Development of myelofibrosis in mice genetically impaired for GATA-1 expression (GATA-1(low) mice).
The phenotype induced by the GATA-1(low) (neodeltaHS) mutation is here further characterized by analyzing the hemopoietic system during the aging (up to 20 months) of a GATA-1(low) colony (135 mutants and 40 normal littermates). Mutants expressed normal hematocrit values (Hct = 45.9 +/- 4.0) until 12 months but became anemic from 15 months on (Hct = 30.9 +/- 3.9; P <.05). Anemia was associated with several markers of myelofibrosis such as the presence of tear-drop poikilocytes and progenitor cells in the blood, collagen fibers in the marrow and in the spleen, and hemopoietic foci in the liver. Semiquantitative reverse transcription-polymerase chain reaction showed that growth factor genes implicated in the development of myelofibrosis (such as osteocalcin, transforming growth factor-beta1, platelet-derived growth factor, and vascular endothelial growth factor) were all expressed in the marrow from the mutants at higher levels than in corresponding normal tissues. The GATA-1(low) mutants experienced a slow progression of the disease because the final exitus was not observed until at least 15 months with a probability of survival more favorable than that of W/Wv mice concurrently kept in the animal facility (P <.001, by Kaplan-Meier analysis). In conclusion, impaired GATA-1 expression may contribute to the development of myelofibrosis, and the GATA-1(low) mutants may represent a suitable animal model for the human disease that may shed light on its pathogenesis.
Vannucchi
Alessandro Maria
AM
Department of Ematologia, University of Florence, Italy.
Bianchi
Lucia
L
Cellai
Cristina
C
Paoletti
Francesco
F
Rana
Rosa Alba
RA
Lorenzini
Rodolfo
R
Migliaccio
Giovanni
G
Migliaccio
Anna Rita
AR
D000740:Anemia / Q000097:blood / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000737:chemistry; D003094:Collagen / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D016228:Endothelial Growth Factors / Q000235:genetics; D004912:Erythrocytes / Q000473:pathology; D015672:Erythroid Precursor Cells; D050981:Erythroid-Specific DNA-Binding Factors; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000235:genetics; D050982:GATA1 Transcription Factor; D015870:Gene Expression; D006400:Hematocrit; D006411:Hematopoiesis, Extramedullary; D008099:Liver / Q000473:pathology; D008222:Lymphokines / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D015675:Osteocalcin / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000737:chemistry; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016220:Fibroblast Growth Factor 1; D015675:Osteocalcin; D003094:Collagen