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ACUTE MYELOID LEUKEMIA

Combination of menin and kinase inhibitors as an effective treatment for leukemia with NUP98 translocations

Leukemia volume 38, pages 1674–1687 (2024)Cite this article

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Abstract

Chromosomal translocations of the nucleoporin 98 (NUP98) gene are found in acute myeloid leukemia (AML) patients leading to very poor outcomes. The oncogenic activity of NUP98 fusion proteins is dependent on the interaction between Mixed Lineage Leukemia 1 and menin. NUP98-rearranged (NUP98-r) leukemia cells also rely on specific kinases, including CDK6 and/or FLT3, suggesting that simultaneous targeting of these kinases and menin could overcome limited sensitivity to single agents. Here, we found that combinations of menin inhibitor, MI-3454, with kinase inhibitors targeting either CDK6 (Palbociclib) or FLT3 (Gilteritinib) strongly enhance the anti-leukemic effect of menin inhibition in NUP98-r leukemia models. We found strong synergistic effects of both combinations on cell growth, colony formation and differentiation in patient samples with NUP98 translocations. These combinations also markedly augmented anti-leukemic efficacy of menin inhibitor in Patient Derived Xenograft models of NUP98-r leukemia. Despite inhibiting two unrelated kinases, when Palbociclib or Gilteritinib were combined with the menin inhibitor, they affected similar pathways relevant to leukemogenesis, including cell cycle regulation, cell proliferation and differentiation. This study provides strong rationale for clinical translation of the combination of menin and kinase inhibitors as novel treatments for NUP98-r leukemia, supporting the unexplored combinations of epigenetic drugs with kinase inhibitors.

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Fig. 1: Effect of MI-3454 menin inhibitor in NUP98-rearranged leukemia models.
Fig. 2: Effect of combinatorial treatment with menin and CDK6 inhibitors in primary patient samples with NUP98 translocations.
Fig. 3: Combination of menin and CDK6 inhibitors induces differentiation.
Fig. 4: Combinatorial effect of menin and FLT3 inhibitors in primary AML samples with NUP98 translocations.
Fig. 5: In vivo activity of MI-3454 in combination with CDK6 and FLT3 inhibitors in PDX models of NUP98-r leukemia.
Fig. 6: Global gene expression studies for combination of MI-3454 with kinase inhibitors in NUP98_1055 primary AML sample.
Fig. 7: Comparison of genes and pathways affected by combinations of menin and kinase inhibitors.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding authors on reasonable request.

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Acknowledgements

We thank Drs. Gwenn Danet-Desnoyers and Martin Carroll from the Stem Cell and Xenograft Core at the University of Pennsylvania for providing patient samples for these studies. We thank Joshua Ray and Sydney Musser for critical reading of this manuscript. The mouse work was performed under oversight of UCUCA at the University of Michigan. This work was funded by the National Institute of Health (NIH) R01 grants (1R01CA160467, 1R01CA272561 and R01CA244254) to JG, NIH R01 grants (1R01 CA226759 and 1R01 CA282082) to TC, NIH F32 (F31HL160072) and NIH K99 (K99HL166790) to JR, LLS TRP (6649-23) to JG, ALSF Reach grant (22-25561) to J.G., and Rogel Scholar grants to JG and TC.

Author information

Author notes

  1. Adolfo Ferrando

    Present address: Regeneron Genetics Center, Tarrytown, NY, 10591, USA

  2. These authors contributed equally: Hongzhi Miao, Dong Chen, James Ropa.

Authors and Affiliations

  1. Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA

    Hongzhi Miao, Dong Chen, Trupta Purohit, EunGi Kim, Tomasz Cierpicki & Jolanta Grembecka

  2. Department of Microbiology and Immunology, Indiana University, School of Medicine, Indianapolis, IN, 46202, USA

    James Ropa

  3. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Maria-Luisa Sulis

  4. Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA

    Adolfo Ferrando

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Contributions

HM, DC and JR contributed equally to this work. DC designed and synthesized compounds. HM designed and performed in vivo efficacy studies and biological studies in leukemia cell lines and primary patient samples. JR analyzed RNA-seq data. TP performed cell biology experiments. EK performed in vivo efficacy studies. AF and M-LS supported the project with primary patient samples and interpreted data. JG and TC directed the entire project, designed the experiments, analyzed the results and wrote the manuscript with the input from all authors.

Corresponding authors

Correspondence to Tomasz Cierpicki or Jolanta Grembecka.

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Competing interests

The authors declare the following competing financial interest(s): JG and TC received research support from Kura Oncology, Inc. They have also served as consultants for Kura Oncology, have equity ownership in the company and are co-inventors on patent applications covering MI-3454. Kura Oncology, Inc. and University of Michigan have filed patent applications covering MI-3454 and they hold intellectual property rights on this compound. HM is co-inventor on patent applications covering MI-3454 or related compounds, which were licensed by Kura Oncology. JG, TC and HM receive royalties from the University of Michigan on the patents covering menin inhibitors that were licensed to Kura Oncology. AF is an employee of Regeneron Pharmaceuticals. Other co-authors declare no potential conflict of interest.

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Miao, H., Chen, D., Ropa, J. et al. Combination of menin and kinase inhibitors as an effective treatment for leukemia with NUP98 translocations. Leukemia 38, 1674–1687 (2024). https://doi.org/10.1038/s41375-024-02312-9

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