Ruxolitinib ameliorates progressive anemia and improves survival during episodes of emergency granulopoiesis in Fanconi C mice.

Fanconi anemia (FA) is an inherited disorder of DNA repair with hematologic manifestations that range from anemia to bone marrow failure to acute myeloid leukemia. In a murine model of FA (Fancc mice), we found bone marrow failure was accelerated by repeated attempts to induce emergency (stress) granulopoiesis, the process for granulocyte production during the innate immune response. Fancc mice exhibited an impaired granulocytosis response and died with profound anemia during repeated challenge. In the current study, we found erythropoiesis and serum erythropoietin decreased in Fancc and wild-type (Wt) mice as emergency granulopoiesis peaked. Serum erythropoietin returned to baseline during steady-state resumption, and compensatory proliferation of erythroid progenitors was associated with DNA damage and apoptosis in Fancc mice, but not Wt mice. The erythropoietin receptor activates Janus kinase 2 (Jak2), and we found treatment of Fancc mice with ruxolitinib (Jak1/2-inhibitor) decreased anemia, enhanced granulocytosis, delayed clonal progression and prolonged survival during repeated emergency granulopoiesis episodes. This was associated with a decrease in DNA damage and apoptosis in Fancc erythroid progenitors during this process. Transcriptome analysis of these cells identified enhanced activity of pathways for metabolism of reactive oxygen species, and decreased apoptosis- and autophagy-related pathways, as major ruxolitinib-effects in Fancc mice. In contrast, ruxolitinib influenced primarily pathways involved in proliferation and differentiation in Wt mice. Ruxolitinib is approved for treatment of myeloproliferative disorders and graft-versus-host disease, suggesting the possibility of translational use as a bone marrow protectant in FA.