| First Author | Libbrecht C | Year | 2021 |
| Journal | Leukemia | Volume | 35 |
| Issue | 5 | Pages | 1405-1417 |
| PubMed ID | 33542482 | Mgi Jnum | J:305488 |
| Mgi Id | MGI:6706757 | Doi | 10.1038/s41375-021-01146-z |
| Citation | Libbrecht C, et al. (2021) Menin is necessary for long term maintenance of meningioma-1 driven leukemia. Leukemia 35(5):1405-1417 |
| abstractText | Translocations of Meningioma-1 (MN1) occur in a subset of acute myeloid leukemias (AML) and result in high expression of MN1, either as a full-length protein, or as a fusion protein that includes most of the N-terminus of MN1. High levels of MN1 correlate with poor prognosis. When overexpressed in murine hematopoietic progenitors, MN1 causes an aggressive AML characterized by an aberrant myeloid precursor-like gene expression program that shares features of KMT2A-rearranged (KMT2A-r) leukemia, including high levels of Hoxa and Meis1 gene expression. Compounds that target a critical KMT2A-Menin interaction have proven effective in KMT2A-r leukemia. Here, we demonstrate that Menin (Men1) is also critical for the self-renewal of MN1-driven AML through the maintenance of a distinct gene expression program. Genetic inactivation of Men1 led to a decrease in the number of functional leukemia-initiating cells. Pharmacologic inhibition of the KMT2A-Menin interaction decreased colony-forming activity, induced differentiation programs in MN1-driven murine leukemia and decreased leukemic burden in a human AML xenograft carrying an MN1-ETV6 translocation. Collectively, these results nominate Menin inhibition as a promising therapeutic strategy in MN1-driven leukemia. |
