The efficacy of hypoxia-inducible factor prolyl hydroxylase inhibitor AND017 in NUP98-HOXD13transgenic mouse

Abstract

Abstract Introduction Most of patients with myelodysplastic syndromes/neoplasms (MDS) exhibit variable degrees of anemia at diagnosis, primarily due to ineffective erythropoiesis. Therapeutic strategies that ameliorate anemia and reduce transfusion dependence could enhance quality of life and improve survival of MDS patients. AND017 is a new kind of hypoxia-inducible factor prolyl hydroxylase (PHD) inhibitors, while the efficacy and mechanism to improve anemia in MDS is unclear. In the study, we aimed to evaluate the efficacy and explore the specific mechanism of AND017 in a MDS mouse model, NUP98-HOXD13 (NHD13) transgenic mouse. Methods Age-matched NHD13 MDS mice were randomly assigned to two groups, which were orally dosed three times per week with vehicle and AND017 respectively. Erythroid progenitors and erythroblasts in different stages were measured by flow cytometric analysis. Erythroid-committed progenitor (ErP, Lineage−c-kit+Sca1− CD34−Fcγ−CD71+CD41-) cells from two groups were sorted to perform transcriptome sequencing and bioinformatics analysis. Results After two-week administration of AND017 or vehicle, NHD13 mice in AND017 group showed significantly higher hemoglobin, higher red blood cell count, larger mean corpuscular volume and higher reticulocyte count than those in vehicle group (P < 0.0001). In AND017 group, the hemoglobin of each NHD13 mice after two-week administration of AND017 elevated 8.97%-45.96%(14-74g/L) compared with hemoglobin before treatment. As of now, NHD13 mice in the AND017 group have shown higher level of hemoglobin compared to those in the vehicle group for at least the past 4 months (all P < 0.05), while overall survival of two groups showed no significant difference.After two-week administration of AND017, the percentage of basophilic erythroblasts significantly decreased, while orthochromatic erythroblasts and reticulocytes increased in bone marrow and spleen compared to the vehicle group. In the bone marrow of AND017 group, the frequency of ErPs within megakaryocyte-erythroid progenitor cells was higher. Transcriptome sequencing of ErPs in the two groups exhibited that HIF-1, PI3K−Akt and apoptosis signaling pathway were significantly upregulated, while porphyrin metabolism, cell cycle，p53 signaling pathways and ferroptosis were downregulated in the AND017 group. Conclusions AND017 can significantly and sustainably improve anemia of NHD13 mice. It may play a certain role in regulating erythroid progenitors and can efficiently promote terminal erythroid differentiation in NHD13 mice, while the specific mechanism needs to be study further.