miR-22 has a potent anti-tumor role in acute myeloid leukaemia (AML)

miR-22 has a potent anti-tumor role in acute myeloid leukaemia (AML)

 

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
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