Abstract
BackgroundAlthough current chemotherapy regimens have remarkably improved the cure rate of pediatric acute promyelocytic leukemia (APL) over the past decade, more than 20% of patients still die of the disease, and the 5-year cumulative incidence of relapse is 17%. The precise gene pathways that exert critical control over the determination of cell lineage fate during the development of pediatric APL remain unclear.MethodsIn this study, we analyzed miR-125b expression in 169 pediatric acute myelogenous leukemia (AML) samples including 76 APL samples before therapy and 38 APL samples after therapy. The effects of enforced expression of miR-125b were evaluated in leukemic cell and drug-resistant cell lines.ResultsmiR-125b is highly expressed in pediatric APL compared with other subtypes of AML and is correlated with treatment response, as well as relapse of pediatric APL. Our results further demonstrated that miR-125b could promote leukemic cell proliferation and inhibit cell apoptosis by regulating the expression of tumor suppressor BCL2-antagonist/killer 1 (Bak1). Remarkably, miR-125b was also found to be up-regulated in leukemic drug-resistant cells, and transfection of a miR-125b duplex into AML cells can increase their resistance to therapeutic drugs,ConclusionsThese findings strongly indicate that miR-125b plays an important role in the development of pediatric APL at least partially mediated by repressing BAK1 protein expression and could be a potential therapeutic target for treating pediatric APL failure.
Highlights
Current chemotherapy regimens have remarkably improved the cure rate of pediatric acute promyelocytic leukemia (APL) over the past decade, more than 20% of patients still die of the disease, and the 5year cumulative incidence of relapse is 17%
APL is characterized by a specific t(15;17) translocation that encodes a fusion of the promyelocytic leukemia (PML) and retinoic acid receptor-a (RARA) proteins [1,2,3,4,5]
Results miR-125b is highly expressed in pediatric APL Using genome-wide miRNA expression profiles in 36 diagnostic acute leukemia bone marrow samples, we previously identified up-regulated and down-regulated miRNAs that were significantly deregulated in pediatric primary acute myelogenous leukemia (AML) compared with healthy samples [26]
Summary
Current chemotherapy regimens have remarkably improved the cure rate of pediatric acute promyelocytic leukemia (APL) over the past decade, more than 20% of patients still die of the disease, and the 5year cumulative incidence of relapse is 17%. APL is characterized by a specific t(15;17) translocation that encodes a fusion of the promyelocytic leukemia (PML) and retinoic acid receptor-a (RARA) proteins [1,2,3,4,5]. MiRNA expression signatures associated with specific cytogenetic changes and clinical outcomes of adult CLL, AML, and Hodgkin’s lymphoma have been reported [15,16,17,18,19,20]. Dysregulated miRNA expression in APL cells following retinoic acid (RA) induction was reported [22,23,24,25]. These studies, mainly focused on APL cell lines and included very few clinical APL samples. The role of miRNAs in the clinical progression of APL, especially in pediatric APL, remains to be explained
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