Gfi1 as a Regulator of Hematopoietic Differentiation
| Autor: | Haiming Xu, Shane R. Horman, David A. Williams, Brian Gebelein, Aditya Chaubey, William E. Paul, Tristan Bourdeau, Chinavenmeni S. Velu, Jinfang Zhu, Clemencia Colmenares, H. Leighton Grimes |
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| Rok vydání: | 2008 |
| Předmět: |
Myeloid
Growth factor medicine.medical_treatment Immunology T-Cell Transformation Mutagenesis (molecular biology technique) Cell Biology Hematology Biology Biochemistry Haematopoiesis medicine.anatomical_structure medicine Cancer research Signal transduction Congenital Neutropenia Transcription factor |
| Zdroj: | Blood. 112:sci-16 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Growth Factor Independent-1 (Gfi1) is a transcriptional repressor originally identified as a target of Moloney leukemia virus insertion mutagenesis. Gfi1 potently collaborates with Myc and Pim oncogenes to mediate T cell transformation. Retroviral insertions which activate Gfi1 are among the most frequent events in MoMLV-induced T cell, but not myeloid, leukemias. Orthologous proteins in Drosophila (Senseless) and C.elegans (Pag-3) are key regulators of developmental decisions. Gfi1−/− mice display lymphopenia, neutropenia, and abnormally proliferative HSC and progenitors which eventually lead to bone marrow failure. Humans with bone marrow failure syndromes, such as Severe Congenital Neutropenia or Non-Immune Chronic Idiopathic Neutropenia of Adults, display mutations in GFI1, which produce dominant negative acting GFI1 proteins. The SCN-associated GFI1N382S mutant proteins derepress a subset of GFI1 target genes, including CSF1 and CSF1R, to block granulopoeisis. Normally, Gfi1 antagonizes monopoiesis mediated by Pu.1, Egr1, Egr2, and Nab2. Thus, Gfi1 loss of function may impair granulopoiesis by failing to successfully repress monopoeitic differentiation. GFI1 dysfunction may also underlie Specific Granule Deficiency. GFI1 is able to synergize with C/EBP transcription factors to activate genes, such as neutrophil collagenase. Gfi1 may, therefore, enhance granulopoietic differentiation through C/EBP factors. Though great progress has been made in understanding Gfi1 biological and biochemical functions, we are only beginning to understand the role of Gfi1 in integrating hematopoietic transcriptional programming. We find that Gfi1 signaling controls both the differentiation and transformation of myeloid progenitors through an evolutionarily conserved transcriptional and post-transcriptional network. |
| Databáze: | OpenAIRE |
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