Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l.
The t(6;11)(q27;q23) is a recurrent chromosomal rearrangement that encodes the MLLAF6 fusion oncoprotein and is observed in patients with diverse hematologic malignancies. The presence of the t(6;11)(q27;q23) has been linked to poor overall survival in patients with AML. In this study, we demonstrate that MLL-AF6 requires continued activity of the histone-methyltransferase DOT1L to maintain expression of the MLL-AF6-driven oncogenic gene-expression program. Using gene-expression analysis and genome-wide chromatin immunoprecipitation studies followed by next generation sequencing, we found that MLL-fusion target genes display markedly high levels of histone 3 at lysine 79 (H3K79) dimethylation in murine MLL-AF6 leukemias as well as in ML2, a human myelomonocytic leukemia cell line bearing the t(6;11)(q27;q23) translocation. Targeted disruption of Dot1l using a conditional knockout mouse model inhibited leukemogenesis mediated by the MLL-AF6 fusion oncogene. Moreover, both murine MLL-AF6-transformed cells as well as the human MLL-AF6-positive ML2 leukemia cell line displayed specific sensitivity to EPZ0004777, a recently described, selective, small-molecule inhibitor of Dot1l. Dot1l inhibition resulted in significantly decreased proliferation, decreased expression of MLL-AF6 target genes, and cell cycle arrest of MLL-AF6-transformed cells. These results indicate that patients bearing the t(6;11)(q27;q23) translocation may benefit from therapeutic agents targeting aberrant H3K79 methylation.
Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA.
Aniruddha J
AJ
Deshpande
Liying
L
Chen
Maurizio
M
Fazio
Amit U
AU
Sinha
Kathrin M
KM
Bernt
Deepti
D
Banka
Stuart
S
Dias
Jenny
J
Chang
Edward J
EJ
Olhava
Scott R
SR
Daigle
Victoria M
VM
Richon
Roy M
RM
Pollock
Scott A
SA
Armstrong
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016547:Kinesins / Q000235:genetics*; D008239:Lysine / Q000378:metabolism; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009218:Myosins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010671:Phenylurea Compounds / Q000494:pharmacology
C490657:Afdn protein, mouse; C581325:EPZ004777; D004791:Enzyme Inhibitors; D015514:Oncogene Proteins, Fusion; D010671:Phenylurea Compounds; D051788:Myeloid-Lymphoid Leukemia Protein; C481527:Dot1l protein, mouse; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D009218:Myosins; D016547:Kinesins; D008239:Lysine; D000241:Adenosine