Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor

By S. Daigle, E. Olhava, Carly A. Therkelsen, C. Majer, C. Sneeringer, Jeffrey Song, L. Johnston, M. Scott, Jesse J. Smith, Yonghong Xiao and 11 more. Cancer Cell, 2011

928 citations recorded by the source corpus.

SUMMARY Mislocated enzymatic activity of DOT1L has been proposed as a driver of leukemogenesis in mixed lineage leukemia (MLL). The characterization of EPZ004777, a potent, selective inhibitor of DOT1L is reported. Treatment of MLL cells with the compound selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Exposure of leukemic cells to EPZ004777 results in selective killing of those cells bearing the MLL gene translocation, with little effect on non-MLL-translocated cells. Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f953b6e7fb39594ff85df5acd226d62e94788390

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Hematology

1. M. Dawson
2. Tony Kouzarides
3. Peter A. Jones
4. S. Baylin

In Molecular Biology

1. S. Baylin
2. Peter A. Jones
3. J. You
4. V. Richon
5. R. Pollock
6. M. Dawson
7. M. Scott
8. Tony Kouzarides

Citations in the corpus

• Epigenetic Determinants of Cancer. (2016, background): “Examples of epigenetic drugs in development include a potent small-molecule DOT1L inhibitor, which can selectively kill MLL cells (Daigle et al. 2011).”
• Cancer Genetics and Epigenetics: Two Sides of the Same Coin? (2012, background): “Recently, several proteins have been implicated to be erasers of DNA methylation including TET (ten-eleven-translocation) and AID (activation-induced cytidine deaminase) (De Carvalho et al., 2010; Ko et al., 2010; Wu and Zhang, 2010).”
• Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2 (2013, methodology): “Histones were isolated from tumors as previously described (23) and were prepared in coating buffer (PBS with 0.”
• Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. (2013, methodology): “Proliferation assays and IC50 value determinations were performed as described previously.(30) Cell-cycle analysis and Annexin staining.”
• Cancer epigenetics: from mechanism to therapy. (2012, background): “These efforts will only be encouraged by the recent demonstration that small-molecule inhibition of DOT1L shows preclinical promise as a targeted therapy in MLL leukemia (Daigle et al., 2011), a disease in which aberrant DOT1L activity is ill defined but clearly involved (Krivtsov and Armstrong, 200”
• Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “survival time of mice with MLL-rearranged leukemia, but it had little killing effect on non-MLL translocated cells (Daigle et al., 2011; Chen et al., 2013a).”