Dexamethasone enhances venetoclax-induced apoptosis in acute myeloid leukemia cells.

Acute myeloid leukemia (AML) therapies have been significantly improved by the development of medicines that can target BCL-2. On the other hand, non-recurrent alterations in oncogenic pathways and gene expression patterns have already been linked to therapeutic resistance to venetoclax therapy. Bone marrow mesenchymal stromal cells (BM-MSCs) support leukemic cells in preventing chemotherapy-induced apoptosis by mitochondrial transfer in leukemic microenvironment. In this study, we investigated the enhancement of the antitumor effect of BCL-2 inhibitor venetoclax by dexamethasone. In particular, dexamethasone had no significant effect on the viability of AML cells, but dexamethasone combined with venetoclax could significantly increase the apoptosis of AML cells induced by venetoclax. When AML cells were co-cultured with BM-MSCs, dexamethasone combined with venetoclax showed additional anti-tumor effect compared to venetoclax alone. Venetoclax increased reactive oxygen species level in co-cultured AML cells, contributed to transfer more mitochondria from BM-MSCs to AML cells and protect AML cells from apoptosis. Dexamethasone combined with venetoclax induced more apoptosis, but dexamethasone reduced the venetoclax-induced reactive oxygen species level in AML cells and reduced the transfer of mitochondria from BM-MSCs to AML cells. This may lead to a diminished protective effect of BM-MSCs on AML cells. Together, our findings indicated that venetoclax in combination with dexamethasone could be a promising therapy in AML.

Bioinformatics analysis of the endoplasmic reticulum stress-related prognostic model and immune cell infiltration in acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is the most common malignant hematological disease originating from hematopoietic stem cells. Endoplasmic reticulum stress (ERs) has been reported to be involved in multiple tumor-related biological processes. However, the prognostic role of ERs-related genes in AML has not been fully investigated. METHODS: The TCGA-LAML RNA-seq dataset was downloaded from the UCSC Xena website as the training cohort. Univariate Cox regression analysis was used to identify 42 ER stress-related genes associated with prognosis. Then, a ERs risk score prognostic model was established through LASSO regression analysis. AML patients were divided into high- and low-risk groups according to the median risk score. The Kaplan-Meier survival curve, time ROC curve analysis and univariate and multivariate independent prognostic analyses were presented for the high- and low-risk groups. Moreover, we verified the ERs risk model in the TARGET-AML and GSE37642 datasets. Next, we performed immune cell infiltration analysis, immune checkpoint gene expression analysis and drug sensitivity analysis. RESULTS: We found 42 ER stress-related genes with prognostic significance, and a prognostic model consisting of 13 genes was constructed and verified. The survival rate of AML patients in the low-risk group was better than that in the high-risk group. The tumor microenvironment and immune cell infiltration results showed that immune cell infiltration was correlated with the survival status of patients. CONCLUSION: This research identified a ERs risk model with significant prognostic value. These genes are expected to be potential prognostic biomarkers in AML, providing a new theoretical basis for disease management.