No 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.
Core binding factor (CBF) participates in specification of the hematopoietic stem cell and functions as a critical regulator of hematopoiesis. Translocation or point mutation of AML1, which encodes the DNA-binding subunit of CBF, plays a central role in the pathogenesis of acute myeloid leukemia and myelodysplasia. We characterized the translocation t(X;21)(p22.3;q22.1) in a patient with myelodysplasia that fuses AML1 to the novel partner gene Friend of GATA-2 (FOG2). The reciprocal gene fusions AML1-FOG2 and FOG2-AML1 are both expressed. AML1-FOG2, which fuses the DNA-binding domain of AML1 to most of FOG2, represses transcription from the promoter of a hematopoietic target of AML1. AML1-FOG2 retains a motif that recruits the corepressor C-terminal binding protein (CtBP) and both proteins associate in a protein complex. These results suggest a role for CtBP in AML1-FOG2 transcriptional repression and implicate coordinated disruption of the AML1 and GATA developmental programs in the pathogenesis of myelodysplasia.
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