Loss of an Atypical Ribosomal Protein Kinase Riok2 phenocopies MDS: Pathogenic Role of IL-22
EvansMDS Discovery Research Grant 2019
Myelodysplastic syndromes (MDS) are the most commonly identified blood-related neoplasms in the United States (US). MDS occurs when the blood-forming cells in the body malfunction leading to abnormal numbers of one or more type of cells in the blood, bleeding and increased vulnerability to infections. In about one-third of patients, MDS can progress to an aggressive and fatal cancer of blood cells called acute myeloid leukemia (AML). The average age of MDS diagnosis is ~ 60 yrs. In the US, about 13,000 new cases of MDS are diagnosed each year. This number is expected to increase as the average age of the population and life expectancy increases. The 3-year survival rate for MDS patients is a grim 35-40%.
Apart from a genetic defect that is known to cause 15% of MDS cases, the origin of most MDS cases is unknown. This deficiency in knowledge of MDS causation has limited the development of new and effective therapeutics for MDS treatment. Current treatments for MDS work only in a subset of patients and are also known to cause serious side effects thus reducing overall efficacy. Some patients also develop resistance to these treatments rendering them untreatable. Novel and more effective therapeutic approaches are urgently needed to complement the current treatments and improve the dismal prognosis of MDS patients.
The role of the immune system in causation of MDS is increasingly being recognized. However, a link between genetic abnormalities seen in MDS and the immune system has not yet been identified. In my laboratory, we have uncovered a direct relationship between the immune system and the deficiency of blood forming cells in the body. We have identified a protein, Riok2, whose deficiency results in MDS by affecting blood-forming cells directly as well as by secretion of proteins (IL-22) from immune cells that further affect the blood-forming cells. This proposal therefore aims at uncovering and characterizing the mechanisms through which Riok2 contributes to MDS via its effect on two different cell types. Furthermore, this study will also undertake a translational approach in testing the efficacy of disabling IL-22 secreted by immune cells in alleviating MDS symptoms. The central premise of the research outlined here is that genetic defects in MDS impact blood-forming cells and immune cells simultaneously and targeting the latter is a viable therapeutic approach. Findings from our research will provide a mechanistic understanding of MDS pathogenesis and provide new clinically relevant therapeutic targets to reduce suffering and improve the quality of life for MDS patients. Collectively, these studies will not only inform the biology of Riok2 and associated mutations in MDS but will also lay the foundation for the development of new immune-targeted therapies for the treatment of MDS.