As one of the most common and fatal forms of hematopoietic malignancies, acute myeloid leukaemia (AML) is frequently associated with diverse chromosome translocations and molecular abnormalities and mutations in nucleophosmin (NPM1c+)). Despite intensive chemotherapies, the majority of patients with AML fail to survive longer than 5 years. Thus, development of effective therapeutic strategies based on a better understanding of the molecular mechanisms underlying the pathogenesis of AML is urgently needed.
MicroRNAs (miRNAs) are a class of small, non-coding RNAs that post-transcriptionally regulate gene expression. Individual miRNAs may play distinct roles in cancers originating from different tissues or even from different lineages of hematopoietic cells. It is unclear whether a single miRNA can play distinct roles between malignancies originating from the same hematopoietic lineage, such as de novo AML and myelodysplastic syndrome (MDS).
Although around 30% of MDS cases transform to AML, the genetic and epigenetic landscapes of MDS or MDS-derived AML are largely different from those of de novo AML. MDS and MDS-derived AML are more responsive to hypomethylating agents than de novo AML. The molecular mechanisms underlying the distinct pathogenesis and drug response between MDS (or MDS-derived AML) and de novo AML remain unclear.
The ten-eleven translocation (Tet1/2/3) proteins play critical transcriptional regulatory roles in normal developmental processes as activators or repressors. In contrast to the frequent loss-of-function mutations and tumor-suppressor role of TET2 observed in hematopoietic malignancies, authors recently reported that TET1 plays an essential oncogenic role in MLL-rearranged AML where it activates expression of homeobox genes. However, it is unknown whether TET1 can also function as a transcriptional repressor in cancer. Moreover, Tet1-mediated regulation of miRNA expression has rarely been studied.
In the present study, researchers demonstrate that miR-22, an oncogenic miRNA reported in breast cancer and MDS, is significantly downregulated in most cases of de novo AML
Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways.
The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo.
Together, the study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy.http://www.nature.com/ncomms/2016/160426/ncomms11452/full/ncomms11452.html