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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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).
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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Kuepper, M.K., Bütow, M., Herrmann, O. et al. Stem cell persistence in CML is mediated by extrinsically activated JAK1-STAT3 signaling. Leukemia 33, 1964–1977 (2019). https://doi.org/10.1038/s41375-019-0427-7
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