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

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.

• Authors: Lixiazi He, Christian Arnold, Judith Thoma, Christian Rohde, Maksim Kholmatov, Swati Garg, Cheng-Chih Hsiao, Linda Viol, Kaiqing Zhang, Rui Sun, Christina Schmidt, Maike Janssen, Tara MacRae, Karin Huber, Christian Thiede, Josée Hébert, Guy Sauvageau, Julia Spratte, Herbert Fluhr, Gabriela Aust, Carsten Müller-Tidow, Christof Niehrs, Gislene Pereira, Jörg Hamann, Motomu Tanaka, Judith B Zaugg, Caroline Pabst
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 14 Issue 4 Pg. e14990 (04 07 2022) ISSN: 1757-4684 [Electronic] England
• PMID: 35253392 (Publication Type: Journal Article)
• Copyright: ©2022 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Hedgehog Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• CDC2 Protein Kinase
• CDK12 protein, human
• CDK13 protein, human
• Cyclin-Dependent Kinases
• venetoclax
• Cyclin-Dependent Kinase-Activating Kinase
• CDK7 protein, human

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• CDC2 Protein Kinase (antagonists & inhibitors)
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Drug Synergism
• Hedgehog Proteins (metabolism, therapeutic use)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism, therapeutic use)
• Sulfonamides (pharmacology)
• Cyclin-Dependent Kinase-Activating Kinase