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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.
Insights
Meningioma-1 (MN1) overexpression drives aggressive acute myeloid leukemia (AML) by activating Hoxa9 and Meis1. Targeting DOT1L, a key regulator, shows therapeutic potential in MN1-driven AML.
Area of Science:
- Hematology
- Oncology
- Epigenetics
Background:
- Meningioma-1 (MN1) overexpression is linked to poor prognosis in acute myeloid leukemia (AML).
- MN1-induced AML in mice relies on a specific gene program involving Hoxa9 and Meis1.
Purpose of the Study:
- To investigate the epigenetic regulators controlling the MN1-driven gene expression program in AML.
- To evaluate DOT1L as a potential therapeutic target in MN1-overexpressing AML.
Main Methods:
- Utilized murine models with MN1 overexpression in hematopoietic progenitors.
- Assessed the impact of MLL1 and DOT1L inactivation on leukemogenesis and gene expression.
- Analyzed coexpression of MN1, HOXA9, and MEIS1 in clinical AML samples.
- Investigated sensitivity of human MN1hi/HOXA9hi leukemias to DOT1L inhibition.
Main Results:
- Deletion of Mll1 or Dot1l in MN1-expressing cells abrogated the Hoxa9/Meis1 gene program.
- Genetic inactivation of Mll1 or Dot1l impaired MN1-mediated leukemogenesis in murine models.
- HOXA9 and MEIS1 were coexpressed with MN1 in a subset of human AML.
- Human MN1hi/HOXA9hi leukemias demonstrated sensitivity to DOT1L pharmacologic inhibition.
Conclusions:
- The MN1-driven gene expression program is epigenetically controlled by MLL1 and DOT1L.
- DOT1L is a promising therapeutic target for MN1-overexpressing AML.
- Epigenetic modulation offers therapeutic potential in AML by targeting oncogenic lesions and cooperating developmental programs.
