Abstract
Homoharringtonine (HHT) has been widely used in China to treat patients with acute and chronic myeloid leukemia for decades. Since response to HHT varies among patients, our study aimed to identify biomarkers that might influence the response to HHT using a panel of various human lymphoblastoid cell lines (LCLs). Genome-wide association (GWA) analysis using single nucleotide polymorphism (SNP) and mRNA expression data was assessed for association with cytotoxicity to HHT in LCLs. Integrated analysis among SNPs, expression, AUC value was also performed to help select candidate genes for further functional characterization. Functional validation of candidate genes was performed using leukemia cell lines (U937, K562). Candidate genes were knocked down using specific siRNA and its response to HHT was assessed using MTS assay. We found that 15 expression probes were associated with HHT AUC with P < 10−4, and 96 individual probe sets with P < 10−3. Eighteen SNPs were associated with HHT AUC with P < 10−5 and 281 SNPs with P < 10−4. The integrated analysis identified 4 unique SNPs that were associated with both expression and AUC. Functional validation using siRNA knockdown in leukemia cell lines showed that knocking down CCDC88A, CTBP2, SOCS4 genes in U937 and K562 cells significantly altered HHT cytotoxicity. In summary, this study performed with LCLs can help to identify novel biomarker that might contribute to variation in response to HHT therapy.
Highlights
Homoharringtonine (HHT) is a natural cephalotaxus alkaloid that is derived from the Cephalotaxus species found in China
HHT CYTOTOXICITY HHT cytotoxicity studies were performed to determine the range of variation in HHT area under the curve (AUC) among the 278 individual lymphoblastoid cell lines (LCLs) cell lines from three ethnic groups
CORRELATION BETWEEN EXPRESSION AND AUC We performed correlation analysis for the association of expression array and HHT AUC data to identify genes which might be associated with HHT cytotoxicity at the gene expression level (Figure 2A)
Summary
Homoharringtonine (HHT) is a natural cephalotaxus alkaloid that is derived from the Cephalotaxus species found in China It has been widely used in China for the treatment of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) for more than 3 decades. Previous studies have shown that HHT has significant synergistic effects with cytarabine (Zhou et al, 1995). Based on these observations, investigators in China attempted to add HHT into the conventional induction therapy (anthracycline plus cytarabine regimen) in newly diagnosed patients with AML to improve therapeutic outcomes. The addition of HHT increased early death rate due to more severe marrow suppression (Jin et al, 2013). Selection of patients predicted to respond to HHT would maximize drug efficacy while minimizing drug-related toxicity
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