Abstract

Tyrosine kinase inhibitor (TKI) therapy effectively blocks oncogenic Bcr-Abl signaling and induces molecular remission in the majority of CML patients. However, the disease-driving stem cell population is not fully targeted by TKI therapy in the majority of patients, and leukemic stem cells (LSCs) capable of re-inducing the disease can persist. In TKI-resistant CML, STAT3 inhibition was previously shown to reduce malignant cell survival. Here, we show therapy-resistant cell-extrinsic STAT3 activation in TKI-sensitive CML cells, using cell lines, HoxB8-immortalized murine BM cells, and primary human stem cells. Moreover, we identified JAK1 but not JAK2 as the STAT3-activating kinase by applying JAK1/2 selective inhibitors and genetic inactivation. Employing an IL-6-blocking peptide, we identified IL-6 as a mediator of STAT3 activation. Combined inhibition of Bcr-Abl and JAK1 further reduced CFUs from murine CML BM, human CML MNCs, as well as CD34+ CML cells, and similarly decreased LT-HSCs in a transgenic CML mouse model. In line with these observations, proliferation of human CML CD34+ cells was strongly reduced upon combined Bcr-Abl and JAK1 inhibition. Remarkably, the combinatory therapy significantly induced apoptosis even in quiescent LSCs. Our findings suggest JAK1 as a potential therapeutic target for curative CML therapies.

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Acknowledgments

The authors thank Julia Plum and Kristina Feldberg for excellent technical assistance. Hans Häcker kindly provided the MSCV-ERBDH-Hoxb8-Neo plasmid. Dieter Görtz (Institute of Biochemistry and Molecular Biology, RWTH Aachen University) generated and provided the IL-6 RFP. This work was supported by the Interdisciplinary Center for Clinical Research (IZKF) Aachen within the Faculty of Medicine at RWTH Aachen University (O1–3/531430; O3–5/531805; O3–3/531803) and DFG (SCHE 1938/1–1).

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  1. These authors contributed equally: Maja Kim Kuepper, Marlena Bütow, Gerhard Müller-Newen and Mirle Schemionek

Affiliations

  1. Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    • Maja Kim Kuepper
    • , Marlena Bütow
    • , Oliver Herrmann
    • , Janine Ziemons
    • , Nicolas Chatain
    • , Angela Maurer
    • , Martin Kirschner
    • , Steffen Koschmieder
    • , Tim H. Brümmendorf
    •  & Mirle Schemionek
  2. Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, RWTH Aachen University, Aachen, Germany

    • Tiago Maié
    •  & Ivan G. Costa
  3. Department of Orthopedics, Aachen University Hospital, Aachen, Germany

    • Jörg Eschweiler
  4. Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany

    • Gerhard Müller-Newen

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Contributions

MKK designed research, performed experiments, analyzed the data, and wrote the manuscript. MB performed experiments, analyzed the data, designed research, and amended the manuscript. OH, JZ performed experiments. NC designed research, analyzed the data, and amended the manuscript. AM and MK performed research, analyzed the data, and amended the manuscript. IGC and TM analyzed expression data. SK and THB contributed research material and revised the manuscript. GMN designed research, analyzed the data, and revised the manuscript. MS designed research, analyzed the data, and wrote the manuscript. Final approval of the manuscript was provided by all authors.

Conflict of interest

Steffen Koschmieder reports having served on the advisory boards for Pfizer, Incyte/Ariad, Novartis, AOP, BMS, and CTI; honoraria: Novartis, BMS, Pfizer, Incyte/Ariad, Shire, Janssen; scientific research support: Novartis Foundation, BMS, Novartis; Others: Alexion. The remaining authors declare that they have no conflict of interest.

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Correspondence to Mirle Schemionek.

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https://doi.org/10.1038/s41375-019-0427-7