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Stat5a serine 725 and 779 phosphorylation is a prerequisite for hematopoietic transformation
- Source :
- Blood, Blood, American Society of Hematology, 2010, 116 (9), pp.1548-1558, Blood, American Society of Hematology, 2010, 116 (9), pp.1548-1558. ⟨10.1182/blood-2009-12-258913⟩
- Publication Year :
- 2010
- Publisher :
- HAL CCSD, 2010.
-
Abstract
- International audience; Stat5 transcription factors are essential gene regulators promoting proliferation, survival, and differentiation of all hematopoietic cell types. Mutations or fusions of oncogenic tyrosine kinases often result in constitutive Stat5 activation. We have modeled persistent Stat5 activity by using an oncogenic Stat5a variant (cS5). To analyze the hitherto unrecognized role of Stat5 serine phosphorylation in this context, we have generated cS5 constructs with mutated C-terminal serines 725 and 779, either alone or in combination. Genetic complementation assays in primary Stat5(null/null) mast cells and Stat5(Delta N) T cells demonstrated reconstitution of proliferation with these mutants. Similarly, an in vivo reconstitution experiment of transduced Stat5(null/null) fetal liver cells transplanted into irradiated wild-type recipients revealed that these mutants exhibit biologic activity in lineage differentiation. By contrast, the leukemogenic potential of cS5 in bone marrow transplants de-creased dramatically in cS5 single-serine mutants or was completely absent upon loss of both serine phosphorylation sites. Our data suggest that Stat5a serine phosphorylation is a prerequisite for cS5-mediated leukemogenesis. Hence, interference with Stat5a serine phosphorylation might provide a new therapeutic option for leukemia and myeloid dysplasias without affecting major functions of Stat5 in normal hematopoiesis. (Blood. 2010;116(9):1548-1558)
- Subjects :
- Male
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology
Myeloid
T-Lymphocytes
Biochemistry
Immunoenzyme Techniques
Serine
Mice
0302 clinical medicine
STAT5 Transcription Factor
Mast Cells
Phosphorylation
Cells, Cultured
STAT5
Bone Marrow Transplantation
0303 health sciences
Leukemia
Myeloid Neoplasia
biology
Reverse Transcriptase Polymerase Chain Reaction
food and beverages
[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology
Hematology
Middle Aged
Flow Cytometry
Cell biology
Haematopoiesis
Cell Transformation, Neoplastic
medicine.anatomical_structure
030220 oncology & carcinogenesis
Female
Tyrosine kinase
Adult
Blotting, Western
Immunology
[SDV.CAN]Life Sciences [q-bio]/Cancer
03 medical and health sciences
Fetus
medicine
Animals
Humans
Cell Lineage
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
RNA, Messenger
Transcription factor
Aged
Cell Proliferation
030304 developmental biology
Precursor Cells, B-Lymphoid
Tumor Suppressor Proteins
Cell Biology
medicine.disease
Molecular biology
Hematopoiesis
Liver Transplantation
Mice, Inbred C57BL
biology.protein
Subjects
Details
- Language :
- English
- ISSN :
- 00064971 and 15280020
- Database :
- OpenAIRE
- Journal :
- Blood, Blood, American Society of Hematology, 2010, 116 (9), pp.1548-1558, Blood, American Society of Hematology, 2010, 116 (9), pp.1548-1558. ⟨10.1182/blood-2009-12-258913⟩
- Accession number :
- edsair.doi.dedup.....b4d1c5416b21904a9d4cd75067f3467b