While elevated expression of miR-155 has been associated with FLT3-ITD mutations, other mechanisms which may regulate expression of this miRNA in AML remain largely unknown.
We found that the EV miR155 levels were significantly higher in chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and Waldenström's macroglobulinemia (WM) cases compared to controls.
These findings collectively describe a novel dose-dependent role for miR-155 in the regulation of AML, which may have important therapeutic implications.
Consistent with our observations in mice, primary FLT3-ITD<sup>+</sup> AML clinical samples have significantly higher miR-155 levels and a lower IFN response compared with FLT3-WT AML samples.
Overall, hsa-miR-155, hsa-miR-192, <i>ANXA2</i>, <i>FZD3</i> and <i>PLAG1</i> may be associated with the development of AML via the involvement of the Wnt signaling pathway, melanogenesis and other cancer-associated signaling pathways.
Integration of the miR-155 targets with information from the protein interaction database STRING revealed proteins indirectly affected by AML exosome-derived miRNA.
In conclusion, our evidence show that IRF3 overexpression in AML promotes cell growth and survival, and miR-155 is involved, indicating that IRF3 may be a potential new biomarker and therapeutic target for AML.
Then, we reconstructed a non-redundant miRNA-gene regulatory network in MM, linking miRNAs, such as let-7g, miR-19a, mirR-20a, mir-21, miR-29 family, miR-34 family, miR-125b, miR-155, miR-221 to pathways associated with MM subtypes, in particular the ErbB, the Hippo, and the Acute myeloid leukemia associated pathways.
We also show for the first time that miR-155 levels are correlated with MLL translocations, but that miR-155 expression is dispensable for the formation of AML and has no effect on leukemia progression.
These results suggest that microRNA-155 is a potential diagnostic biomarker for all subgroups of paediatric AML, whereas microRNA-196b is specific for subgroups M4-M5.
From these analyses, we derived a sub-network, called "miR-155 module" that describes functional relationship among miR-155 and transcription factors in FLT3-mutated AML.
Our study demonstrates the potential of miR-155 as a novel therapeutic target in AML via pharmacologic interference with NF-κB-dependent regulatory mechanisms.
Analysis of miR-155 expression patterns in AML patients found that Fms-like tyrosine kinase 3 (FLT3)-wildtype AML has the same expression level as normal bone marrow, with increased expression restricted to AML with the FLT3-ITD mutation.
Furthermore, deregulation of both MYB and miR-155 coupled with PU.1 downregulation was observed in human AML, suggesting that MYB/miR-155/PU.1 mechanism may be involved in the pathogenesis of AML and its aggressiveness characterized by p53 mutation.
Silvestrol efficiently inhibited FLT3 translation reducing FLT3 protein expression by 80-90% and decreased miR-155 levels (~60%), a frequently co-regulated onco-miR in FLT3-ITD-positive AML.
The availability of emerging compounds with antagonistic activity to microRNAs in the clinic provides the opportunity for future therapeutic targeting of miR-155 in AML.
These results support that miR-128, let-7b, miR-223 and miR181a have a diagnosis value in AL, while miR-181a and miR-155 are of great prognostic significance in AML.