Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l

  • Leukemia. 2013 Apr;27(4):813-22. doi: 10.1038/leu.2012.327.
L Chen  1 ,  A J Deshpande ,  D Banka ,  K M Bernt ,  S Dias ,  C Buske ,  E J Olhava ,  S R Daigle ,  V M Richon ,  R M Pollock ,  S A Armstrong
Affiliations
  • 1. Division of Hematology/Oncology, Children's Hospital, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
PMID: 23138183 DOI: 10.1038/leu.2012.327
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.

Products