The role of the leukemia-associated ETO homologue repressors in hematopoiesis

The fusion protein AML1-ETO is observed in acute myeloid patients with the chromosomal translocation t(8;21). Cells with this chimeric protein have impaired granulocytic and erythroid differentiation with accumulation of myeloblasts. The transcriptional co-repressor ETO (Eight Twenty One) was identified from the cloning of AML1-ETO. Subsequently, MTGR1 (Myeloid Translocation Gene-Related protein 1) and MTG16 (Myeloid Translocation Gene on chromosome 16) were found to be homologues to ETO, all these proteins being transcriptional co-repressors present in complexes together with other co-repressors such as SIN3, N-CoR and SMRT, and histone deacetylases. The objective of this thesis was to investigate the role of the ETO-homologues in hematopoiesis and leukemia. First, the finding of physical interactions between ETO homologues suggested a possible cooperation. Second, a ubiquitous expression was observed for MTGR1 and MTG16 in hematopoietic lineages. We also discovered that the expression of ETO was restricted to the erythroid lineage suggesting a role for ETO in erythroid development. Furthermore, we found that MTG16 was downregulated during erythroid and granulocytic differentiation, which also implements a role for MTG16 in the regulation of hematopoietic differentiation. Additionally, cells expressing AML1-ETO showed downregulation of MTG16, which possibly can contribute to the impaired differentiation of these cells. Finally, we studied the transcriptional repression of the ETO-homologues in a reporter gene system. MTG16 was found to be a potent co-repressor. Despite a physical interaction, the co-repressors N-CoR and hSIN3B did not augment MTG16-mediated repression. Collectively, our data suggests that the ETO homologues may have differential roles in the regulation of hematopoietic differentiation.

Grantor dc:publisher

Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University

Year dc:date

2006

Author dc:creator

• Olsson, André

• Hematology
• MTGR1
• ETO
• MTG16
• AML1-ETO
• hematopoiesis
• leukemia
• diffferentiation
• extracellular fluids
• Haematology
• Medicin (människa och djur)
• extracellulära vätskor
• Hematologi
• Medicine (human and vertebrates)

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

urn:isbn:91-85559-49-0

OAI identifier oai:identifier

oai:lup.lub.lu.se:849623b6-f75d-4602-8b98-d3368b075c72