Low Expression of GFI-1 Gene Is Associated with Chemotherapy-Resistant in Acute Myeloid Leukemia through Influencing the Level of HO-1

In order to improve the poor cure rate of acute myeloid leukemia (AML), epigenetic modification has become a new treatment of leukemia in recent years. As a zinc-finger transcriptional repressor exerts, GFI-1 were found associated with poor prognosis in AML, but the underlying mechanism is not clear. Our investigation committed to studying the potential mechanism of resistance to Panobinostant in AML with low expression of GFI-1. Low level of GFI-1 implicated the poor prognosis of AML patients. In this study, we investigated the correlation of GFI-1 at transcription level in de novo AML patients. Follow up detection the progress of treatment of patients. After two courses of induction, we selected 32 patients in complete remission(CR stages)and 32 patients in relapsed or drug-resistant (relapsed stages), samples were selected to collect at the time of initial diagnosis. The transcription level of GFI-1 found that low expression of Gfi-1 also leads to chemotherapy resistance(P<0.05). Then our study explored its mechanisms of chemoresistance to Panobinostant invitro. Same with Same result in the vitro experiment, GFI-1 knock down by siRNA eliminated Panobinostat -induced cell apoptosis. Meanwhile, low level GFI-1 could enhance HO-1 expression at mRNA and protein level. As a previous study in our laboratory, HO-1 high expression could improve the sensitivity of drug resistant and tumor prolife in AML. However, correlation between GFI-1 and HO-1 has been no reported. So we try to found correlation between GFI-1 and HO-1 on chemotherapeutic response and explored the underlying mechanism. We regulated the level of HO-1 and found that the apoptosis rate between the low level of GFI-1 and empty vector has eased. GFI-1 regulates the HO-1 through the PI3K-AKT pathway, which affects the sensitivity of the cells to Panobinostat .Our data show that HO-1 plays a crucial role in GFI-1-dependent in chemotherapy-resistant AML. This provides a novel promising candidate for myeloid leukemia therapeutic method.