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Loss of HIF-1 alpha accelerates murine FLT-3(ITD)-induced myeloproliferative neoplasia
Lund University, Sweden.
Skånes University Hospital, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Lund University, Sweden; Skånes University Hospital, Sweden.
2015 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, no 12, 2366-2374 p.Article in journal (Refereed) PublishedText
Abstract [en]

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.
National Category
Hematology
Identifiers
URN: urn:nbn:se:liu:diva-123766DOI: 10.1038/leu.2015.156ISI: 000366393900011PubMedID: 26104662OAI: oai:DiVA.org:liu-123766DiVA: diva2:892967
Note

Funding Agencies|Barncancerfonden; Cancerfonden; SSF through the Hemato-Linne and StemTherapy consortium (Sweden); Barncancerfonden (Sweden)

Available from: 2016-01-11 Created: 2016-01-11 Last updated: 2016-03-30

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Cammenga, Jörg
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Division of Clinical SciencesFaculty of Medicine and Health SciencesDepartment of Haematology
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