1. Academic Validation
  2. Ruxolitinib ameliorates progressive anemia and improves survival during episodes of emergency granulopoiesis in Fanconi C-/- mice

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

  • Exp Hematol. 2022 May;109:55-67.e2. doi: 10.1016/j.exphem.2022.03.001.
Shirin Hasan 1 Liping Hu 1 Olatundun Williams 2 Elizabeth A Eklund 3
Affiliations

Affiliations

  • 1 Department of Medicine, Northwestern University, Chicago, IL.
  • 2 Lurie Children's Hospital, Chicago, IL.
  • 3 Department of Medicine, Northwestern University, Chicago, IL; Jesse Brown VA Medical Center, Chicago, IL. Electronic address: e-eklund@northwestern.edu.
Abstract

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.

Figures
Products