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

Autor: 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
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 14, Iss 4, Pp 1-22 (2022)
Druh dokumentu: article
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.202114990
Popis: 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.
Databáze: Directory of Open Access Journals
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