Abstract
BackgroundRecent evidence has accumulated that MicroRNA (miRNA) dysregulation occurs in the majority of human malignancies including acute myeloid leukemia (AML) and may contribute to onco-/leukemo-genesis.MethodsThe expression levels of miR-370 and FoxM1 were assessed in 48 newly diagnosed AML patients, 40 AML patients in 1st complete remission (CR) and 21 healthy controls. Quantitative real-time PCR, western blots, colony formation assay, and β-Galactosidase ( SA-β-Gal) staining were used to characterize the changes induced by overexpression or inhibition of miR-370 or FoxM1.ResultsWe found that the down-regulation of miR-370 expression was a frequent event in both leukemia cell lines and primary leukemic cells from patients with de novo AML. Lower levels of miR-370 expression were found in 37 of 48 leukemic samples from AML patients compared to those in bone marrow cells derived from healthy adult individuals. Ectopic expression of miR-370 in HL60 and K562 cells led to cell growth arrest and senescence. In contrast, depletion of miR-370 expression using RNA interference enhanced the proliferation of those leukemic cells. Mechanistically, miR-370 targets the transcription factor FoxM1, a well established oncogenic factor promoting cell cycle progression. Moreover, when HL60 and K562 cells were treated with 5-aza-2′-deoxycytidine, a DNA methylation inhibitor, miR-370 expression was up-regulated, which indicates epigenetic silencing of miR-370 in leukemic cells.ConclusionsTaken together, miR-370 may function as a tumor suppressor by targeting FoxM1, and the epigenetic silence of miR-370 thus leads to derepression of FoxM1 expression and consequently contributes to AML development and progression.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic haematopoietic diseases characterized by proliferation and maturation arrest of myeloid blasts in bone marrow and blood [1]
More than 50% of miRNA genes are located in cancer-associated genomic regions or in fragile sites, and both oncogenic and tumor suppressive functions have far been ascribed to specific miRNAs [13]
Down-regulation of miR-370 expression in BM blasts from de novo acute myeloid leukemia (AML) patients We analyzed miR-370 expression in BM samples from 48 de novo AML patients at diagnosis time using qRTPCR
Summary
Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic haematopoietic diseases characterized by proliferation and maturation arrest of myeloid blasts in bone marrow and blood [1]. MicroRNAs (miRNAs), small (~22 nucleotide), singlestranded noncoding RNAs, are a novel class of biological molecules. Their genes may either give rise to single miRNAs, or contain several miRNAs in one transcriptional unit as miRNA clusters [3]. More than 50% of miRNA genes are located in cancer-associated genomic regions or in fragile sites, and both oncogenic and tumor suppressive functions have far been ascribed to specific miRNAs [13]. We sought to define the role of miR-370 in AML by investigating its expression and biological function in leukemic cell lines and blast cells from patients with de novo AML. Recent evidence has accumulated that MicroRNA (miRNA) dysregulation occurs in the majority of human malignancies including acute myeloid leukemia (AML) and may contribute to onco-/leukemo-genesis
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