| Activating PTPN11 mutants promote hematopoietic progenitor cell-cycle progression and survival. | |
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MedLine Citation:
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PMID: 18640765 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: Mutations in PTPN11, which encodes the protein tyrosine phosphatase Shp2, are commonly found in juvenile myelomonocytic leukemia (JMML). We hypothesized that PTPN11 mutations promote cell-cycle progression and confer enhanced survival to hematopoietic progenitors. MATERIALS AND METHODS: Murine bone marrow low-density mononuclear cells were transduced with pMIEG3, pMIEG3-WT Shp2, pMIEG3-Shp2D61Y, or pMIEG3-Shp2E76K followed by cell-cycle and survival functional analysis as well as biochemical analysis for key cell-cycle and programmed cell-death regulatory proteins. RESULTS: A higher proportion of hematopoietic progenitors bearing the gain-of-function Shp2 mutants were residing in the S or G2 phase of the cell cycle in response to low doses of granulocyte-macrophage colony-stimulating factor compared to cells transduced with empty vector (MIEG3) or with WT Shp2. Likewise, Shp2D61Y- or Shp2E76K-expressing hematopoietic cells demonstrated reduced apoptosis based on Annexin-V staining and produced increased progenitor colonies after 48 hours in minimal media compared to cells transduced with empty vector or WT Shp2. To differentiate enhanced survival vs hyperproliferation, cells were stained with PKH26 to distinguish undivided cells from divided progeny. Shp2D61Y- or Shp2E76K-expressing PKH26+ cells similarly demonstrated reduced apoptosis. Upon biochemical analysis, expression of Akt- and Erk-responsive cell-cycle and programmed cell-death regulatory proteins were altered, including increased levels of cyclin D1, Bcl2, and BclXL and reduced levels of p27, p21, and Bim. CONCLUSION: Collectively, these data demonstrate that gain-of-function Shp2 mutants promote hematopoietic progenitor cell-cycle progression and survival and imply that agents targeting the cell cycle or promoting apoptosis may have therapeutic potential in JMML. |
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Authors:
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Zhenyun Yang; Yiping Li; Fuqin Yin; Rebecca J Chan |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-07-21 |
Journal Detail:
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Title: Experimental hematology Volume: 36 ISSN: 0301-472X ISO Abbreviation: Exp. Hematol. Publication Date: 2008 Oct |
Date Detail:
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Created Date: 2008-10-16 Completed Date: 2008-12-03 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 0402313 Medline TA: Exp Hematol Country: Netherlands |
Other Details:
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Languages: eng Pagination: 1285-96 Citation Subset: IM |
Affiliation:
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Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bone Marrow Cells / cytology, physiology Cell Cycle / physiology* Cell Survival / physiology* Child Cyclins / genetics, physiology Flow Cytometry Gene Expression Regulation* Hematopoietic Stem Cells / cytology*, physiology* Humans Leukemia, Myelomonocytic, Acute / genetics Mice Mice, Inbred C57BL Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics*, physiology |
| Grant Support | |
ID/Acronym/Agency:
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R01 HL082981/HL/NHLBI NIH HHS; R01 HL082981-02/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cyclins; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 11; EC 3.1.3.48/Ptpn11 protein, mouse |
| Comments/Corrections | |
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