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

Andrew G. Muntean, Wei Chen, Morgan Jones, Eric M. Granowicz, Ivan Maillard, Jay Hess

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

MLL rearrangements are common in leukemia and considered an adverse risk factor. Through interactions with the polymerase-associated factor complex (PAFc), mixed lineage leukemia (MLL) fusion proteins activate genes critical for blocking differentiation, such as HOXA9. Here we investigate whether the MLL-PAFc interaction can be exploited therapeutically using both genetic and biochemical approaches. We tested the genetic requirement of the PAFc in acute myeloid leukemia (AML) using a conditional allele of the PAFc subunit, Cdc73. We show that the PAFc is indiscriminately necessary for the proliferation of AML cells through the epigenetic regulation of proleukemogenic target genes, such as MEIS1 and Bcl2. To investigate the therapeutic potential of targeting the MLL-PAFc interaction, we engineered a dominant negative fragment of MLL capable of binding to the PAFc. Disruption of the MLL-PAFc interaction selectively inhibits the proliferation of MLL leukemic cells without affecting cells transformed by an unrelated E2A-HLF fusion protein. Using in vivo hematopoietic reconstitution assays, we demonstrate that disruption of the MLL-PAFc does not alter normal hematopoietic stem cell function. Together, our data show a selective growth inhibition of MLL-associated leukemic cells and tolerance of normal hematopoiesis to disruption of the MLL-PAFc interaction establishing the MLL-PAFc interaction as an attractive therapeutic target.

Original languageEnglish
Pages (from-to)1914-1922
Number of pages9
JournalBlood
Volume122
Issue number11
DOIs
StatePublished - Sep 12 2013
Externally publishedYes

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Myeloid-Lymphoid Leukemia Protein
Acute Myeloid Leukemia
Leukemia
Fusion reactions
Stem cells
Assays
Proteins
Genes
Hematopoiesis
Myeloid Cells
Hematopoietic Stem Cells
Epigenomics

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

MLL fusion protein-driven AML is selectively inhibited by targeted disruption of the MLL-PAFc interaction. / Muntean, Andrew G.; Chen, Wei; Jones, Morgan; Granowicz, Eric M.; Maillard, Ivan; Hess, Jay.

In: Blood, Vol. 122, No. 11, 12.09.2013, p. 1914-1922.

Research output: Contribution to journalArticle

Muntean, Andrew G. ; Chen, Wei ; Jones, Morgan ; Granowicz, Eric M. ; Maillard, Ivan ; Hess, Jay. / MLL fusion protein-driven AML is selectively inhibited by targeted disruption of the MLL-PAFc interaction. In: Blood. 2013 ; Vol. 122, No. 11. pp. 1914-1922.
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