Pathological interactions between hematopoietic stem cells and their niche revealed by mouse models of primary myelofibrosis

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.

Keywords::

• animal model
• GATA1
• hematopoietic stem cell
• megakaryocyte
• primary myelofibrosis
• transcription factor

Financial & competing interests disclosure

This study was supported by Ministero per la Ricerca Scientifica and Alleanza sul Cancro, Italy and the National Cancer Institute, grant number P01-CA108671, NIH, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance was utilized in the production of this manuscript. The editorial help of Thomas Hayes is gratefully acknowledged.