The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity

Myeloproliferative neoplasms (MPNs) are characterized by overproduction of myeloid lineage cells with frequent acquisition of oncogenic JAK2V617F kinase mutations. The molecular mechanisms that regulate energy requirements in these diseases are poorly understood. Transformed cells tend to rely on fe...

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Main Authors:	Reddy, Mamatha M., Fernandes, Margret S., Deshpande, Anagha, Weisberg, Ellen, Inguilizian, Haig V., Abdel-Wahab, Omar, Kung, Andrew L., Levine, Ross L., Griffin, James D., Sattler, Martin
Format:	Online
Language:	English
Published:	2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227767/

id	pubmed-3227767
recordtype	oai_dc
spelling	pubmed-32277672012-09-01 The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity Reddy, Mamatha M. Fernandes, Margret S. Deshpande, Anagha Weisberg, Ellen Inguilizian, Haig V. Abdel-Wahab, Omar Kung, Andrew L. Levine, Ross L. Griffin, James D. Sattler, Martin Article Myeloproliferative neoplasms (MPNs) are characterized by overproduction of myeloid lineage cells with frequent acquisition of oncogenic JAK2V617F kinase mutations. The molecular mechanisms that regulate energy requirements in these diseases are poorly understood. Transformed cells tend to rely on fermentation instead of more efficient oxidative phosphorylation for energy production. Our data in JAK2V617F-transformed cells show that growth and metabolic activity were strictly dependent on the presence of glucose. Uptake of glucose and cell surface expression of the glucose transporter Glut1 required the oncogenic tyrosine kinase. Importantly, JAK2V617F as well as active STAT5 increased the expression of the inducible rate-limiting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which controls glycolytic flux through 6-phosphofructo-1-kinase. PFKFB3 was required for JAK2V617F-dependent lactate production, oxidative metabolic activity and glucose uptake. Targeted knockdown of PFKFB3 also limited cell growth under normoxic and hypoxic conditions and blocked in vivo tumor formation in mice. Overall, these data suggest that inducible PFKFB3 is required for increased growth, metabolic activity and is regulated through active JAK2 and STAT5. Novel therapies that specifically block PFKFB3 activity or expression would therefore be expected to inhibit JAK2/STAT5-dependent malignancies and related cancers. 2011-08-23 2012-03 /pmc/articles/PMC3227767/ /pubmed/21860432 http://dx.doi.org/10.1038/leu.2011.225 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Reddy, Mamatha M. Fernandes, Margret S. Deshpande, Anagha Weisberg, Ellen Inguilizian, Haig V. Abdel-Wahab, Omar Kung, Andrew L. Levine, Ross L. Griffin, James D. Sattler, Martin
spellingShingle	Reddy, Mamatha M. Fernandes, Margret S. Deshpande, Anagha Weisberg, Ellen Inguilizian, Haig V. Abdel-Wahab, Omar Kung, Andrew L. Levine, Ross L. Griffin, James D. Sattler, Martin The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity
author_facet	Reddy, Mamatha M. Fernandes, Margret S. Deshpande, Anagha Weisberg, Ellen Inguilizian, Haig V. Abdel-Wahab, Omar Kung, Andrew L. Levine, Ross L. Griffin, James D. Sattler, Martin
author_sort	Reddy, Mamatha M.
title	The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity
title_short	The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity
title_full	The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity
title_fullStr	The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity
title_full_unstemmed	The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity
title_sort	jak2v617f oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity
description	Myeloproliferative neoplasms (MPNs) are characterized by overproduction of myeloid lineage cells with frequent acquisition of oncogenic JAK2V617F kinase mutations. The molecular mechanisms that regulate energy requirements in these diseases are poorly understood. Transformed cells tend to rely on fermentation instead of more efficient oxidative phosphorylation for energy production. Our data in JAK2V617F-transformed cells show that growth and metabolic activity were strictly dependent on the presence of glucose. Uptake of glucose and cell surface expression of the glucose transporter Glut1 required the oncogenic tyrosine kinase. Importantly, JAK2V617F as well as active STAT5 increased the expression of the inducible rate-limiting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which controls glycolytic flux through 6-phosphofructo-1-kinase. PFKFB3 was required for JAK2V617F-dependent lactate production, oxidative metabolic activity and glucose uptake. Targeted knockdown of PFKFB3 also limited cell growth under normoxic and hypoxic conditions and blocked in vivo tumor formation in mice. Overall, these data suggest that inducible PFKFB3 is required for increased growth, metabolic activity and is regulated through active JAK2 and STAT5. Novel therapies that specifically block PFKFB3 activity or expression would therefore be expected to inhibit JAK2/STAT5-dependent malignancies and related cancers.
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227767/
_version_	1611491090190303232

The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity

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