Decreased TCF1 and BCL11B expression predicts poor prognosis for patients with chronic lymphocytic leukemia

Abstract

T cell immune dysfunction is a prominent characteristic of chronic lymphocytic leukemia (CLL) and the main cause of failure for immunotherapy and multi-drug resistance. There remains a lack of specific biomarkers for evaluating T cell immune status with outcome for CLL patients. T cell factor 1 (TCF1, encoded by the TCF7 gene) can be used as a critical determinant of successful anti-tumor immunotherapy and a prognostic indicator in some solid tumors; however, the effects of TCF1 in CLL remain unclear. Here, we first analyzed the biological processes and functions of TCF1 and co-expressing genes using the GEO and STRING databases with the online tools Venny, Circos, and Database for Annotation, Visualization, and Integrated Discovery (DAVID). Then the expression and prognostic values of TCF1 and its partner gene B cell leukemia/lymphoma 11B (BCL11B) were explored for 505 CLL patients from 6 datasets and validated with 50 CLL patients from Henan cancer hospital (HNCH). TCF1 was downregulated in CLL patients, particularly in CD8+ T cells, which was significantly correlated with poor time-to-first treatment (TTFT) and overall survival (OS) as well as short restricted mean survival time (RMST). Function and pathway enrichment analysis revealed that TCF1 was positively correlated with BCL11B, which is involved in regulating the activation and differentiation of T cells in CLL patients. Intriguingly, BCL11B was highly consistent with TCF1 in its decreased expression and prediction of poor prognosis. More importantly, the combination of TCF1 and BCL11B could more accurately assess prognosis than either alone. Additionally, decreased TCF1 and BCL11B expression serves as an independent risk factor for rapid disease progression, coinciding with high-risk indicators, including unmutated IGHV, TP53 alteration, and advanced disease. Altogether, this study demonstrates that decreased TCF1 and BCL11B expression is significantly correlated with poor prognosis, which may be due to decreased TCF1+CD8+ T cells, impairing the effector CD8+ T cell differentiation regulated by TCF1/BCL11B.

T‐cell lymphoma patient harboring BCL11B mutations had favorable overall survival

“…or MDS, the reason is thought that lower BCL11B related lower T cell activity. 18,36 In contrast, BCL11B is also considered as oncogene in T-ALL, 22,37 overexpression of BCL11B is frequently identified in T-ALL, inhibition of BCL11B effectively induces growth retardation and apoptosis of T-ALL cells. [22][23][24]38,39 These findings were consistent with present study that TCL patients harboring BCL11B mutation might predict favorable prognosis.…”

“…Similarly, BCL11B haplo‐insufficiency occurs in each major T‐ALL molecular subtypes, such as early T‐cell precursor and TAL1‐positive subtypes, which exhibit differentiation arrest at different thymocyte development stages 35 . Moreover, decreased BCL11B expression was associated adverse clinical outcomes for patients with chronic lymphocytic leukemia (CLL) or MDS, the reason is thought that lower BCL11B related lower T cell activity 18,36 . In contrast, BCL11B is also considered as oncogene in T‐ALL, 22,37 overexpression of BCL11B is frequently identified in T‐ALL, inhibition of BCL11B effectively induces growth retardation and apoptosis of T‐ALL cells 22–24,38,39 .…”

Qi Fu Yin ameliorates neuroinflammation through inhibiting RAGE and TLR4/NF-κB pathway in AD model rats

“…The Ethics Committee of Hunan University of Chinese Medicine exempted the use of public database data from ethical review. We obtained AD-related targets from DisGeNET and screened for overlaps between the predicted targets of the compounds and AD-related targets using the VENNY online tool [ 21 ]. The common targets were considered potential targets of QFY for treating AD and were imported into Cytoscape to construct the C-T-AD network.…”

Regulatory effects of IRF4 on immune cells in the tumor microenvironment

“…In addition, recent studies have shown that TCF1 is essential for maintaining CD8+ T CM cells and serves as a positive biomarker for prolonged survival and effective responses to PD1 inhibitors in various solid tumors and hematological malignancies (82)(83)(84)(85). Undoubtedly, high-level IRF4 is beneficial to the initial effector function, but sustained overexpression of IRF4 inhibits the expression of TCF1, which further damages the production of antigen-specific T CM cells and is not conductive to the rapid effect function in recall responses (24).…”