Results reported online yesterday in Cell Reports discuss the identification of a genetic network that may fuel certain aggressive cases of acute myeloid leukemia (AML), as well as its precursor disease myelodysplastic syndrome (MDS). The work, carried out by investigators at Cincinnati Children’s Hospital Medical Center (OH, USA), could provide a new strategy for the development of therapeutics for this hematologic malignancy.
The forms of MDS and AML studied in this investigation, termed del(5q) AML/MDS, were all associated with chromosome 5 deletions.
“Unfortunately, a large portion of del(5q) AML and MDS patients have increased number of bone marrow blasts and additional chromosomal mutations,” lead investigator Daniel Starczynowski (Cincinnati Children’s Hospital Medical Center) explained. “These patients have very poor prognosis because the disease is very resistant to available treatments such as chemotherapy and radiation. Finding new therapies is important and this study identifies new therapeutic possibilities.”
Utilizing both human AML/MDS cells and mouse models of del(5q) AML/MDS, the Cincinnati team demonstrated that reduced expression of miR-146a resulted in activation of a molecular signaling network involving several components of NF-kB. One of these components was identified as p62, which is a known regulator of cell metabolism and cellular remodeling.
The deletion of miR-146a was demonstrated to lead to overexpression of p62, which in turn was found to sustain activation of the NF-kB signaling network. The activation of this network promoted both the growth and survival of leukemic cells in vitro and in mouse models.
As the authors explain, previous attempts to directly inhibit NF-kB in leukemia have proven unsuccessful and thus they performed follow-up investigations targeting instead p62 within the NF-kB signaling network. Inhibiting or knocking down p62 in both human cells and mouse models resulted in reduced cell growth.
It is unclear at this time how these findings could impact clinical treatment, and work will continue to further verify the results and to learn more about the processes involved.