title: MLL fusion protein-driven AML is selectively inhibited by targeted disruption of the MLL-PAFc interaction.
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.
authors.affiliation: Department of Pathology, Department of Medicine;
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Muntean
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Morgan
authors.initials: M
authors.lastname: Jones
authors.forename: Eric M
authors.initials: EM
authors.lastname: Granowicz
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.forename: Jay L
authors.initials: JL
authors.lastname: Hess
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C529591:HRPT2 protein, mouse; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C551356:MLL-AF9 fusion protein, mouse; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C501972:PAF1 protein, human; D021122:Protein Subunits; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C097899:homeobox protein HOXA9
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