Menin is necessary for long term maintenance of meningioma-1 driven leukemia

Abstract

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.

The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia

“…Other leukaemia genotypes have recently been identified as susceptible to menin inhibition, such as AML with rearrangement of the nucleoporin 98 gene ( NUP98 ), a common and adverse genotype among children with relapsed and refractory disease 25 . Another example is the rare occurrence of AML with translocations involving the meningioma-1 gene (MN1) 26 . Therefore, menin inhibitors have the potential to reach a larger subset of acute leukaemia with similar dependency on the menin–KMT2A interaction, which could be identified using precision approaches testing characteristic gene expression.…”

Extramedullary T-lymphoblastic Crisis in a Myelodysplastic/Myeloproliferative Neoplasm with a t(12;22)/MN1::ETV6 Translocation

“…Acute leukemia with this genetic alteration may share several clinical and, especially, molecular characteristics with leukemia with rearrangements involving the lysine methyltransferase 2A ( KMT2A ) gene. One of these features, which may be therapeutically important in the future, is the overexpression of Hoxa and Meis1 [ 22 ]. The expression of these genes may constitute a potential biomarker to predict the response to new drugs that are under development, such as menin inhibitors, as the menin binding site is a crucial co-factor for the activity of Hox gene promoters [ 23 ].…”

Small Molecule Menin Inhibitors: Novel Therapeutic Agents Targeting Acute Myeloid Leukemia with KMT2A Rearrangement or NPM1 Mutation

“…AML subsets with translocations involving the MN1 gene that result in high expression of MN1 are also aggressive AML. They are characterized by an aberrant myeloid precursor-like gene expression program that shares features of KMT2Ar leukemia, including high levels of HOXA and MEIS1 gene expression [ 39 ]. While the mechanism of response remains unclear, a complete response has been reported in a patient with mutations in RUNX1 and SETD2 genes after treatment with the menin inhibitor KO-529 [ 40 ].…”