1. Academic Validation
  2. Stem cell persistence in CML is mediated by extrinsically activated JAK1-STAT3 signaling

Stem cell persistence in CML is mediated by extrinsically activated JAK1-STAT3 signaling

  • Leukemia. 2019 Aug;33(8):1964-1977. doi: 10.1038/s41375-019-0427-7.
Maja Kim Kuepper 1 Marlena Bütow 1 Oliver Herrmann 1 Janine Ziemons 1 Nicolas Chatain 1 Angela Maurer 1 Martin Kirschner 1 Tiago Maié 2 Ivan G Costa 2 Jörg Eschweiler 3 Steffen Koschmieder 1 Tim H Brümmendorf 1 Gerhard Müller-Newen 4 Mirle Schemionek 5
Affiliations

Affiliations

  • 1 Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
  • 2 Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, RWTH Aachen University, Aachen, Germany.
  • 3 Department of Orthopedics, Aachen University Hospital, Aachen, Germany.
  • 4 Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.
  • 5 Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany. mschemionek@ukaachen.de.
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.

Figures
Products