title: The methyltransferase G9a regulates HoxA9-dependent transcription in AML.
abstract: Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. Here we establish the histone methyltransferase G9a/EHMT2 as a selective regulator of fast proliferating myeloid progenitors with no discernible function in hematopoietic stem cells (HSCs). In mouse models of acute myeloid leukemia (AML), loss of G9a significantly delays disease progression and reduces leukemia stem cell (LSC) frequency. We connect this function of G9a to its methyltransferase activity and its interaction with the leukemogenic transcription factor HoxA9 and provide evidence that primary human AML cells are sensitive to G9A inhibition. Our results highlight a clinical potential of G9A inhibition as a means to counteract the proliferation and self-renewal of AML cells by attenuating HoxA9-dependent transcription.
authors.affiliation: University of British Columbia, Biomedical Research Centre, Vancouver, British Columbia V6T 1Z3, Canada;
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lehnertz
authors.forename: Caroline
authors.initials: C
authors.lastname: Pabst
authors.forename: Le
authors.initials: L
authors.lastname: Su
authors.forename: Michelle
authors.initials: M
authors.lastname: Miller
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Yi
authors.forename: Regan
authors.initials: R
authors.lastname: Zhang
authors.forename: Jana
authors.initials: J
authors.lastname: Krosl
authors.forename: Eric
authors.initials: E
authors.lastname: Yung
authors.forename: Jeanette
authors.initials: J
authors.lastname: Kirschner
authors.forename: Patty
authors.initials: P
authors.lastname: Rosten
authors.forename: T Michael
authors.initials: TM
authors.lastname: Underhill
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: Josée
authors.initials: J
authors.lastname: Hébert
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
authors.forename: R Keith
authors.initials: RK
authors.lastname: Humphries
authors.forename: Fabio M
authors.initials: FM
authors.lastname: Rossi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000201:enzymology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008810:Mice, Inbred C57BL; D011799:Quinazolines / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D011799:Quinazolines; C561310:UNC 0638; C097899:homeobox protein HOXA9; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase
keywords: Hox genes; hematopoiesis; histone methylation; leukemia