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

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.

Prognostic Significance of Dual-Specificity Phosphatase 23 Expression in Acute Myeloid Leukemia

“…Hub proteins and key nodes in the constructed PPI network were identified using the Cytoscape plugin CytoHubba. 5 , 22 …”

“…Hub proteins and key nodes in the constructed PPI network were identified using the Cytoscape plugin CytoHubba. 5,22 Immune Infiltration Analysis SSGSEA analysis was performed using the GSVA package in R (version 3.6.3) to analyze immune infiltration in DUSP23. Data on 24 types of infiltrating immune cells, as previously described, were obtained.…”

“…It was observed that the DUSP23 gene exhibited differential low expression in HHT-resistant cells than sensitive cells. 5 This indicated that DUSP23 may serve as a therapeutic target and a potential prognostic factor in AML. DUSP23 is located on chromosome 1q23 and is characterized by a dual-specificity phosphatase catalytic domain.…”