TC-PTP–deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-γ
| Autor: | Annie Bourdeau, Karen M. Doody, Michel L. Tremblay, Nadia Dubé, Jean-François Théberge, Krista M. Heinonen |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_specialty
Stromal cell medicine.medical_treatment Immunology Bone Marrow Cells Models Biological Biochemistry Interferon-gamma Mice Internal medicine medicine Animals Homeostasis Interferon gamma Lymphopoiesis STAT1 Phosphorylation Cells Cultured Cell Proliferation Mice Knockout B-Lymphocytes Protein Tyrosine Phosphatase Non-Receptor Type 2 Hematology biology Interleukin-7 Cell Biology medicine.disease Leukemia STAT1 Transcription Factor medicine.anatomical_structure Cytokine Endocrinology biology.protein Cancer research Bone marrow Protein Tyrosine Phosphatases Stromal Cells Protein Kinases medicine.drug |
| Zdroj: | Blood. 109:4220-4228 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | The T-cell protein tyrosine phosphatase (TC-PTP) is a negative regulator of the Jak/Stat cytokine signaling pathway. Our study shows that the absence of TC-PTP leads to an early bone marrow B-cell deficiency characterized by hindered transition from the pre-B cell to immature B-cell stage. This phenotype is intrinsic to the B cells but most importantly due to bone marrow stroma abnormalities. We found that bone marrow stromal cells from TC-PTP−/− mice have the unique property of secreting 232-890 pg/mL IFN-γ. These high levels of IFN-γ result in 2-fold reduction in mitotic index on IL-7 stimulation of TC-PTP−/− pre-B cells and lower responsiveness of IL-7 receptor downstream Jak/Stat signaling molecules. Moreover, we noted constitutive phosphorylation of Stat1 in those pre-B cells and demonstrated that this was due to soluble IFN-γ secreted by TC-PTP−/− bone marrow stromal cells. Interestingly, culturing murine early pre-B leukemic cells within a TC-PTP–deficient bone marrow stroma environment leads to a 40% increase in apoptosis in these malignant cells. Our results unraveled a new role for TC-PTP in normal B lymphopoiesis and suggest that modulation of bone marrow microenvironment is a potential therapeutic approach for selected B-cell leukemia. |
| Databáze: | OpenAIRE |
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