The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells Journal Article
| Authors: | Mulloy, J. C.; Cammenga, J.; Mackenzie, K. L.; Berguido, F. J.; Moore, M. A. S.; Nimer, S. D. |
| Article Title: | The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells |
| Abstract: | The acute myelogenous leukemia-1 (AML1)-ETO fusion protein is generated by the t(8;21), which is found in 40% of AMLs of the French-American-British M2 subtype. AML1-ETO interferes with the function of the AML1 (RUNX1, CBFA2) transcription factor in a dominant-negative fashion and represses transcription by binding its consensus DNA-binding site and via protein-protein interactions with other transcription factors. AML1 activity is critical for the development of definitive hematopoiesis, and haplo insufficiency of AML1 has been linked to a propensity to develop AML. Murine experiments suggest that AML1-ETO expression may not be sufficient for leukemo genesis; however, like the BCR-ABL isoforms, the cellular background in which these fusion proteins are expressed may be critical to the phenotype observed. Retroviral gene transfer was used to examine the effect of AML1-ETO on the in vitro behavior of human hematopoietic stem and progenitor cells. Following transduction of CD34+ cells, stem and progenitor cells were quantified in clonogenic assays, cytokine-driven expansion cultures, and long-term stromal cocultures. Expression of AML1-ETO inhibited colony formation by committed progenitors, but enhanced the growth of stem cells (cobblestone area-forming cells), resulting in a profound survival advantage of transduced over nontransduced cells. AML1-ETO-expressing cells retained progenitor activity and continued to express CD34 throughout the 5-week long-term culture. Thus, AML1-ETO enhances the self-renewal of pluripotent stemcells, the physiological target of many acute myeloid leukemias. © 2002 by The American Society of Hematology. |
| Keywords: | acute granulocytic leukemia; human cell; nonhuman; flow cytometry; animals; mice; bone marrow cells; cell survival; cell division; cd34 antigen; gene expression; protein protein interaction; green fluorescent protein; cell line; transfection; genetic vectors; luminescent proteins; transcription factors; cytokines; acute leukemia; hybrid protein; leukemia cell; leukemogenesis; oncogene proteins, fusion; retrovirus vector; hematopoietic stem cells; chromosome translocation; green fluorescent proteins; hematopoiesis; hematopoietic stem cell; dna binding; colony-forming units assay; stromal cells; antigens, cd34; retroviridae; core binding factor alpha 2 subunit; coculture techniques; humans; human; priority journal; article; colony forming unit c |
| Journal Title: | Blood |
| Volume: | 99 |
| Issue: | 1 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2002-01-01 |
| Start Page: | 15 |
| End Page: | 23 |
| Language: | English |
| DOI: | 10.1182/blood.V99.1.15 |
| PUBMED: | 11756147 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 14 November 2014 -- Source: Scopus |
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