Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l Journal Article
| Authors: | Deshpande, A. J.; Chen, L.; Fazio, M.; Sinha, A. U.; Bernt, K. M.; Banka, D.; Dias, S.; Chang, J.; Olhava, E. J.; Daigle, S. R.; Richon, V. M.; Pollock, R. M.; Armstrong, S. A. |
| Article Title: | Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l |
| Abstract: | 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. |
| Keywords: | oncoprotein; genetics; cell proliferation; mouse; animal; metabolism; mouse mutant; animals; mice; mice, knockout; cells, cultured; biological model; models, biological; drug effect; enzyme inhibitor; mice, inbred c57bl; physiology; c57bl mouse; cell transformation, neoplastic; methyltransferase; drug antagonism; methyltransferases; cell culture; adenosine; enzyme inhibitors; histone methyltransferase; cell transformation; histone-lysine n-methyltransferase; oncogene proteins, fusion; drug derivative; myosin; lysine; kinesin; histone lysine methyltransferase; mixed lineage leukemia protein; myeloid-lymphoid leukemia protein; myosins; epz004777; phenylurea compounds; carbanilamide derivative; dot1l protein, mouse; mll protein, mouse; mllt4 protein, mouse |
| Journal Title: | Blood |
| Volume: | 121 |
| Issue: | 13 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2013-03-28 |
| Start Page: | 2533 |
| End Page: | 2541 |
| Language: | English |
| DOI: | 10.1182/blood-2012-11-465120 |
| PUBMED: | 23361907 |
| PROVIDER: | scopus |
| PMCID: | PMC3612861 |
| DOI/URL: | |
| Notes: | --- - Cited By (since 1996):1 - "Export Date: 31 October 2013" - "Source: Scopus" |
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