Targeting Meningeoma-1 Driven AML through Epigenetic Modulation of the Cell of Origin

Meningeoma-1 (MN1) overexpression in AML is common and predicts a poor prognosis. Forced expression of MN1 in early murine hematopoietic progenitors (CMP and LSK) but not hematopoietic stem cells (HSC) or committed progenitors (GMP) induces an aggressive myeloid leukemia as a single hit. This leukemia is strictly dependent on the high-level expression of a defined gene expression program in the cell of origin, which includes the key component HoxA9. This “susceptibility program” has been proposed as a therapeutic target in MN1^high AML, but means to modulate this program have so far remained elusive.

We previously showed that the pharmacologically targetable histone methyltransferase Dot1l is critically required for HoxA9 expression in MLL-rearranged leukemias. We now report dependence on Dot1l of the MN1 “susceptibility-program” in murine MN1-driven leukemia using a genetic loss of function model. Key genes including HoxA9 depend on Dot1l in normal LSK-cells, and in MN1 transduced leukemogenic early progenitors. Inactivation of Dot1l prevents leukemia establishment and abrogates leukemia maintenance in vivo. Phenotypically, deletion of Dot1l in MN1-driven leukemias induces differentiation, cell cycle arrest and apoptosis. RNA-Seq data document that deletion of Dot1l antagonizes the cell of origin-derived susceptibility program in MN1 leukemias, including HoxA9 expression. We also confirm previous reports that MN1-transduced HSC can expand ex vivo but fail to cause leukemia in vivo. This has been linked to a lower expression level of HoxA9 in normal and MN1-transformed HSCs compared to early progenitors. We confirm that HoxA9 expression levels in MN1-transduced HSCs are lower than in MN1 transduced progenitors. Importantly, in contrast to MN1-transduced progenitors, this lower, “HSC-level” expression of HoxA9 is independent of Dot1l. This suggests a developmental switch at the HSC-to-progenitor transition that involves increased expression of HoxA9 and a change from Dot1l-independent to Dot1l-dependent regulation. The high HoxA9 expression necessary to cooperate with MN1 to cause AML is strictly Dot1l-dependent.

HOXA9 is co-expressed with MN1 in a subset of clinical MN1^high AML. Exposure of MN1^highHOXA9^high AML primary patient samples to a pharmacologic inhibitor of DOT1L (EPZ4777) demonstrated sensitivity to DOT1L inhibition as expected from the murine model. Taken together, these data point to DOT1L as a potential therapeutic target in MN1^high AML. The targeted epigenetic modulation of the interplay between an oncogenic lesion and its cooperating normal developmental program could represent a new paradigm for the treatment of AML.