Abstract
Although monocytic zinc finger protein (MOZ/MYST3) maintains normal hematopoietic stem cells, its fusion to the coactivator CREB-binding protein (CBP/CREBBP) induces acute myeloid leukemia (AML). Since leukemic stem cells in AML often exhibit excessive signal-dependent activity of the transcription factor NFκB, we hypothesized that cooperation between NFκB and MOZ-CBP represents an alternative mechanism for enhancing NFκB transcriptional activity. In reporter assays, MOZ and CBP separately induce transcription from the NFκB-dependent interleukin-8 promoter; however, these two proteins together markedly activate its expression. Although MOZ has less potent transcriptional activity than MOZ-CBP, both proteins cooperate with steroid receptor coactivator-1 (SRC1/NCOA1) to activate transcription. Since cooperation between MOZ-CBP and SRC1 is strongly reminiscent of the interaction between MOZ-TIF2/SRC2 and CBP required to induce AML (Deguchi et al, 2003), these findings suggest that MYST family fusion proteins may assemble a conserved leukemogenic transcriptional complex composed of a MYST protein (MOZ, MORF), molecular integrator (CBP, p300), and nuclear receptor coactivator (SRC1, TIF2/SRC2). MOZ also induces multiple NFκB-dependent viral promoters. Importantly, MOZ associates in a protein complex with the DNA-binding p65/RELA subunit of NFκB in vivo and interacts directly with p65 in vitro. Whereas deletion of the leukemia-associated protein (LAP/PHD) or MYST domains decreases the transcriptional activity of MOZ, deletion of either the acidic domain or C-terminal domain completely abrogates its activity. Since the C-terminal domain is absent from MOZ-CBP, these results indicate that the potent transcriptional activity of MOZ-CBP represents a gain-of-function property derived from the retained portion of CBP. Collectively, these studies not only demonstrate that MOZ and MOZ-CBP cooperate with NFκB to enhance expression of NFκB-dependent promoters but also suggest that aberrant interaction between MOZ-CBP and NFκB may play an important role in the pathogenesis of certain acute myeloid leukemias.
Author notes
Disclosure: Employment: Although he conducted this research as an employee of Indiana University, the presenting author, Dr. Edward M. Chan, is now an employee of Eli Lilly and Company.
