Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity

作者：Wichmann Christian^*; Becker Yvonne; Chen Wichmann Linping; Vogel Vitali; Vojtkova Anna; Herglotz Julia; Moore Sandra; Koch Joachim; Lausen Joern; Maentele Werner; Gohlke Holger; Grez Manuel

来源：Blood, 2010, 116(4): 603-613.

DOI：10.1182/blood-2009-10-248047

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. (Blood. 2010; 116(4): 603-613)

• 出版日期2010-7-29