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The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis

Andrew G Muntean1, Jiaying Tan, Kajal Sitwala

  • 1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Cancer Cell
|June 15, 2010
PubMed

Insights

The study reveals that the polymerase associated factor complex (PAFc) directly interacts with MLL fusion proteins, which is crucial for their ability to activate gene transcription and drive leukemogenesis.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • Chromosomal rearrangements involving the MLL gene are common in infant acute leukemias.
  • MLL fusion proteins drive leukemogenesis through deregulated transcriptional activity, but the underlying mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the interaction between MLL fusion proteins and other cellular factors.
  • To elucidate the role of these interactions in MLL-mediated transcriptional activation and leukemogenesis.

Main Methods:

  • Co-immunoprecipitation assays to demonstrate direct interaction between MLL and PAFc.
  • RNA interference (RNAi) to knockdown PAFc expression.
  • Chromatin immunoprecipitation (ChIP) to assess MLL recruitment to target genes.
  • Functional assays assessing transcriptional activation and cellular immortalization.

Main Results:

  • MLL directly interacts with the polymerase associated factor complex (PAFc) via sequences flanking its CxxC domain.
  • PAFc enhances MLL and MLL-AF9 mediated transcriptional activation of the Hoxa9 gene.
  • Knockdown of PAFc impairs MLL fusion protein-mediated transcription and MLL recruitment to target loci.
  • Disruption of the MLL-PAFc interaction abrogates MLL-AF9 mediated cellular immortalization, a key step in leukemogenesis.

Conclusions:

  • The interaction between MLL fusion proteins and PAFc is essential for their oncogenic function.
  • PAFc plays a critical role in MLL-mediated transcriptional dysregulation and leukemogenesis.
  • Targeting the MLL-PAFc interaction may offer a therapeutic strategy for MLL-driven leukemias.

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