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Loss of HIF-1α accelerates murine FLT-3ITD-induced myeloproliferative neoplasia.

Velasco, Talia LU ; Tornero Prieto, Daniel LU and Cammenga, Jörg LU (2015) In Leukemia 29(12). p.2366-2374
Abstract
Hypoxia-induced signaling is important for normal and malignant hematopoiesis. The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in quiescence and self-renewal of hematopoietic stem cells (HSCs) as well as leukemia-initiating cells (LICs) of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). We have investigated the effect of HIF-1α loss on the phenotype and biology of FLT-3(ITD)-induced myeloproliferative neoplasm (MPN). Using transgenic mouse models, we show that deletion of HIF-1α leads to an enhanced MPN phenotype reflected by higher numbers of white blood cells, more severe splenomegaly and decreased survival. The proliferative effect of HIF-1α loss is cell-intrinsic as shown by... (More)
Hypoxia-induced signaling is important for normal and malignant hematopoiesis. The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in quiescence and self-renewal of hematopoietic stem cells (HSCs) as well as leukemia-initiating cells (LICs) of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). We have investigated the effect of HIF-1α loss on the phenotype and biology of FLT-3(ITD)-induced myeloproliferative neoplasm (MPN). Using transgenic mouse models, we show that deletion of HIF-1α leads to an enhanced MPN phenotype reflected by higher numbers of white blood cells, more severe splenomegaly and decreased survival. The proliferative effect of HIF-1α loss is cell-intrinsic as shown by transplantation into recipient mice. HSCs loss and organ specific changes in number and percentage of long-term hematopoietic stem cells (LT-HSCs) were the most pronounced effects on a cellular level after HIF-1α deletion. Furthermore, we found a metabolic hyperactivation of malignant cells in the spleen upon loss of HIF-1α. Some of our findings are in contrary to what has been previously described for the role of HIF-1α in other myeloid hematologic malignancies and question the potential of HIF-1α as a therapeutic target.Leukemia accepted article preview online, 24 June 2015. doi:10.1038/leu.2015.156. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Leukemia
volume
29
issue
12
pages
2366 - 2374
publisher
Nature Publishing Group
external identifiers
  • pmid:26104662
  • wos:000366393900011
  • scopus:84949883363
ISSN
1476-5551
DOI
10.1038/leu.2015.156
language
English
LU publication?
yes
id
a7ebf8c1-5228-410e-a96b-eed8d4965e35 (old id 7478120)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26104662?dopt=Abstract
date added to LUP
2015-07-10 21:54:18
date last changed
2017-04-02 03:08:55
@article{a7ebf8c1-5228-410e-a96b-eed8d4965e35,
  abstract     = {Hypoxia-induced signaling is important for normal and malignant hematopoiesis. The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in quiescence and self-renewal of hematopoietic stem cells (HSCs) as well as leukemia-initiating cells (LICs) of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). We have investigated the effect of HIF-1α loss on the phenotype and biology of FLT-3(ITD)-induced myeloproliferative neoplasm (MPN). Using transgenic mouse models, we show that deletion of HIF-1α leads to an enhanced MPN phenotype reflected by higher numbers of white blood cells, more severe splenomegaly and decreased survival. The proliferative effect of HIF-1α loss is cell-intrinsic as shown by transplantation into recipient mice. HSCs loss and organ specific changes in number and percentage of long-term hematopoietic stem cells (LT-HSCs) were the most pronounced effects on a cellular level after HIF-1α deletion. Furthermore, we found a metabolic hyperactivation of malignant cells in the spleen upon loss of HIF-1α. Some of our findings are in contrary to what has been previously described for the role of HIF-1α in other myeloid hematologic malignancies and question the potential of HIF-1α as a therapeutic target.Leukemia accepted article preview online, 24 June 2015. doi:10.1038/leu.2015.156.},
  author       = {Velasco, Talia and Tornero Prieto, Daniel and Cammenga, Jörg},
  issn         = {1476-5551},
  language     = {eng},
  number       = {12},
  pages        = {2366--2374},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia},
  title        = {Loss of HIF-1α accelerates murine FLT-3ITD-induced myeloproliferative neoplasia.},
  url          = {http://dx.doi.org/10.1038/leu.2015.156},
  volume       = {29},
  year         = {2015},
}