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 <i>de novo</i> acute myeloid leukemia (AML) by quantitative real-time PCR (qRT-PCR) in a training cohort and validated the results using transcriptome data from 167 <i>de novo</i> AML patients from the Cancer Genome Atlas (TCGA) database. In the training cohort, higher expression of <i>TOX</i> and <i>TOX4</i> was detected in the AML samples, whereas lower <i>TOX3</i> expression was found. Moreover, both the training and validation results indicated that higher <i>TOX2</i>, <i>TOX3</i>, and <i>TOX4</i> expression of AML patients (3-year OS: 0% <i>vs.</i> 37%, <i>P</i> = 0.036; 3-year OS: 4% <i>vs.</i> 61%, <i>P</i> < 0.001; 3-year OS: 0% <i>vs.</i> 32%, <i>P</i> = 0.010) and the AML patients with highly co-expressed <i>TOX</i>, <i>TOX2</i>, <i>TOX4</i> genes (3-year OS: 0% <i>vs.</i> 25% <i>vs.</i> 75%, <i>P</i> = 0.001) were associated with poor overall survival (OS). Interestingly, <i>TOX2</i> was positively correlated with <i>CTLA-4</i>, <i>PD-1</i>, <i>TIGIT</i>, and <i>PDL-2</i> (r_s = 0.43, <i>P</i> = 0.006; r_s = 0.43, <i>P</i> = 0.006; r_s = 0.56, <i>P</i> < 0.001; r_s = 0.54, <i>P</i> < 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.