title: Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l.
abstract: The t(10;11)(p12;q23) translocation and the t(10;11)(p12;q14) translocation, which encode the MLL (mixed lineage leukemia)-AF10 and CALM (clathrin assembly lymphoid myeloid leukemia)-AF10 fusion oncoproteins, respectively, are two recurrent chromosomal rearrangements observed in patients with acute myeloid leukemia and acute lymphoblastic leukemia. Here, we demonstrate that MLL-AF10 and CALM-AF10-mediated transformation is dependent on the H3K79 methyltransferase Dot1l using genetic and pharmacological approaches in mouse models. Targeted disruption of Dot1l using a conditional knockout mouse model abolished in vitro transformation of murine bone marrow cells and in vivo initiation and maintenance of MLL-AF10 or CALM-AF10 leukemia. The treatment of MLL-AF10 and CALM-AF10 transformed cells with EPZ004777, a specific small-molecule inhibitor of Dot1l, suppressed expression of leukemogenic genes such as Hoxa cluster genes and Meis1, and selectively impaired proliferation of MLL-AF10 and CALM-AF10 transformed cells. Pretreatment with EPZ004777 profoundly decreased the in vivo spleen-colony-forming ability of MLL-AF10 or CALM-AF10 transformed bone marrow cells. These results show that patients with leukemia-bearing chromosomal translocations that involve the AF10 gene may benefit from small-molecule therapeutics that inhibit H3K79 methylation.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: A J
authors.initials: AJ
authors.lastname: Deshpande
authors.forename: D
authors.initials: D
authors.lastname: Banka
authors.forename: K M
authors.initials: KM
authors.lastname: Bernt
authors.forename: S
authors.initials: S
authors.lastname: Dias
authors.forename: C
authors.initials: C
authors.lastname: Buske
authors.forename: E J
authors.initials: EJ
authors.lastname: Olhava
authors.forename: S R
authors.initials: SR
authors.lastname: Daigle
authors.forename: V M
authors.initials: VM
authors.lastname: Richon
authors.forename: R M
authors.initials: RM
authors.lastname: Pollock
authors.forename: S A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D051379:Mice; D008817:Mice, Mutant Strains; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C114359:AF10-CALM fusion protein, human; D004791:Enzyme Inhibitors; C470550:MLL-AF10 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D008780:Methyltransferases