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Acute myeloid leukemia

Requirement for LIM kinases in acute myeloid leukemia

Leukemia volume 34, pages 3173–3185 (2020)Cite this article

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Abstract

Acute myeloid leukemia (AML) is an aggressive disease for which only few targeted therapies are available. Using high-throughput RNA interference (RNAi) screening in AML cell lines, we identified LIM kinase 1 (LIMK1) as a potential novel target for AML treatment. High LIMK1 expression was significantly correlated with shorter survival of AML patients and coincided with FLT3 mutations, KMT2A rearrangements, and elevated HOX gene expression. RNAi- and CRISPR-Cas9-mediated suppression as well as pharmacologic inhibition of LIMK1 and its close homolog LIMK2 reduced colony formation and decreased proliferation due to slowed cell-cycle progression of KMT2A-rearranged AML cell lines and patient-derived xenograft (PDX) samples. This was accompanied by morphologic changes indicative of myeloid differentiation. Transcriptome analysis showed upregulation of several tumor suppressor genes as well as downregulation of HOXA9 targets and mitosis-associated genes in response to LIMK1 suppression, providing a potential mechanistic basis for the anti-leukemic phenotype. Finally, we observed a reciprocal regulation between LIM kinases (LIMK) and CDK6, a kinase known to be involved in the differentiation block of KMT2A-rearranged AML, and addition of the CDK6 inhibitor palbociclib further enhanced the anti-proliferative effect of LIMK inhibition. Together, these data suggest that LIMK are promising targets for AML therapy.

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Fig. 1: High LIMK1 expression in AML is associated with patient survival and genetic subgroups.
Fig. 2: Genetic suppression of LIMK1/2 inhibits proliferation and colony formation of KMT2A-rearranged AML cell lines.
Fig. 3: Transcriptome analyses identify potential effectors of LIMK1.
Fig. 4: CDK6 and LIMK are reciprocally regulated.

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Acknowledgements

The authors thank the DKFZ Genome and Proteome, Flow Cytometry, Light Microscopy, Omics IT and Data Management, and Tumor Models Core Facilities for excellent technical assistance; Cihan Erkut and Annette Kopp-Schneider for support with bioinformatic and statistical analysis; Stephen M. Sykes for providing transformed murine bone marrow cells; and Gina Walter-Bausch, Saskia Rudat, and Marie Groth for helpful discussions. Patrizia Jensen was supported by a grant from the German José Carreras Leukemia Foundation (DJCLS F 15/04). Ya-Yun Cheng was supported by a stipend from the Helmholtz International Graduate School for Cancer Research. Simon Weisemann was supported by a stipend from the German Academic Scholarship Foundation.

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  1. These authors jointly supervised this work: Claudia Scholl, Stefan Fröhling

Authors and Affiliations

  1. Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Patrizia Jensen, Ines Brunner, Mikołaj Słabicki, Ya-Yun Cheng & Stefan Fröhling

  2. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany

    Patrizia Jensen & Ya-Yun Cheng

  3. Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Center Munich, German Center for Environmental Health, Munich, Germany

    Michela Carlet & Irmela Jeremias

  4. Clinical Trials Center, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Richard F. Schlenk

  5. Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany

    Richard F. Schlenk

  6. Division of Applied Functional Genomics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany

    Andrea Weber, Jana Kress, Gregor Grill, Simon Weisemann & Claudia Scholl

  7. Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany

    Irmela Jeremias

  8. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany

    Irmela Jeremias

  9. German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany

    Claudia Scholl & Stefan Fröhling

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Contributions

PJ, SF, and CS designed the study and wrote the manuscript; PJ, MC, RFS, JK, AW, IB, GG, and SW performed experiments and/or analyzed data; MC and IJ provided human AML PDX samples, and MS and YYC gave conceptual input.

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Correspondence to Claudia Scholl or Stefan Fröhling.

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Conflict of interest

SF has had a consulting or advisory role, received honoraria, research funding, and/or travel/accommodation expenses funding from the following for-profit companies: Amgen, AstraZeneca, Bayer, Eli Lilly, Pfizer, PharmaMar, and Roche. RFS has had a consulting or advisory role, received honoraria, research funding, and/or travel/accommodation expenses funding from the following for-profit companies: Roche, Daiichi Sankyo, Pfizer, Novartis, PharmaMar, and AstraZeneca. The other authors declare no competing financial interests.

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Jensen, P., Carlet, M., Schlenk, R.F. et al. Requirement for LIM kinases in acute myeloid leukemia. Leukemia 34, 3173–3185 (2020). https://doi.org/10.1038/s41375-020-0943-5

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