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 8

HOXA9 expression and sensitivity to DOT1L inhibition in MN1hi AML patient samples.

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HOXA9 expression and sensitivity to DOT1L inhibition in MN1hi AML patie...
(A) qPCR analysis of MN1 (left axis) and HOXA9 (right axis) in 25 primary patient AML samples. MN1 expression values are shown as fold-enrichment compared with normal CD33+ myeloid progenitors and plotted dichotomized at the median (median = 70-fold overexpression). HOXA9 values are plotted as fold-enrichment compared with AML25 (MLL-rearranged, with known high HOXA9 expression set to 1). Error bars represent ±SEM of 2–3 technical replicates. n.d., not detected. (B) MN1 and HOXA9 expression by genotype in Wouters Leukemia data set (Oncomine). Full legend: 0, not determined (90); 1, +8 (20); 2, -5/7(Q) (29); 3, -9q (6); 4, 11q23 (10); 5, complex (13); 6, failure (12); 7, MDS -7(Q) (2); 8, MDS -Y (1); 9, MDS complex (3); 10, normal (187); 11, other (53); 12, abn(3q) (2); 13, idv(16) (34); 14, t(15;17) (21); 15, t(6;9) (6); 16, t(8;21) (35); 17, t(9;22) (2). n = 526 AML samples. (C–F) Exposure of primary patient AML samples to the DOT1L inhibitor EPZ004777 at the indicated concentrations. AML12 (MLL-rearranged [MLL-r], positive control), AML38 (high MN1/HOXA9, complex karyotype with 5q-/7q-), AML 40 (high MN1/HOXA9, complex karyotype with 5q-), AML51 (inv[16], high MN1/no HOXA9), and AML24 (AML/ETO, intermediate high MN1/no HOXA9). Shown are fold-expansion over a 14-day culture period (serial cell counts and Trypan Blue staining; error bars represent duplicate counts) (C). Wright-Giemsa stain on cytospin of AML 40 (high MN1/HOXA9, complex karyotype with 5q-) treated with DMSO or EPZ004777 (D). HOXA9 expression in AML 38 and 40 (high MN1/HOXA9) treated with DMSO or EPZ004777. Error bars over technical replicates; *P < 0.05 (two-sided t test) (E). Summary of cell growth of 3 inv(16) AML patient samples treated with DMSO or EPZ004777 (F). n = 3; *P < 0.05 (two-sided t test).