Anemia and Ineffective Erythropoiesis Caused by Somatic RAS Mutation.

Ras proteins modulate cell fates by integrating extracellular stimuli and transducing signals that regulate proliferation, survival, and differentiation via downstream effector cascades. Somatic activating mutations in RAS oncogenes are found in approximately one third of cases of myelodysplastic syndrome (MDS), and are common in myeloproliferative disorders (MPDs) such as CMML and JMML that frequently have a dysplastic component. We have modeled these human diseases in the mouse using a conditional allele of oncogenic Kras, which is activated in mice bearing the inducible Mx1-Cre transgene by injection with polyinosinic-polycytidilic acid (pI-pC). Mice treated with pI-pC to induce K-ras^G12D expression at 21 days of life develop not only myeloid proliferation, but also progressive anemia which is the likely cause of death with median survival 84 days after injection. Erythroid precursors are abundant in spleens of anemic mice, suggesting ineffective erythropoiesis. These features are highly reminiscent of human MDS, and suggest that anemia in MDS is a direct consequence of hyperactive RAS signaling. Further analysis reveals that although erythroblasts are absent from the bone marrow, earlier erythroid progenitors such as BFU-E and CFU-E are abundant in both bone marrow and spleens of anemic mice. However, despite hyperproliferation of primitive erythroid cells, there is a block in terminal erythroid differentiation. This is also seen in primary E14.5 fetal liver cells acutely induced to express K-ras^G12Din vitro, and in wild type recipients of Mx1-Cre, Kras^G12D bone marrow, demonstrating this to be a cell-intrinsic property of erythroid progenitors expressing oncogenic Ras. Together, these findings support a model in which RAS mutations in MDS both confer a proliferative advantage to a neoplastic clone as well as directly impede differentiation, resulting in ineffective erythropoiesis and anemia. The improved efficiency of differentiation observed in spleen relative to bone marrow also suggests that microenvironmental influences modify the cell-intrinsic effects of oncogenic Ras.