Histone deacetylase inhibitors regulate the proteasomal degradation of oncoproteins Leukemogenesis is often linked to fusion proteins generated by chromosomal translocation products. Examples are AML1 ETO and PML RAR which contribute to the pathogenesis of acute myeloid leukemia (AML). The work presented here reveals the novel insight that the turnover of both AML1 ETO and PML RAR depends on the HDACi inducible ubiquitin conjugase UBCH8 and the ubiquitin ligase SIAH1. Beyond showing that HDACi promote the degradation of oncoproteins this work reveals that the ubiquitin ligase RLIM equally is a substrate for SIAH1. Thus a formerly unknown hierarchical order of ubiquitin ligases affects the ubiquitin proteasome system. Since constitutively activated mutant FMS like tyrosine kinase 3 (FLT3 ITD) causally contributes to leukemic transformation and is frequently found in conjunction with AML1 ETO and PML RAR in AML patients it was also tested whether HDACi attenuate FLT3 ITD. Indeed UBCH8 together with SIAH1 interact in a tyrosine phosphorylation dependent way with FLT3 ITD and promote its proteasomal degradation. Accordingly unstimulated wild type FLT3 is hardly affected by HDACi. Thus UBCH8 which has been implicated primarily in nuclear processes could be identified as a novel important HDACi inducible modulator of FLT3 ITD stability and leukemic cell survival. In summary I could demonstrate in various AML cell lines and heterologous expression systems that UBCH8 and SIAH1 physically interact with and target FLT3 ITD AML1 ETO PML RARα and RLIM for proteasomal degradation. This work furthermore provides a deeper understanding on how enzymes promoting proteasomal degradation are regulated and how they interact with each other as well as with their cancer relevant substrates. Conclusions presented here reveal novel biochemical mechanisms and molecular networks. In addition they have implications for translational research.