Submit a comment

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

×

Guidelines

The Editorial Board will only consider comments that are deemed relevant and of interest to readers. The Journal will not post data that have not been subjected to peer review; or a comment that is essentially a reiteration of another comment.

  • Comments appear on the Journal’s website and are linked from the original article’s web page.
  • Authors are notified by email if their comments are posted.
  • The Journal reserves the right to edit comments for length and clarity.
  • No appeals will be considered.
  • Comments are not indexed in PubMed.

Specific requirements

  • Maximum length, 400 words
  • Entered as plain text or HTML
  • Author’s name and email address, to be posted with the comment
  • Declaration of all potential conflicts of interest (even if these are not ultimately posted); see the Journal’s conflict-of-interest policy
  • Comments may not include figures
This field is required
This field is required
This field is required
This field is required
This field is required
This field is required