Janus kinase 2 (V617F) mutation status, signal transducer and activator of transcription-3 phosphorylation and impaired neutrophil apoptosis in myelofibrosis with myeloid metaplasia

An activating point mutation in Janus kinase 2 (JAK2 V617F) was recently identified in myelofibrosis with myeloid metaplasia (MMM). To further elucidate the pathogenic significance, we examined the JAK2 mutation burden, phosphorylation of JAK2 substrates and neutrophil apoptotic resistance. Immunobl...

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Bibliographic Details
Published in:	Leukemia Vol. 20; no. 10; pp. 1800 - 1808
Main Authors:	MESA, R. A, TEFFERI, A, LASHO, T. S, LOEGERING, D, MCCLURE, R. F, POWELL, H. L, DAI, N. T, STEENSMA, D. P, KAUIMANN, S. H
Format:	Journal Article
Language:	English
Published:	London Nature Publishing 01-10-2006 Nature Publishing Group
Subjects:	AKT protein Alleles Anemia Apoptosis Apoptosis - physiology Biological and medical sciences Cells, Cultured Cytokines Extracellular Signal-Regulated MAP Kinases - metabolism Granulocytes Hematologic and hematopoietic diseases Hematology Humans Immunoblotting Janus kinase Janus Kinase 2 Kinases Leukemia Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Leukocytes (neutrophilic) Medical schools Medical sciences Medicine Metaplasia Mutants Mutation Myelofibrosis Myeloid metaplasia Myeloproliferative diseases Neutrophils Neutrophils - enzymology Neutrophils - pathology Oncology Pathogenesis Phosphorylation Point Mutation Primary Myelofibrosis - genetics Primary Myelofibrosis - metabolism Primary Myelofibrosis - pathology Protein-Tyrosine Kinases - genetics Protein-Tyrosine Kinases - metabolism Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Stat3 protein STAT3 Transcription Factor - metabolism Stat5 protein Stem cells Substrates Transcription Tumor necrosis factor-TNF United States > US Phosphorylation Myelofibrosis Hematology JAK2 protein tyrosine kinase Granulocyte STAT3 Hemopathy myeloproliferative disorders Myeloproliferative syndrome Metaplasia Signal transduction Activator Cell death Transcription factor STAT3 JAK2-V617F myelofibrosis with myeloid metaplasia Genetics Mutation Neutrophil neutrophils Apoptosis
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Summary:	An activating point mutation in Janus kinase 2 (JAK2 V617F) was recently identified in myelofibrosis with myeloid metaplasia (MMM). To further elucidate the pathogenic significance, we examined the JAK2 mutation burden, phosphorylation of JAK2 substrates and neutrophil apoptotic resistance. Immunoblotting revealed phosphorylation of signal transducer and activator of transcription-3 (STAT3) in all four JAK2 with high V617F mutant allele burden and seven of eight with intermediate mutant allele burden, but only one of eight with wild-type JAK2 (P<0.001). In contrast, STAT5 phosphorylation was undetectable in patient MMM neutrophils; and phosphorylation of Akt and extracellular signal-regulated kinases (ERKs) failed to correlate with JAK2 mutation status. Apoptosis was lower in MMM neutrophils (median 41% apoptotic cells, n=50) compared to controls (median 66%, n=9) or other myeloproliferative disorder patients (median 53%, n=11; P=0.002). Apoptotic resistance in MMM correlated with anemia (P=0.01) and the JAK2-V617F (P=0.01). Indeed, apoptotic resistance was greatest in MMM neutrophils with high mutant allele burden (median 22% apoptosis, n=5) than with intermediate burden (median 39%, n=23) or wild-type JAK2 (median 47%, n=22; P=0.008). These results suggest that mutant JAK2 contributes to MMM pathogenesis by constitutively phosphorylating STAT3 and diminishing myeloid cell apoptosis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0887-6924 1476-5551
DOI:	10.1038/sj.leu.2404338