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Trans-Repressive Effect of NUP98-PMX1 on PMX1-Regulated c-FOS Gene through Recruitment of Histone Deacetylase 1 by FG Repeats

State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China

Requests for reprints: Sai-Juan Chen or Ji Zhang, Shanghai Institute of Hematology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Rui Jin Road II, Shanghai 200025, P.R. China. Phone: 86-21-6437-7859; Fax: 86-21-6474-3206; E-mail: sjchen{at}stn.sh.cn or jizhang@sibs.ac.cn.

The formation of fusion genes between NUP98 and members of the HOX family represents a critical factor for the genesis of acute leukemia or acute transformation of chronic myeloid leukemia (CML). To gain insights into the molecular mechanisms underlying the leukemogenesis of NUP98-HOX fusion products, we cloned NUP98-PMX1 from a CML-blast crisis patient with t(1;11) as a secondary chromosomal translocation, and functionally studied the fusion products in detail through various molecular and protein biochemical assays. In addition to many interesting features, we have found that the NUP98-PMX1 fusion protein exerts a repressive effect on PMX1 or serum response factor–mediated c-FOS activation, probably through the recruitment of a common corepressor histone deacetylase 1 by FG domains of the NUP98-PMX1 fusion protein. Moreover, we have provided evidence that the FG domains of NUP98-PMX1 and two other NUP98-containing fusion proteins, i.e., NUP98-HOXA9 and NUP98-HOXC11, all exhibit dual binding ability to both CREB binding protein, a coactivator, and histone deacetylase 1, a corepressor. Accordingly, we have hypothesized that this dual binding activity is shared by most, if not all, NUP98-HOX-involved fusion proteins, enabling these fusion proteins to act as both trans-activators and trans-repressors, and contributing to the genesis of acute leukemia or acute transformation of CML. (Cancer Res 2006; 66(9): 4584-90)

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