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MLL fusion protein-driven AML is selectively inhibited by targeted disruption of the MLL-PAFc interaction

Andrew G Muntean1, Wei Chen, Morgan Jones

  • 1Department of Pathology, Department of Medicine;

Blood
|August 1, 2013
PubMed

Insights

Targeting the mixed lineage leukemia (MLL)-polymerase-associated factor complex (PAFc) interaction selectively inhibits MLL-driven leukemia cell proliferation. This approach spares normal hematopoietic stem cell function, establishing the MLL-PAFc interaction as a promising therapeutic target.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cancer Research

Background:

  • Mixed lineage leukemia (MLL) rearrangements are frequent in leukemia and associated with poor prognosis.
  • MLL fusion proteins interact with the polymerase-associated factor complex (PAFc) to promote leukemogenesis by blocking cell differentiation.
  • Targeting the MLL-PAFc interaction presents a potential therapeutic strategy for MLL-associated leukemias.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting the MLL-PAFc interaction in acute myeloid leukemia (AML).
  • To determine the role of the PAFc in AML cell proliferation and epigenetic regulation.
  • To assess the safety of disrupting the MLL-PAFc interaction on normal hematopoietic stem cell function.

Main Methods:

  • Utilized a conditional allele of the PAFc subunit, Cdc73, to assess its genetic requirement in AML.
  • Engineered a dominant-negative MLL fragment to disrupt the MLL-PAFc interaction.
  • Employed in vivo hematopoietic reconstitution assays to evaluate effects on normal hematopoiesis.

Main Results:

  • The PAFc is essential for AML cell proliferation, regulating proleukemogenic genes like MEIS1 and Bcl2.
  • Disruption of the MLL-PAFc interaction selectively inhibited MLL leukemic cell proliferation.
  • Normal hematopoietic stem cell function remained unaffected by the disruption of the MLL-PAFc interaction.

Conclusions:

  • The MLL-PAFc interaction is crucial for the proliferation of MLL-associated leukemias.
  • Targeting the MLL-PAFc interaction offers a selective therapeutic approach for MLL leukemias.
  • This strategy demonstrates tolerance in normal hematopoiesis, highlighting its therapeutic promise.

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