CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia
- EMBO Mol Med. 2022 Apr 7;14(4):e14990. doi: 10.15252/emmm.202114990.
- 1. Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.
- 2. Molecular Medicine Partnership Unit (MMPU), University of Heidelberg and European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
- 3. European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
- 4. Physical Chemistry of Biosystems, Institute of Physical Chemistry, Heidelberg University, Heidelberg, Germany.
- 5. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
- 6. Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Centers, Amsterdam, Netherlands.
- 7. Centre for Organismal Studies (COS)/Centre for Cell and Molecular Biology (ZMBH), University of Heidelberg, Heidelberg, Germany.
- 8. German Cancer Research Centre (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
- 9. Division of Molecular Embryology, DKFZ-ZMBH Alliance, Heidelberg, Germany.
- 10. Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
- 11. Department of Internal Medicine I, University Hospital of Dresden Carl Gustav Carus, Dresden, Germany.
- 12. The Quebec Leukemia Cell Bank and Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montréal, Canada.
- 13. Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, Canada.
- 14. Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
- 15. Department of Gynecology and Obstetrics, University Hospital Heidelberg, Heidelberg, Germany.
- 16. Department of Surgery, Research Laboratories, Leipzig University, Leipzig, Germany.
- 17. Institute of Molecular Biology (IMB), Mainz, Germany.
- 18. Center for Integrative Medicine and Physics, Institute for Advanced Study, Kyoto University, Kyoto, Japan.
The heterogeneous response of acute myeloid leukemia (AML) to current anti-leukemic therapies is only partially explained by mutational heterogeneity. We previously identified GPR56 as a surface marker associated with poor outcome across genetic groups, which characterizes two leukemia stem cell (LSC)-enriched compartments with different self-renewal capacities. How these compartments self-renew remained unclear. Here, we show that GPR56+ LSC compartments are promoted in a complex network involving epithelial-to-mesenchymal transition (EMT) regulators besides Rho, Wnt, and Hedgehog (Hh) signaling. Unexpectedly, Wnt pathway inhibition increased the more immature, slowly cycling GPR56+ CD34+ fraction and Hh/EMT gene expression, while Wnt activation caused opposite effects. Our data suggest that the crucial role of GPR56 lies in its ability to co-activate these opposing signals, thus ensuring the constant supply of both LSC subsets. We show that CDK7 inhibitors suppress both LSC-enriched subsets in vivo and synergize with the Bcl-2 Inhibitor venetoclax. Our data establish reciprocal transition between LSC compartments as a novel concept underlying the poor outcome in GPR56high AML and propose combined CDK7 and Bcl-2 inhibition as LSC-directed therapy in this disease.