Higher TOX Genes Expression Is Associated With Poor Overall Survival for Patients With Acute Myeloid Leukemia

Abstract

Thymocyte selection-associated HMG box (TOX) is a transcription factor that belongs to the high mobility group box (HMG-box) superfamily, which includes four subfamily members: TOX, TOX2, TOX3, and TOX4. TOX is related to the formation of multiple malignancies and contributes to CD8+ T cell exhaustion in solid tumors. However, little is known about the role of TOX genes in hematological malignancies. In this study, we explored the prognostic value of TOX genes from 40 patients with de novo acute myeloid leukemia (AML) by quantitative real-time PCR (qRT-PCR) in a training cohort and validated the results using transcriptome data from 167 de novo AML patients from the Cancer Genome Atlas (TCGA) database. In the training cohort, higher expression of TOX and TOX4 was detected in the AML samples, whereas lower TOX3 expression was found. Moreover, both the training and validation results indicated that higher TOX2, TOX3, and TOX4 expression of AML patients (3-year OS: 0% vs. 37%, P = 0.036; 3-year OS: 4% vs. 61%, P < 0.001; 3-year OS: 0% vs. 32%, P = 0.010) and the AML patients with highly co-expressed TOX, TOX2, TOX4 genes (3-year OS: 0% vs. 25% vs. 75%, P = 0.001) were associated with poor overall survival (OS). Interestingly, TOX2 was positively correlated with CTLA-4, PD-1, TIGIT, and PDL-2 (rs = 0.43, P = 0.006; rs = 0.43, P = 0.006; rs = 0.56, P < 0.001; rs = 0.54, P < 0.001). In conclusion, higher expression of TOX genes was associated with poor OS for AML patients, which was related to the up-regulation of immune checkpoint genes. These data might provide novel predictors for AML outcome and direction for further investigation of the possibility of using TOX genes in novel targeted therapies for AML.

Increased TOX expression concurrent with PD‐1, Tim‐3, and CD244 expression in T cells from patients with acute myeloid leukemia

“…In this study, we examined the characteristics of TOX in T cell subsets and found a significantly increased percentage of TOX+ CD3+, CD4+, and CD8+ T cells in PB from AML patients. This result is consistent with findings of upregulation of TOX in solid tumors and lymphomas (Huang et al, 2021; Kim et al, 2020; Liang, Zhao, et al, 2021; Wang et al, 2019; Yang et al, 2021). TOX+CD244+, TOX+PD‐1+, and TOX+Tim‐3+ double‐positive T cells were evidently increased in the CD3+, CD4+, and CD8+ T cell populations, suggesting that TOX may play a vital role as a transcription factor in the formation of exhaustive T cells.…”

Different expression patterns of VISTA concurrent with PD-1, Tim-3, and TIGIT on T cell subsets in peripheral blood and bone marrow from patients with multiple myeloma

“…Up-regulated IC protein expression is closely associated with adverse clinical outcome in cancer and hematological malignancies ( 23 , 50 , 51 ). In this study, we also made the observation that VISTA expression increases with several adverse clinical characteristics, such as advanced ISS stage, lower hemoglobin, and higher levels of β2-MG and LDH, indicating that the development of MM is likely to be related to dynamic changes in the dysfunctional characteristics of VISTA+ T cells.…”

Higher TOX（Thymocyte selection-associated high mobility group box）expression in tumor microenvironment predicts poor prognosis in patients with ovarian cancer

“…Moreover, TOX correlated not only the prognosis of solid tumor but also hematological malignancy. For example, Liang et al reported that higher TOX expression was associated with poor OS for patients with acute myeloid leukemia (22).However, the relationship between TOX expression and prognosis in ovarian cancer has not been comprehensively investigated. Thus, we demonstrated TOX was a potential prognosis-related biomarker in ovarian cancer and suggested a new direction to understand the correlations between TOX, immune in ltration and T cells function in tumor microenvironment.…”