Anemia affects roughly one-third of the world population. Patients with hematological neoplasms, such as myelodysplastic syndromes (MDS), predominantly display anemia but the underlying mechanisms remain elusive thus far. Right open reading frame kinase 2 (RIOK2) is a protein kinase located at human chromosomal DNA 5q15, a genetic region frequently deleted in MDS del(5q) patients. Here, (a) we report that 50% reduction in Riok2 expression resulted in reduced red blood cell (RBC) production leading to anemia. Furthermore, analysis of multiple patient-derived loss-of-function RIOK2 mutations showed marked attenuation of RBC development. We discovered that immune cell- derived protein interleukin-22 (IL-22) drives anemia in Riok2-deficient mice. Neutralizing IL-22 signaling alleviated induced-anemia not only in Riok2-deficient mice but also in wild- type mice. Levels of IL-22 were also increased in del(5q) MDS patients. Importantly, retrospective analysis of data from a clinical trial analyzing the efficacy of anti-IL22 in arthritis revealed a significant increase in hemoglobin in the anti-IL-22 administered group compared to the placebo group. (b) We also discovered that RIOK2 functions as a master regulator of human blood cell development by regulating the production of RBCs, white blood cells and platelets. We identified that RIOK2 is a rare protein that regulates both protein and RNA production in cells. This work reveals a possible therapeutic opportunity for reversing many stress-induced anemias (MDS, chronic kidney disease, chronic inflammation, chemotherapy-induced) by targeting IL-22 signaling and enhancing RIOK2 functions.