Abstract
BackgroundFusion of the MOZ and TIF2 genes by an inv (8) (p11q13) translocation has been identified in patients with acute mixed-lineage leukemia. Characterization of the molecular structure of the MOZ-TIF2 fusion protein suggested that the fusion protein would effect on nuclear receptor signaling.ResultsA series of deletions from the N-terminus of the MOZ-TIF2 fusion protein demonstrated that the MOZ portion is essential for nuclear localization of the fusion protein. Transient expression of MOZ-TIF2 dramatically decreased both basal and estradiol inducible reporter gene activity in an estrogen receptor element (ERE) driven luciferase reporter system and decreased androgen-inducible reporter gene activity in an androgen receptor element (ARE) luciferase reporter system. Deletions in the MOZ portion of the MOZ-TIF2 fusion protein reduced the suppression in the ER reporter system. Stable expression of MOZ-TIF2 inhibited retinoic acid (RA) inducible endogenous CD11b and C/EBPβ gene response. The suppression of the reporter systems was released with either a CID domain deletion or with mutations of leucine-rich repeats in the TIF2 portion of MOZ-TIF2. The co-expression of TIF2, but not CBP, with MOZ-TIF2 partially restored the inhibition of the reporter systems. In addition, analysis of protein interactions demonstrated MOZ-TIF2 interaction with the C-terminus of CBP through both the MOZ and TIF2 portions of the fusion protein.ConclusionMOZ-TIF2 inhibited nuclear receptor-mediated gene response by aberrant recruitment of CBP and both the MOZ and TIF2 portions are required for this inhibition.
Highlights
Fusion of the MOZ and TIF2 genes by an inv (8) (p11q13) translocation has been identified in patients with acute mixed-lineage leukemia
We have previously identified by yeast twohybrid analysis and co-immunoprecipitation two human chromatin assembly factors, the p150 subunit of chromatin assembly factor (CAF) and anti-silencing function 1b (ASF1b), that interact with MOZ and the MOZ portion of the MOZ-TIF2 protein [18]
To address if the levels of transcription cofactors could be limiting in vivo, we examined the RNA expression of several transcription co-factors in leukemic blasts and found significant decreases in RNA expression of TIF2 and CBP in the cells of the patient with the MOZTIF2 fusion compared to levels in leukemic blasts from patients without the MOZ-TIF2 fusion (Figure 6)
Summary
Fusion of the MOZ and TIF2 genes by an inv (8) (p11q13) translocation has been identified in patients with acute mixed-lineage leukemia. The MOZ-TIF2 fusion protein consists of the N-terminus of MOZ and the C-terminus of TIF2. Patients with these translocations often exhibit rapid progression and poor response to therapy. Various translocations involving MOZ have been described such as MOZ-CBP (cAMPresponse element binding protein t(8;16)(p11;p13), MOZ-P300 t(8;22)(p11;q13), and MOZ-TIF2 (inv(8)(p11q13). In a pediatric patient with therapyrelated myelodysplastic syndrome a MOZ translocation was found between t(2;8)(p23;p11) [1,2,3,4,5,6,7,8].
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