Development of myelofibrosis in mice genetically impaired for GATA-1 expression (GATA-1low mice)

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Abstract
The phenotype induced by the GATA-1low (neoδHS) mutation is here further characterized by analyzing the hemopoietic system during the aging (up to 20 months) of a GATA-1lowcolony (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-β1, 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-1low 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-1low mutants may represent a suitable animal model for the human disease that may shed light on its pathogenesis.