STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia
| Autor: | Kathy L. McGraw, Satu Mustjoki, Mikkael A. Sekeres, Hideki Makishima, Thomas L. Olson, Eric D. Hsi, Andres Jerez, Lisa Durkin, Bartlomiej P Przychodzen, Hanna Koskela, Kathryn M Guinta, Marcin W. Wlodarski, Manuel G. Afable, Michael J. Clemente, Kwok Peng Ng, Francis R LeBlanc, Dan Zhang, Thomas P. Loughran, Alan F. List, Jaroslaw P. Maciejewski, Kimmo Porkka, Inés Gómez-Seguí |
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| Rok vydání: | 2012 |
| Předmět: |
Adult
Male STAT3 Transcription Factor Large granular lymphocytic leukemia Blotting Western Immunology Lymphoproliferative disorders Apoptosis Enzyme-Linked Immunosorbent Assay Biology Gene mutation Real-Time Polymerase Chain Reaction Biochemistry Pathogenesis Young Adult Biomarkers Tumor medicine Humans Cytotoxic T cell RNA Messenger T-Cell Large Granular Lymphocyte Leukemia Aged Cell Proliferation Oligonucleotide Array Sequence Analysis Aged 80 and over Lymphoid Neoplasia Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling Cell Biology Hematology Middle Aged Flow Cytometry medicine.disease Lymphoproliferative Disorders Killer Cells Natural Leukemia Large Granular Lymphocytic Gene expression profiling Leukemia Mutation Female T-Lymphocytes Cytotoxic |
| Zdroj: | Blood. 120:3048-3057 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs) and T-cell large granular lymphocytic leukemias (T-LGLs) are clonal lymphoproliferations arising from either natural killer cells or cytotoxic T lymphocytes (CTLs). We have investigated for distribution and functional significance of mutations in 50 CLPD-NKs and 120 T-LGL patients by direct sequencing, allele-specific PCR, and microarray analysis. STAT3 gene mutations are present in both T and NK diseases: approximately one-third of patients with each type of disorder convey these mutations. Mutations were found in exons 21 and 20, encoding the Src homology 2 domain. Patients with mutations are characterized by symptomatic disease (75%), history of multiple treatments, and a specific pattern of STAT3 activation and gene deregulation, including increased expression of genes activated by STAT3. Many of these features are also found in patients with wild-type STAT3, indicating that other mechanisms of STAT3 activation can be operative in these chronic lymphoproliferative disorders. Treatment with STAT3 inhibitors, both in wild-type and mutant cases, resulted in accelerated apoptosis. STAT3 mutations are frequent in large granular lymphocytes suggesting a similar molecular dysregulation in malignant chronic expansions of NK and CTL origin. STAT3 mutations may distinguish truly malignant lymphoproliferations involving T and NK cells from reactive expansions. |
| Databáze: | OpenAIRE |
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