Serotonin Targeting Using Common Antidepressants Induces Rapid Recovery of Cytopenia

Background. Hematopoiesis is a highly regulated system where multiple, yet undiscovered, factors orchestrate the self-renewal of bone marrow stem cells and their differentiation into blood cells. Following acute stresses like infections, inflammation, chemotherapy or radiation, the hematopoietic system quickly adapts by a process termed "emergency" or "stress" hematopoiesis. For instance, switches from steady state to emergency granulopoiesis or emergency erythropoiesis have been described in response to infection or bleeding. We recently identified, both in human and murine erythroid progenitors, a functional cell-autonomous serotonergic network with pro-survival and proliferative functions. Furthermore, pharmacologic restoration of serotonin levels using selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, a common antidepressant, was demonstrated to rescue the anemic phenotype in mice models. Here, we hypothesized that serotonin also has a role on other hematopoietic lineages, and that the serotonergic system could be a valuable therapeutic target in radiation or chemotherapy-induced cytopenia. Moreover, as our previous work suggested a cross-talk between serotonin and erythropoietin, we postulate that serotonin could act in cooperation with known hematopoietic growth factors. Material and method. For mice models, we submitted C57BL/6 wild-type 8-10 weeks old mice to sub-lethal irradiation and monitored hematopoietic recovery through complete blood counts. We compared mice treated with fluoxetine administrated orally (~ 20 mg/kg/day in drinking water) to a control group, with or without hematopoietic growth factors. For the retrospective human cohort, we used a computerized database to identify patients who underwent autologous hematopoietic stem cell transplantation (ASCT) in the adult hematology department of Necker hospital between 2008 and 2018. We compared 22 patients treated with an SSRI to 66 controls, matched according to number of injected CD34+ cells/kg, age, sex, conditioning chemotherapy, pathology, depth of response before transplantation, previous lines of chemotherapy, and year of transplantation. The study was conducted according to the Declaration of Helsinki. Results. First, we confirmed that, following sub-lethal irradiation, pharmacologic restoration of 5-HT levels in mice using fluoxetine improved normalization of the erythroid lineage (at day 17 post-irradiation, mean hemoglobin was 8.1 versus 2.8 g/dL in the fluoxetine versus control group (p=0.0002)). Second, the data revealed that the use of SSRI lead to a more rapid restoration of the leukocytes and platelets levels (at day 17 post-irradiation, mean leukocyte level was 1740 versus 314/mm3 (p Third, we observed an additive effect between fluoxetine and Granulocyte-Colony Stimulating Factor (G-CSF) on the recovery of the three myeloid lineages (at day 17 post-irradiation, mean hemoglobin was 10.5 versus 4.0 g/dL (p Finally, analysis of the in vivo murine model under steady state condition showed that without any hematopoietic stress, fluoxetine did not impact hematopoiesis. In human, analysis of the retrospective ASCT cohort demonstrated that patients treated with SSRI had a more rapid neutrophil recovery than matched control patients (mean duration of neutropenia Conclusion. In this work, we report a previously unknown role of SSRI in the hematopoietic recovery of cytopenia, both after sub-lethal irradiation in mice and after autologous hematopoietic stem cell transplantation in human. We also observed a significant cooperation between SSRI and G-CSF on the three myeloid lineages. We propose that the serotonergic system could be a valuable therapeutic target in stress hematopoiesis such as in therapy-induced aplasia in patients. Disclosures Hermine: AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene: Research Funding; Novartis: Research Funding. OffLabel Disclosure: Fluoxetine is a selective serotonin reuptake inhibitor for oral administration. It is an antidepressant approved for major depressive disorder, obsessive compulsive disorder, bulimia nervosa and panic disorder. We believe its role on serotonin can improve hematopoiesis.