Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia
Szymon Klossowski, … , Tomasz Cierpicki, Jolanta Grembecka
Szymon Klossowski, … , Tomasz Cierpicki, Jolanta Grembecka
Published December 19, 2019
Citation Information: J Clin Invest. 2020;130(2):981-997. https://doi.org/10.1172/JCI129126.
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Research Article Hematology

Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia

Abstract

The protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) plays a critical role in acute leukemias with translocations of the MLL1 gene or with mutations in the nucleophosmin 1 (NPM1) gene. As a step toward clinical translation of menin-MLL1 inhibitors, we report development of MI-3454, a highly potent and orally bioavailable inhibitor of the menin-MLL1 interaction. MI-3454 profoundly inhibited proliferation and induced differentiation in acute leukemia cells and primary patient samples with MLL1 translocations or NPM1 mutations. When applied as a single agent, MI-3454 induced complete remission or regression of leukemia in mouse models of MLL1-rearranged or NPM1-mutated leukemia, including patient-derived xenograft models, through downregulation of key genes involved in leukemogenesis. We also identified MEIS1 as a potential pharmacodynamic biomarker of treatment response with MI-3454 in leukemia, and demonstrated that this compound is well tolerated and did not impair normal hematopoiesis in mice. Overall, this study demonstrates, for the first time to our knowledge, profound activity of the menin-MLL1 inhibitor as a single agent in clinically relevant PDX models of leukemia. These data provide a strong rationale for clinical translation of MI-3454 or its analogs for leukemia patients with MLL1 rearrangements or NPM1 mutations.

Authors

Szymon Klossowski, Hongzhi Miao, Katarzyna Kempinska, Tao Wu, Trupta Purohit, EunGi Kim, Brian M. Linhares, Dong Chen, Gloria Jih, Eric Perkey, Huang Huang, Miao He, Bo Wen, Yi Wang, Ke Yu, Stanley Chun-Wei Lee, Gwenn Danet-Desnoyers, Winifred Trotman, Malathi Kandarpa, Anitria Cotton, Omar Abdel-Wahab, Hongwei Lei, Yali Dou, Monica Guzman, Luke Peterson, Tanja Gruber, Sarah Choi, Duxin Sun, Pingda Ren, Lian-Sheng Li, Yi Liu, Francis Burrows, Ivan Maillard, Tomasz Cierpicki, Jolanta Grembecka

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Figure 2

In vivo activity of MI-3454 in xenograft models of MLL leukemia.

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In vivo activity of MI-3454 in xenograft models of MLL leukemia. (A) Bio...
(A) Bioluminescent imaging of NSG mice transplanted with MV-4-11 human MLL leukemic cells expressing luciferase performed on the indicated days after initiation of treatment with MI-3454 or vehicle, n = 5. (B) Quantification of bioluminescence level in MV-4-11 mice on the indicated days after initiation of treatment with MI-3454 or vehicle (mean ± SEM, n = 5). (C) Flow cytometric quantification of human CD45+ cells in peripheral blood, spleen, and bone marrow samples harvested from MV-4-11–transplanted mice after 7 days of treatment with MI-3454 (120 mg/kg, b.i.d., p.o. or 120 mg/kg, q.d., p.o.) or vehicle; mean ± SD, n = 5. (D) Gene expression measured by qRT-PCR of RNA extracted from bone marrow samples harvested from MV-4-11 mice after 7 days of treatment with MI-3454 (120 mg/kg, b.i.d., p.o.) or vehicle. Transcript levels are normalized to HPRT1 and referenced to the mean transcript level in the vehicle-treated group, which is set as 1 (n = 5). In C and D, *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; NS, not significant; calculated using 2-way ANOVA with Tukey’s post hoc test (C) or Student’s 2-tailed t test (D). (E) Wright-Giemsa–stained cytospins for bone marrow samples isolated from MV-4-11 mice after 7 days of treatment with MI-3454 (120 mg/kg, b.i.d., p.o.) or vehicle. (F) Kaplan-Meier survival curves of vehicle- and MI-3454–treated (100 mg/kg, b.i.d., p.o.) NSG mice transplanted with MOLM13 cells (n = 8). P value was calculated using log-rank (Mantel-Cox) test. (G) Flow cytometric quantification of human CD45+ cells in peripheral blood (PB) of MOLM13 mice during treatment with MI-3454 or vehicle. Mean ± SEM, n = 8. P values in B and G were calculated using 2-way ANOVA with Sidak’s multiple-comparisons test.