Venetoclax Overcomes Sorafenib Resistance in Acute Myeloid Leukemia by Targeting BCL2
by
Xi Xu
1,†, 
Weiwei Ma
2,†,
Guo Qiu
1,
Li Xuan
1,
Chong He
3,
Tian Zhang
1,
Jian Wang
4,5,* and
Qifa Liu
1,* 1
Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510091, China
2
Department of Hematology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, China
3
Key Laboratory of Stem Cells and Tissue Engineering, Zhongshan School of Medicine, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
4
Children’s Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510080, China
5
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510080, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work and share first authorship.
Biology 2023, 12(10), 1337; https://doi.org/10.3390/biology12101337
Submission received: 24 August 2023
/
Revised: 26 September 2023
/
Accepted: 26 September 2023
/
Published: 16 October 2023
(This article belongs to the Special Issue The Regulation of Normal and Leukemia Stem Cells)
Simple Summary
Drug resistance is the main cause of sorafenib treatment failure in clinical acute myeloid leukemia (AML) patients, but the mechanism is currently not fully clear. In this study, we analyzed the genetic characteristics of sorafenib-resistant AML cell subclusters using single-cell and bulk transcription data and found that sorafenib-resistant AML cells can promote BCL2 transcription by activating STAT3. The BCL2 inhibitor venetoclax can enhance the chemotherapy sensitivity of AML cells to sorafenib.
Abstract
Sorafenib, a kinase inhibitor, has shown promising therapeutic efficacy in a subset of patients with acute myeloid leukemia (AML). However, despite its clinical effectiveness, sorafenib resistance is frequently observed in clinical settings, and the mechanisms underlying this resistance as well as effective strategies to overcome it remain unclear. We examined both single-cell and bulk transcription data in sorafenib-resistant and control AML patients and integrated a sorafenib resistance gene signature to predict the sensitivity of AML cells and the clinical outcomes of AML patients undergoing sorafenib therapy. In addition, our drug sensitivity analysis of scRNA-seq data using deconvolution methods showed that venetoclax was effective in targeting sorafenib-resistant AML cells. Mechanistically, sorafenib was found to activate the JAK-STAT3 pathway and upregulate BCL2 expression in sorafenib-resistant AML cells. This upregulation of BCL2 expression rendered the cells vulnerable to the BCL2 inhibitor venetoclax. In conclusion, we developed a platform to predict sorafenib resistance and clinical outcomes in AML patients after therapy. Our findings suggest that the combination of sorafenib and venetoclax could be an effective therapeutic strategy for AML treatment.
Keywords:
sorafenib; acute myeloid leukemia; chemoresistance; leukemia; BCL2; venetoclax
