Impact of genetic variation in FKBP5 on clinical response in pediatric acute myeloid leukemia patients: a pilot study.

摘要

Although front-line chemotherapy regimens containing cytar-abine induce complete remission in 65-80 of patients with newly diagnosed acute myeloid leukemia (AML), persistence of disease in a substantial proportion of patients leads to disease recurrence. A recent report showed positive correlation between the expression of FKBP5, a 51 kDa protein with peptidyl-propyl-isomerase activity and cellular sensitivity to cytarabine. Genetic variants in FKBP5 have been studied extensively for association with depression, and mood disorders Although the role of FKBP5 in steroid signaling through heat shock protein 90 has been well established, recent reports have shown an additional function as a negative regulator of the AKT signaling. FKBP5 promotes the dephosphorylation of AKT-Ser473 by acting as a scaffolding protein for AKT and PH-domain leucine-rich repeat protein phosphatase (PHLPP). This decreased AKT phosphorylation can contribute to increased cytotoxicity by enhancing the apoptosis in response to chemotherapeutic agents such as cytarabine. Thus, inter-patient variation in FKBP5 expression/activity due to genetic polymorphisms could influence the response to chemotherapy, hence in this study we determined the clinical significance of FKBP5 single-nucleotide polymorphisms (SNPs) in pediatric AML patients treated with cytarabine-containing chemotherapy.