Abstract
In summary, we reveal that STAT3 activity in patients carrying the P715L-STAT3 mutation can be modulated by either IL-6 stimulation or targeted inhibition. Furthermore, based on our findings in cell lines, P715L-STAT3 is not constitutively active in patients carrying the mutation.
In these patients, STAT3 interacts with proinflammatory binding partners. Finally, P715L-STAT3 GOF manifests with faster kinetic and prolonged STAT3 phosphorylation, causing deviated STAT5 activity in our in vitro model of hematopoiesis.
This imbalance in STATs' activity suppresses erythropoietic capacity as evidenced by low erythropoietic potential of peripheral CD342 precursors. The chronic state of severe anemia seen in P1 was accompanied by oligoclonal lymphoid infiltrates in the BM.
This observation, together with successful treatment of pure red cell aplasia using a combination of high-dose methylprednisolone, IL-6R inhibitor, and cyclosporine A after the use of a JAK inhibitor, shows that this chronic state of severe anemia can be reversed. This indicates that erythropoiesis in patients with STAT3 GOF mutations is a system under strain, in which inflammatory triggers may unbalance erythroid differentiation and suppress proliferative capacity of red blood cell precursors, rendering patients less able to respond with stress erythropoiesis.