TABLE 5.
Combining clinical and cell models
| Clinical Problem | Evidence |
|
|---|---|---|
| Clinical | Cell Model | |
| Use of AraC in AML therapy regimens has increased overall survival, but some patients are resistant | Low DCK mRNA levels predict poor survival in patients with AML treated with AraC; low intracellular concentrations of AraC in leukemia cells also predict poorer outcome to therapy | SNPs in DCK are associated with basal expression and drug sensitivity in the HapMap cell lines as well as low intracellular AraC concentrations |
| Development of t-AML occurs in some patients with ALL after etoposide treatment | Presence of MLL translocations that cause t-AML is not associated with etoposide dosage administered to patients with ALL or to toxicity; basal differences in the focal adhesion pathway are associated with etoposide-induced leukemias | No association exists between sensitivity to etoposide and frequency of MLL translocations in HapMap cells; GWAS using HapMap samples also found enrichment of SNPs in the focal adhesion pathway associated with levels of etoposide-induced MLL translocations |
| Reduced response to statins has been observed in some patients | Haplotype H7 (containing rs2846662) and rs2846662 alone associate with reduced response to 2 statins; statin-induced HMGCR13(−) expression inversely correlated with blood lipid measurements after statin treatment | rs2846662 associated with statin-induced expression of alternatively spliced transcript HMGCR13(−); specific siRNA knockdown of full-length HMGCR results in reduced sensitivity to statins |
| About 20% of childhood ALL patients are resistant to therapy, which includes prednisolone | Expression of SMARCB1 contributes to prednisolone sensitivity in leukemic cells | −228 G>T SNP identified which controls SMARCB1 expression via altered binding of PARP1; prednisolone IC50 associated with SMARCB1 expression in cell lines |
| Trimodal distribution of degree of myelosuppression in patients being treated with 6-mercaptopurine | TPMT genotypes are associated with TPMT enzymatic activity and myelosuppression in clinical studies | GWAS performed with HapMap cell lines found TPMT SNPs to be in the top 0.5% of SNPs associated with enzymatic activity |