1. Academic Validation
  2. CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia

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.
Lixiazi He 1 2 Christian Arnold 2 3 Judith Thoma 4 Christian Rohde 1 2 Maksim Kholmatov 2 3 Swati Garg 1 2 5 Cheng-Chih Hsiao 6 Linda Viol 7 8 Kaiqing Zhang 9 Rui Sun 9 Christina Schmidt 1 Maike Janssen 1 Tara MacRae 10 Karin Huber 1 Christian Thiede 11 Josée Hébert 12 13 14 Guy Sauvageau 10 13 14 Julia Spratte 15 Herbert Fluhr 15 Gabriela Aust 16 Carsten Müller-Tidow 1 2 Christof Niehrs 9 17 Gislene Pereira 7 8 Jörg Hamann 6 Motomu Tanaka 4 18 Judith B Zaugg 2 3 Caroline Pabst 1 2
Affiliations

Affiliations

  • 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.
Abstract

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.

Keywords

AML; CDK7 inhibition; GPR56; leukemia stem cell; self-renewal.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-80013
    99.84%, CDK7 Inhibitor
    CDK