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

• 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
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2404338

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.