AML1-Evi-1 specifically transforms hematopoietic stem cells through fusion of the entire Evi-1 sequence to AML1.

Abstract

The t(3;21) chromosomal translocation seen in blastic crisis of chronic myeloid leukemia and secondary leukemias results in a formation of a chimeric protein AML1-Evi-1, which suppresses wild-type AML1 function. Loss of AML1 function causes expansion of hematopoietic progenitor cells, whereas it is not sufficient for the development of leukemia. To identify essential mechanisms through which AML1-Evi-1 exerts full leukemogenic potential, we introduced AML1-Evi-1 and its mutants in murine bone marrow cells, and evaluated their transforming activities by colony replating assays. The transforming activity of AML1-Evi-1 was lost when any of the known functional domains of Evi-1 was deleted from the chimeric protein, and forced expression of Evi-1 did not transform the AML1-deleted bone marrow cells. Unlike the MLL-ENL and AML1-ETO leukemia-related chimeric proteins, AML1-Evi-1 could transform only the hematopoietic stem cell fraction. Moreover, AML1-Evi-1-transformed cells show a cell-marker profile distinct from that of the cells transformed by AML1-ETO, which also suppresses AML1 function. Thus, leukemogenic activity of AML1-Evi-1 may be due to activation of molecular mechanisms distinct from those activated by MLL-ENL or AML1-ETO in the hematopoietic stem cell fractions.

• Authors: M Takeshita, M Ichikawa, E Nitta, S Goyama, T Asai, S Ogawa, S Chiba, M Kurokawa
• Journal: Leukemia (Leukemia) Vol. 22 Issue 6 Pg. 1241-9 (Jun 2008) ISSN: 1476-5551 [Electronic] England
• PMID: 18337762 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Core Binding Factor Alpha 2 Subunit
• DNA-Binding Proteins
• MDS1 and EVI1 Complex Locus Protein
• Mecom protein, mouse
• Oncogene Proteins, Fusion
• Transcription Factors
• Proto-Oncogene Proteins c-kit
• Cre recombinase
• Integrases

Topics

• Animals
• Blotting, Western
• Bone Marrow Cells (physiology)
• Cell Transformation, Neoplastic
• Core Binding Factor Alpha 2 Subunit (physiology)
• DNA-Binding Proteins (physiology)
• Flow Cytometry
• Hematopoietic Stem Cells
• Integrases (metabolism)
• MDS1 and EVI1 Complex Locus Protein
• Mice
• Mice, Inbred C57BL
• Mutation (genetics)
• Myeloid Progenitor Cells (physiology)
• NIH 3T3 Cells
• Oncogene Proteins, Fusion (physiology)
• Proto-Oncogene Proteins c-kit (metabolism)
• Proto-Oncogenes (physiology)
• Transcription Factors (physiology)