Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein.

Yang G, Thompson MA, Brandt SJ, Hiebert SW
Oncogene. 2007 26 (1): 91-101

PMID: 16799637 · DOI:10.1038/sj.onc.1209760

The t(8;21) chromosomal translocation that generates the fusion oncoprotein RUNX1-ETO predominates in leukemia patients of the French-American-British (FAB) class M2 subtype. The oncoprotein has the capacity to promote expansion of hematopoietic stem/progenitor cells and induces leukemia in association with other genetic alterations. Here, we show that RUNX1-ETO undergoes degradation in response to treatment with histone deacetylase inhibitors, one of which, depsipeptide (DEP), is currently undergoing phase II clinical testing in a variety of malignancies. These compounds induce turnover of RUNX1-ETO without affecting the stability of RUNX1-ETO partner proteins. In addition, RUNX1-ETO physically interacts with heat shock protein 90 (HSP90). DEP treatment interrupts the association of RUNX1-ETO with HSP90 and induces proteasomal degradation of RUNX1-ETO. DEP and the HSP90 antagonist 17-allylamino-geldanamycin (17-AAG) both triggered RUNX1-ETO degradation, but without any additive or cooperative effects. These findings may stimulate the development of more rational and effective approaches for treating t(8;21) patients using histone deacetylase inhibitors or HSP90 inhibitors.

MeSH Terms (14)

Cell Line, Tumor Chromosomes, Human, Pair 8 Chromosomes, Human, Pair 21 Core Binding Factor Alpha 2 Subunit DNA-Binding Proteins Enzyme Inhibitors Histone Deacetylase Inhibitors Humans Hydrolysis Immunoprecipitation Proto-Oncogene Proteins RUNX1 Translocation Partner 1 Protein Transcription Factors Translocation, Genetic

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