Open AccessCDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia
Author(s) -
He Lixiazi,
Arnold Christian,
Thoma Judith,
Rohde Christian,
Kholmatov Maksim,
Garg Swati,
Hsiao ChengChih,
Viol Linda,
Zhang Kaiqing,
Sun Rui,
Schmidt Christina,
Janssen Maike,
MacRae Tara,
Huber Karin,
Thiede Christian,
Hébert Josée,
Sauvageau Guy,
Spratte Julia,
Fluhr Herbert,
Aust Gabriela,
MüllerTidow Carsten,
Niehrs Christof,
Pereira Gislene,
Hamann Jörg,
Tanaka Motomu,
Zaugg Judith B,
Pabst Caroline
Publication year - 2022
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202114990
Subject(s) - myeloid leukemia , wnt signaling pathway , biology , cancer research , leukemia , venetoclax , stem cell , microbiology and biotechnology , immunology , signal transduction , chronic lymphocytic leukemia
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 GPR56 high AML and propose combined CDK7 and Bcl‐2 inhibition as LSC‐directed therapy in this disease.