Image by Su Jung Song
The microRNA miR-22 is “an essential antitumor gatekeeper” in acute myeloid leukemia (AML), researchers have reported in Nature Communications.
The team found that miR-22 was significantly downregulated in AML, and forced expression of miR-22 produced antileukemic effects in AML cells
and mouse models of the disease.
Futhermore, nanoparticles carrying miR-22 oligonucleotides appeared to cure AML in some mice.
“Previous research has shown that microRNA miR-22 is linked to breast cancer and other blood disorders [myelodysplastic syndromes], which sometimes turn into AML,” said study author Jianjun Chen, PhD, of the University of Cincinnati in Ohio.
“But we found in this study that it could be an essential antitumor gatekeeper in AML when it is downregulated. When we forced miR-22 expression, we saw difficulty in leukemia cells developing, growing, and thriving.”
Dr Chen and his colleagues first found that miR-22 was significantly downregulated (P<0.05) in samples from AML patients, when compared with normal CD34+ hematopoietic stem/progenitor cells, CD33+ myeloid progenitor cells, and mononuclear cells. The set of AML samples included MLL, t(15;17), t(8;21), and inv(16) AML.
When the researchers forced expression of miR-22 in human AML cells, they found the microRNA significantly inhibited cell viability, growth, and proliferation, while promoting apoptosis.
The team also investigated the role of miR-22 in colony formation induced by MLL-AF10/t(10;11), PML-RARA/t(15;17), and AML1-ETO9a/t(8;21). They found that forced expression of miR-22 significantly inhibited colony formation induced by all of these oncogenic fusion genes.
In mice, forced expression of miR-22 blocked MLL-AF9-mediated leukemogenesis and MLL-AF10-mediated leukemogenesis.
Forced expression of miR-22 also inhibited progression of AML induced by MLL-AF9, AE9a, or FLT3-ITD/NPM1c+ in secondary recipient mice. The researchers said this resulted in “largely normal” morphologies in the peripheral blood, bone marrow, spleen, and liver tissues of these mice.
In addition, the team found that nanoparticles carrying miR-22 oligonucleotides significantly delayed AML progression in secondary recipient mice with MLL-AF9 and AE9a-induced AML. At least 40% of the mice appeared to be completely cured.
In a xenotransplantation model, miR-22 nanoparticles significantly delayed AML progression induced by human MV4;11/t(4;11) cells.
Further investigation into the role miR-22 plays in AML revealed that 3 oncogenes—CRTC1, FLT3, and MYCBP—are “functionally important” targets of miR-22 in AML. And miR-22 represses the CREB and MYC signaling pathways.
The researchers also found DNA copy-number loss in the miR-22 gene locus in AML cases, and they discovered the expression of miR-22 is epigenetically repressed in AML.
“The downregulation, or decreased output, of miR-22 in AML is caused by the loss of the number of DNA being copied and/or stopping their expression through a pathway called TET1/GFI1/EZH2/SIN3A,” Dr Chen explained.
“Our study uncovers a previously unappreciated signaling pathway—TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC—and provides new insights into genetic mechanisms causing and progressing AML and also highlights the clinical potential of miR-22-based AML therapy. More research on this pathway and ways to target it are necessary.”
