transcription polymerase chain reaction were performed on RNA from CD4+ peripheral blood cells; serum cytokines were measured with immunoassays; and HLA-DR expression on circulating monocytes, as well as the percentages of Th1, cytotoxic, exhausted, and effector CD4+ T cells, were evaluated by flow cytometry. In addition, cell cultures of clonal B cells and CD14-enriched or -depleted cell fractions were performed. Strikingly, MBL and early-stage CLL differed in pro-inflammatory signatures. An increased inflammatory drive orchestrated mainly by monocytes was identified in MBL, which exhibited enhanced phagocytosis, pattern recognition receptors, interleukin-8 (IL8), HMGB1, and acute response signaling pathways and increased pro-inflammatory cytokines (in particular IL8, interferon γ [IFNγ], and tumor necrosis factor α). This inflammatory signature was diminished in early-stage CLL (reduced IL8 and IFNγ levels, IL8 signaling pathway, and monocytic HLA-DR expression compared with MBL), especially in those patients with mutations in IGHV genes. Additionally, CD4+ T cells of MBL and early-stage CLL exhibited a similar upregulation of Th1 and cytotoxic genes and expanded CXCR3+ and perforin+ CD4+ T cells, as well as PD1+ CD4+ T cells, compared with controls. Cell culture assays disclosed tumor-supporting effects of monocytes similarly observed in MBL and early-stage CLL. These novel findings reveal differences in the inflammatory environment between MBL and CLL, highlighting an active role for antigen stimulation in the very early stages of the disease, potentially related to malignant B-cell transformation.

Dataset Information

A Three-Gene Expression Signature Identifies a Cluster of Patients with Short Survival in Chronic Lymphocytic Leukemia.

Publications

A Three-Gene Expression Signature Identifies a Cluster of Patients with Short Survival in Chronic Lymphocytic Leukemia.

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