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The interaction of ENL with PAF1 mitigates polycomb silencing and facilitates murine leukemogenesis

Katrin Hetzner, Maria-Paz Garcia-Cuellar, Christian Büttner and Robert K. Slany

Key points

  • The MLL fusion partner ENL engages PAF1 to induce anti-silencing H2B ubiquitination.

  • YEATS domain mutations or fusion with MLL increases affinity for PAF1 and transforms hematopoietic cells.

Abstract

ENL is a chromatin reader present in complexes stimulating transcriptional elongation. It is fused to MLL in leukemia and missense mutations have been identified in Wilms' tumor and AML. Here we demonstrate that ENL overcomes polycomb silencing through recruitment of PAF1 via the conserved YEATS domain that recognizes acetylated histone H3. PAF1 was responsible for anti-repressive activities of ENL in vitro and it determined the transforming potential of MLL-ENL. MLL-ENL target loci showed supraphysiological PAF1 binding, hyper-ubiquitination of histone H2B and hypomodification with H2AUb resulting in accelerated transcription rates. YEATS mutations induced a gain-of-function transforming primary hematopoietic cells in vitro and in transplantation assays through aberrant transcription and H2B ubiquitination of Hoxa9 and Meis1. Mechanistically, H3 and PAF1 competed for ENL interaction, with activating mutations favoring PAF1-binding whereas the MLL moiety provided a constitutive PAF1 tether allowing MLL-fusions to circumvent H3 competition.

  • Submitted November 8, 2017.
  • Accepted December 1, 2017.