| First Author | Wichmann C | Year | 2010 |
| Journal | Blood | Volume | 116 |
| Issue | 4 | Pages | 603-13 |
| PubMed ID | 20430957 | Mgi Jnum | J:162798 |
| Mgi Id | MGI:4819905 | Doi | 10.1182/blood-2009-10-248047 |
| Citation | Wichmann C, et al. (2010) Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity. Blood 116(4):603-13 |
| abstractText | RUNX1/ETO, the fusion protein resulting from the chromosomal translocation t(8;21), is one of the most frequent translocation products in acute myeloid leukemia. Several in vitro and in vivo studies have shown that the homo-tetramerization domain of ETO, the nervy homology region 2 (NHR2), is essential for RUNX1/ETO oncogenic activity. We analyzed the energetic contribution of individual amino acids within the NHR2 to RUNX1/ETO dimer-tetramer transition and found a clustered area of 5 distinct amino acids with strong contribution to the stability of tetramers. Substitution of these amino acids abolishes tetramer formation without affecting dimer formation. Similar to RUNX1/ETO monomers, dimers failed to bind efficiently to DNA and to alter expression of RUNX1-dependent genes. RUNX1/ETO dimers do not block myeloid differentiation, are unable to enhance the self-renewal capacity of hematopoietic progenitors, and fail to induce leukemia in a murine transplantation model. Our data reveal the existence of an essential structural motif (hot spot) at the NHR2 dimer-tetramer interface, suitable for a molecular intervention in t(8;21) leukemias. |
