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Pathological interactions between hematopoietic stem cells and their niche revealed by mouse models of primary
Lilian Varricchio1, Annalisa Mancini, Anna Rita Migliaccio
1Department of Medicine, Division of Hematology/Oncology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1079, New York, NY 10029, USA Tel.: +1 212 241 6974 lilian.varricchio@mssm.edu.
Abstract:
Primary myelofibrosis (PMF) belongs to the Philadelphia-negative myeloproliferative neoplasms and is a hematological disorder caused by abnormal function of the hematopoietic stem cells. The disease manifests itself with a plethora of alterations, including anemia, splenomegaly and extramedullary hematopoiesis. Its hallmarks are progressive marrow fibrosis and atypical megakaryocytic hyperplasia, two distinctive features used to clinically monitor disease progression. In an attempt to investigate the role of abnormal megakaryocytopoiesis in the pathogenesis of PMF, several transgenic mouse models have been generated. These models are based either on mutations that interfere with the extrinsic (thrombopoietin and its receptor, MPL) and intrinsic (the GATA1 transcription factor) control of normal megakaryocytopoiesis, or on known genetic lesions associated with the human disease. Here we provide an up-to-date review on the insights into the pathobiology of human PMF achieved by studying these animal models, with particular emphasis on results obtained with Gata1(low) mice.
Insights
Transgenic mouse models reveal insights into primary myelofibrosis (PMF) pathogenesis. Studying these models, especially Gata1(low) mice, clarifies the role of abnormal megakaryocytopoiesis in this Philadelphia-negative myeloproliferative neoplasm.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Primary myelofibrosis (PMF) is a Philadelphia-negative myeloproliferative neoplasm.
- It involves abnormal hematopoietic stem cell function, leading to anemia, splenomegaly, and extramedullary hematopoiesis.
- Key features include progressive marrow fibrosis and atypical megakaryocytic hyperplasia.
Purpose of the Study:
- To review insights into PMF pathobiology using transgenic mouse models.
- To investigate the role of abnormal megakaryocytopoiesis in PMF pathogenesis.
- To highlight findings from Gata1(low) mouse models.
Main Methods:
- Generation of transgenic mouse models mimicking PMF.
- Models based on mutations affecting thrombopoietin/MPL or GATA1.
- Models incorporating genetic lesions associated with human PMF.
- Review of existing literature and data from these models.
Main Results:
- Transgenic models provide valuable tools for studying PMF.
- Abnormal megakaryocytopoiesis is a critical factor in PMF development.
- Gata1(low) mice offer specific insights into disease mechanisms.
Conclusions:
- Transgenic mouse models are instrumental in understanding PMF.
- Further research using these models can elucidate PMF pathobiology.
- Targeting megakaryocytopoiesis may offer therapeutic strategies for PMF.
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