MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia
Simone S. Riedel, … , Tobias Neff, Kathrin M. Bernt
Simone S. Riedel, … , Tobias Neff, Kathrin M. Bernt
Published February 29, 2016
Citation Information: J Clin Invest. 2016;126(4):1438-1450. https://doi.org/10.1172/JCI80825.
View: Text | PDF
Research Article Oncology

MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia

Abstract

Meningioma-1 (MN1) overexpression is frequently observed in patients with acute myeloid leukemia (AML) and is predictive of poor prognosis. In murine models, forced expression of MN1 in hematopoietic progenitors induces an aggressive myeloid leukemia that is strictly dependent on a defined gene expression program in the cell of origin, which includes the homeobox genes Hoxa9 and Meis1 as key components. Here, we have shown that this program is controlled by two histone methyltransferases, MLL1 and DOT1L, as deletion of either Mll1 or Dot1l in MN1-expressing cells abrogated the cell of origin–derived gene expression program, including the expression of Hoxa cluster genes. In murine models, genetic inactivation of either Mll1 or Dot1l impaired MN1-mediated leukemogenesis. We determined that HOXA9 and MEIS1 are coexpressed with MN1 in a subset of clinical MN1hi leukemia, and human MN1hi/HOXA9hi leukemias were sensitive to pharmacologic inhibition of DOT1L. Together, these data point to DOT1L as a potential therapeutic target in MN1hi AML. In addition, our findings suggest that epigenetic modulation of the interplay between an oncogenic lesion and its cooperating developmental program has therapeutic potential in AML.

Authors

Simone S. Riedel, Jessica N. Haladyna, Matthew Bezzant, Brett Stevens, Daniel A. Pollyea, Amit U. Sinha, Scott A. Armstrong, Qi Wei, Roy M. Pollock, Scott R. Daigle, Craig T. Jordan, Patricia Ernst, Tobias Neff, Kathrin M. Bernt

×

Figure 1

The MN1 cooperating program is enriched in Dot1l WT versus KO LSK cells.

Options: View larger image (or click on image) Download as PowerPoint
The MN1 cooperating program is enriched in Dot1l WT versus KO LSK cells....
(A) Total WBC, hemoglobin (Hb), and platelet (Plt) count in Dot1lfl/fl (fl/fl, n = 10) and Mx1-Cre Dot1lfl/fl (–/–, n = 9) mice 3 weeks after the induction of Cre. Two-sided t test Dot1l–/– vs. Dot1lfl/fl; *P < 0.05. (B) Heatmap of expression array data of sorted LSK cells from Dot1lfl/fl (fl/fl) and Mx1-Cre Dot1lfl/fl (–/–) mice 12 days after induction of Cre. Shown are all probe sets/genes with differential expression at P < 0.05 (393 genes), as well as a list of the top 30 differentially expressed probe sets and Meis1; n = 6 mice per group. (C) Venn diagram of genes associated with H3K79 dimethylation in LSK cells by ChIP-Seq (18) and genes downregulated after loss of Dot1l in LSK cells. (D) GSEA showing enrichment of the CMP/MN1 program in Dot1lfl/fl vs. Dot1l–/– LSK cells. NES and P value according to ref. 43.