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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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 7

MI-3454 does not impair normal hematopoiesis.

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MI-3454 does not impair normal hematopoiesis. (A) Analysis of bone marro...
(A) Analysis of bone marrow cellularity after 19 days of treatment of normal C57BL/6 mice with MI-3454 (100 mg/kg, b.i.d., p.o.) or vehicle (n = 9/group, mean ± SD). NS, not significant. (B) Representative contour plots from flow cytometric analysis of hematopoietic stem and progenitor cells: LSK (Lin–Sca-1+c-Kit+) and long-term hematopoietic stem cells (LT-HSCs, defined as Lin–Sca-1+c-Kit+CD48–CD150+). (C) Quantification of LSK and LT-HSC cell frequency by flow cytometry (n = 8–9/group, mean ± SD). **P < 0.01 (treatment is described in A). (D) Representative contour plots (left panel) and quantification (right panel) from flow cytometric analysis of myeloid cells in bone marrow (BM) samples isolated from mice treated with vehicle or MI-3454 (n = 8–9/group, mean ± SD); treatment is described in A. (E and F) Representative contour plots from flow cytometric analysis (E) and quantification of absolute numbers (F) of B cell populations in bone marrow (n = 9/group, mean ± SD). Contour plots in E were pregated on B220+CD43+sIgM– cells (pro-B cells) and B220+CD43– cells (pre-B, immature B, recirculating B cells). In A, C, D, and F, **P < 0.01; NS, not significant; calculated using unpaired Welch’s t test. (G) Quantification of the population of donor cells (CD45.1+) within the specific subtype of blood cells in the C57BL/6-CD45.2 recipient mice after bone marrow transplantation and upon 21 days of treatment with vehicle or MI-3454 (100 mg/kg, b.i.d., p.o.). Mean ± SD, n = 7–8. (H) Blood parameters: white blood cells (WBC), platelets, and hemoglobin (Hb) in C57BL/6-CD45.2 recipient mice after bone marrow transplantation and upon 21 days of treatment with vehicle or MI-3454. Mean ± SD, n = 7–8. K, thousand. Differences in G and H are not significant between the 2 cohorts as calculated using 2-way ANOVA with Sidak’s multiple-comparisons test.