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: L Chen, 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
• Journal: Leukemia (Leukemia) Vol. 27 Issue 4 Pg. 813-22 (Apr 2013) ISSN: 1476-5551 [Electronic] England
• PMID: 23138183 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AF10-CALM fusion protein, human
• Enzyme Inhibitors
• MLL-AF10 fusion protein, human
• Oncogene Proteins, Fusion
• Myeloid-Lymphoid Leukemia Protein
• Methyltransferases

Topics

• Animals
• Apoptosis
• Blotting, Western
• Cell Cycle
• Cell Proliferation
• Enzyme Inhibitors (pharmacology)
• Fluorescent Antibody Technique
• Gene Silencing
• Humans
• Methyltransferases (antagonists & inhibitors)
• Mice
• Mice, Mutant Strains
• Myeloid-Lymphoid Leukemia Protein (genetics)
• Oncogene Proteins, Fusion (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction