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MLL-ENL inhibits polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells.

ABSTRACT: Stimulation of transcriptional elongation is a key activity of leukemogenic MLL fusion proteins. Here, we provide evidence that MLL-ENL also inhibits Polycomb-mediated silencing as a prerequisite for efficient transformation. Biochemical studies identified ENL as a scaffold that contacted the elongation machinery as well as the Polycomb repressive complex 1 (PRC1) component CBX8. These interactions were mutually exclusive in vitro, corresponding to an antagonistic behavior of MLL-ENL and CBX8 in vivo. CBX8 inhibited elongation in a specific reporter assay, and this effect was neutralized by direct association with ENL. Correspondingly, CBX8-binding-defective MLL-ENL could not fully activate gene loci necessary for transformation. Finally, we demonstrate dimerization of MLL-ENL as a neomorphic activity that may augment Polycomb inhibition and transformation.

SUBMITTER: Maethner E

PROVIDER: S-EPMC4124133 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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MLL-ENL inhibits polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells.

Maethner Emanuel E Garcia-Cuellar Maria-Paz MP Breitinger Constanze C Takacova Sylvia S Divoky Vladimir V Hess Jay L JL Slany Robert K RK

Cell reports 20130425 5

Stimulation of transcriptional elongation is a key activity of leukemogenic MLL fusion proteins. Here, we provide evidence that MLL-ENL also inhibits Polycomb-mediated silencing as a prerequisite for efficient transformation. Biochemical studies identified ENL as a scaffold that contacted the elongation machinery as well as the Polycomb repressive complex 1 (PRC1) component CBX8. These interactions were mutually exclusive in vitro, corresponding to an antagonistic behavior of MLL-ENL and CBX8 in ...[more]

PMID: 23623499

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