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.
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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

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Figure 4

The MN1 cooperating program is downregulated after loss of Dot1l in MN1-transformed CMPs (MN1CMP-T).

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The MN1 cooperating program is downregulated after loss of Dot1l in MN1-...
(A) ChIP-Seq for H3K79me2 in 3 MN1-driven murine leukemias. The IGV screen shot shows the overlap of genes associated with H3K79me2 with the genes bound by MN1 as assessed by ChIP-Seq by Heuser et al. (14). (B) Venn diagram showing overlap of genes associated with H3K79me2 (green) and bound by MN1 (blue). (C) qPCR for Hoxa9 and Meis1 in MN1CMP-T 21 days after transduction with Cre. Each bar represents fold-change in Dot1l–/– MN1CMP-T compared with Dot1lfl/fl (set to 1). Error bars represent ±SEM. *P < 0.01 (two-sided t test Dot1l–/– vs. Dot1lfl/fl). (D) RNA-Seq of sorted MN1CMP-T 7 days after transduction with Cre. Shown are all probe sets/genes with differential expression at P < 0.01, fold-change 2.5, as well as a list of the top 30 differentially expressed probe sets and Meis1. n = 3 mice per group. (E) GSEA showing enrichment of the CMP/MN1 program in Dot1lfl/fl vs. Dot1l–/– MN1CMP-T. The core enrichment is marked by a red shaded box. Definition of core enrichment, NES, and P value according to ref. 43. (F) Venn diagram of gene marked by H3K79me2 (green), bound by MN1 (blue), and the core enrichment of genes regulated by MN1 and dependent on DOT1L. (G) H3K79me2 methylation profile of the Hoxa cluster in MN1-driven CMP-derived leukemias (MN1CMP-L). Three individual leukemias are shown.