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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Female
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism*
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Leukemia, Myeloid, Acute / pathology
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Male
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Methyltransferases / genetics
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Methyltransferases / metabolism*
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Mice
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Mice, Knockout
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Myeloid Ecotropic Viral Integration Site 1 Protein
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Myeloid-Lymphoid Leukemia Protein / genetics
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Myeloid-Lymphoid Leukemia Protein / metabolism*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Trans-Activators
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Homeodomain Proteins
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KMT2A protein, human
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MEIS1 protein, human
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MN1 protein, human
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Meis1 protein, mouse
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Mn1 protein, mouse
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Myeloid Ecotropic Viral Integration Site 1 Protein
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Neoplasm Proteins
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Oncogene Proteins
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Trans-Activators
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Tumor Suppressor Proteins
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homeobox protein HOXA9
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Myeloid-Lymphoid Leukemia Protein
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DOT1L protein, human
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Dot1l protein, mouse
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Methyltransferases
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Histone-Lysine N-Methyltransferase
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Kmt2a protein, mouse