Idiopathic myelofibrosis (IM) is a chronic myeloproliferative disorder associated with increased numbers of CD34+ cells circulating in the peripheral blood (PB). To characterize these cells, we transplanted CD34+ or CD34− cells from either G-CSF mobilized PB or IM PB into NOD/SCID mice to test their hematopoietic stem cell function. IM CD34+ cells, but not CD34−, cells engrafted in NOD/SCID mice, demonstrating that IM PB CD34+ cells contain true bone marrow repopulating cells. Furthermore, the differentiation program of IM CD34+ cells was quite different than that of CD34+ cells isolated from normal donors receiving G-CSF. G-CSF mobilized PB CD34+ cells generated predominantly CD19+ cells (B-lymphocytes), while IM PB CD34+ cells generated predominantly myeloid cells as well as larger numbers of CD41+ cells (megakaryocytes), but few CD19+ cells. The molecular basis for this stem cell defect in IM remains poorly defined. We hypothesized that the High Mobility Group Gene, HMGA2, might play a role in the biogenesis of IM. HMGA2 is a nuclear protein, normally expressed only during embryonic and fetal development, which acts as an architectural transcription factor important in the growth and differentiation of cells of mesenchymal origin. It has been reported that this gene has a direct effect on chromatin configuration by promoting DNA relaxation and that it may control the transcriptional activities of several genes. Rearrangement of the HMGA2 gene has frequently been detected in human benign tumors of mesenchymal origin including lipomas and sarcomas. In addition, the gene has been shown to be overexpressed in squamous cell carcinomas of the oral cavity. Previous work has suggested that HMGA2 is overexpressed in the PB mononuclear cells of patients with IM at the mRNA level (

Andrieux, J. et al, Genes, Chromosomes & Cancer, 39: 82, 2004
). Since IM and polycythemia vera (PV) are hematological malignancies that originate at the level of the hematopoietic stem cell, we examined the expression of HMGA2 in CD34+ and CD34− cell fractions isolated from the PB of patients with IM and PV as well as G-CSF mobilized normal donors. Using Western Blotting, we were unable to detect HMGA2 protein in either G-CSF mobilized CD34+ or CD34− cells. By contrast, HMGA2 was clearly expressed in the CD34+ cell fraction, but not the CD34− fraction isolated from IM and PV patients. These data indicate that increased HMGA2 protein levels are unique to IM and PV CD34+ cells and that the aberrant expression of this gene in the CD34+ progenitor cells may contribute to the stem cell defect in these myeloproliferative disorders.

Topics:
genes, hmga2 protein, mobility, myelofibrosis, idiopathic, chronic, polycythemia vera, granulocyte colony-stimulating factor, recombinant granulocyte colony stimulating factor, benign neoplasms, cancer, cd19 antigens
2005, The American Society of Hematology
2004
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