Characterization of the Newly Established Homoharringtonine- (HHT-) Resistant Cell Lines and Mechanisms of Resistance

Fenglin Li; Qing Ling; Chao Hu; Huafeng Wang; Wenle Ye; Xia Li; Xiang Zhang; Xiangjie Lin; Wenwen Wei; Xin Huang; Yu Qian; Haihui Zhuang; Jie Jin; Ying Lu

doi:10.1155/2022/2813938

Characterization of the Newly Established Homoharringtonine- (HHT-) Resistant Cell Lines and Mechanisms of Resistance

J Oncol. 2022 Aug 30:2022:2813938. doi: 10.1155/2022/2813938. eCollection 2022.

Authors

Fenglin Li^{1

2}, Qing Ling², Chao Hu^{2

3}, Huafeng Wang^{2

3}, Wenle Ye², Xia Li^{2

3}, Xiang Zhang^{2

3}, Xiangjie Lin^{2

3}, Wenwen Wei², Xin Huang^{2

3}, Yu Qian², Haihui Zhuang¹, Jie Jin^{2

3}, Ying Lu¹

Affiliations

¹ Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, China.
² Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
³ Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.

Abstract

Homoharringtonine- (HHT-) based HHT, aclarubicin, and cytarabine (HAA) induction regimen is the first-line therapy for nonelder acute myeloid leukemia (AML) patients in China. However, drug resistance is a new challenge, and little attention has been devoted to excavating resistant mechanisms. This study used the classic method to construct six HHT-resistant cell lines with a gradually increasing resistance index (RI) to discover HHT drug resistance mechanisms dynamically. After HHT resistance, the cell growth rate decreased, cell cycle delayed, and P-glycoprotein (p-gp, CD243) expression levels increased. Furthermore, we explored the changes in transcriptomics between HHT-sensitive and HHT-resistant cells using RNA-sequence. Through Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and hub gene analyses, we found that immune activity, especially G-protein coupled receptor (GPR) and related molecules, may mediate HHT resistance. Moreover, Calcitonin Receptor-Like (CALCRL) and G Protein Subunit Alpha I1 (GNAI1), which belong to GPRs, were stimulated in HHT-resistant cell strains in vitro and vivo, indicating that they may play a critical role in HHT resistance. In addition, these two genes have prognostic significance for AML patients. Taken together, we successfully constructed HHT-resistant cell lines with dynamic RIs and explored the resistance mechanisms, which will help identify new drugs for HHT-resistant AML patients.