Loss of HIF-1 alpha accelerates murine FLT-3(ITD)-induced myeloproliferative neoplasia
2015 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, no 12, 2366-2374 p.Article in journal (Refereed) PublishedText
Hypoxia-induced signaling is important for normal and malignant hematopoiesis. The transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha) has a crucial role in quiescence and self-renewal of hematopoietic stem cells (HSCs), as well as leukemia-initiating cells (LICs) of acute myeloid leukemia and chronic myeloid leukemia. We have investigated the effect of HIF-1 alpha loss on the phenotype and biology of FLT-3(ITD)-induced myeloproliferative neoplasm (MPN). Using transgenic mouse models, we show that deletion of HIF-1 alpha leads to an enhanced MPN phenotype reflected by an increased number of white blood cells, more severe splenomegaly and decreased survival. The proliferative effect of HIF-1 alpha loss is cell intrinsic as shown by transplantation into recipient mice. HSC loss and organ-specific changes in the number and percentage of long-term HSCs were the most pronounced effects on a cellular level after HIF-1 alpha deletion. Furthermore, we found a metabolic hyperactivation of malignant cells in the spleen upon loss of HIF-1 alpha. Some of our findings are in contrary to what has been previously described for the role of HIF-1 alpha in other myeloid hematologic malignancies and question the potential of HIF-1 alpha as a therapeutic target.
Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2015. Vol. 29, no 12, 2366-2374 p.
IdentifiersURN: urn:nbn:se:liu:diva-123766DOI: 10.1038/leu.2015.156ISI: 000366393900011PubMedID: 26104662OAI: oai:DiVA.org:liu-123766DiVA: diva2:892967
Funding Agencies|Barncancerfonden; Cancerfonden; SSF through the Hemato-Linne and StemTherapy consortium (Sweden); Barncancerfonden (Sweden)2016-01-112016-01-112016-03-30