%0 Journal Article
%A He, Lixiazi
%A Arnold, Christian
%A Thoma, Judith
%A Rohde, Christian
%A Kholmatov, Maksim
%A Garg, Swati
%A Hsiao, Cheng-Chih
%A Viol, Linda
%A Zhang, Kaiqing
%A Sun, Rui
%A Schmidt, Christina
%A Janssen, Maike
%A MacRae, Tara
%A Huber, Karin
%A Thiede, Christian
%A Hébert, Josée
%A Sauvageau, Guy
%A Spratte, Julia
%A Fluhr, Herbert
%A Aust, Gabriela
%A Müller-Tidow, Carsten
%A Niehrs, Christof
%A Pereira, Gislene
%A Hamann, Jörg
%A Tanaka, Motomu
%A Zaugg, Judith B
%A Pabst, Caroline
%T CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia.
%J EMBO molecular medicine
%V 14
%N 4
%@ 1715-4684
%C Heidelberg
%I EMBO Press
%M DKFZ-2022-00435
%P e14990
%D 2022
%Z DKFZ-ZMBH Alliance / 2022 Apr 7;14(4):e14990
%X 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.
%K AML (Other)
%K CDK7 inhibition (Other)
%K GPR56 (Other)
%K leukemia stem cell (Other)
%K self-renewal (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:35253392
%R 10.15252/emmm.202114990
%U https://inrepo02.dkfz.de/record/179057