The role of prolyl hydroxylases in the function of leukaemic stem cells and the development of leukaemia

[摘要] Leukaemic stem cells (LSCs) are believed to have originated from haemopoietic stem cells (HSCs) or early progenitors, which reside within a hypoxic niche in the bone marrow. Hypoxic adaption in HSCs is mediated by hypoxia-inducible factor-1 (HIF-1), which, under hypoxic conditions, acts as a transcription factor to induce the expression of hypoxic response genes.Under normoxic conditions, HIF-α is targeted for degradation by Prolyl-4-hydroxylases (PHDs). HIF-1α has been shown to play an essential role in maintaining LSCs.Negative regulator PHD has been implicated in various forms of cancer, although the role of PHD in leukaemia has not been clarified. The overall aim of this study was to investigate the role of PHD isoforms in the transformation and function of LSCs. A mouse model lacking PHD isoforms was used (PHD KO), allowing the collection of PHD KO haemopoietic stem and progenitor cells (HSPCs). HSPCs were then transformed in vitro to produce pre-LSCs which were assessed for cellular function under optimal conditions, hypoxic conditions and in response to chemotherapy.This study has indicated that under optimal conditions pre-LSCs lacking PHD1, PHD2 or both PHD1 and PHD2 had a reduced growth rate. Pre-LSCs lacking PHD2 also showed a significant increase in apoptosis. Following treatment with chemotherapy or radiation, pre-LSCs lacking PHD1, PHD2 or PHD1 and PHD2 responded better to chemotherapy and radiation treatment and had an increased frequency of cell death. In vivo experiments were performed in which pre-LSCs were prepared and transplanted to lethally irradiated mice, allowing us to identify if the absence of PHD isoforms had an effect on the leukaemic potential of pre-LSCs. Overall we report that mice transplanted with WT pre-LSCs had impaired survival and developed leukaemia at a higher rate than mice transplanted with pre-LSCs lacking PHD1, PHD2 or PHD1 and PHD2. Overall these results indicate that PHD isoforms may play a role in the development of leukaemia and the response to treatment and warrants further investigation into the role of PHD in leukaemia.

[发布机构] University:University of Glasgow;Department:Institute of Cancer Sciences

[关键词] leukaemia, hypoxia, prolyl hydrylase, PHD, HIF