Abstract
Original language | English |
---|---|
Article number | e14990 |
Journal | EMBO molecular medicine |
Volume | 14 |
Issue number | 4 |
Early online date | 2022 |
DOIs | |
Publication status | Published - 7 Apr 2022 |
Keywords
- AML
- CDK7 inhibition
- GPR56
- leukemia stem cell
- self-renewal
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In: EMBO molecular medicine, Vol. 14, No. 4, e14990, 07.04.2022.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia
AU - He, Lixiazi
AU - Arnold, Christian
AU - Thoma, Judith
AU - Rohde, Christian
AU - Kholmatov, Maksim
AU - Garg, Swati
AU - Hsiao, Cheng-Chih
AU - Viol, Linda
AU - Zhang, Kaiqing
AU - Sun, Rui
AU - Schmidt, Christina
AU - Janssen, Maike
AU - MacRae, Tara
AU - Huber, Karin
AU - Thiede, Christian
AU - Hébert, Josée
AU - Sauvageau, Guy
AU - Spratte, Julia
AU - Fluhr, Herbert
AU - Aust, Gabriela
AU - Müller-Tidow, Carsten
AU - Niehrs, Christof
AU - Pereira, Gislene
AU - Hamann, J. rg
AU - Tanaka, Motomu
AU - Zaugg, Judith B.
AU - Pabst, Caroline
N1 - Funding Information: We thank V. Eckstein for support with cell sorting, R. Schneider for helping with cell culture experiments, and M. Frechette for assistance with experiments. We thank the teams of the Banque de Cellules Leucémiques du Québec (BCLQ), the Biomaterial banks of Medical Department V, Heidelberg University Hospital, the Department of Internal Medicine I, University Hospital of Dresden Carl Gustav Carus, Germany, the Department of Internal Medicine III, Ludwig‐Maximilians‐University, Munich, Germany, the Leukemia Cell Bank of Quebec, Maisonneuve‐Rosemont Hospital, Montreal, Canada, the CHU Sainte‐Justine, Montreal, Canada, the Department of Obstetrics at University Hospital Heidelberg, Germany, and all donors for providing primary human cells. We thank G. Posern for providing the SRF reporter system and positive control plasmids. We thank I. Jeremias and B. Vick, Helmholtz Zentrum München, for providing PDX AML‐491 cells. The work of G.P. and L.V. was supported by the collaborative SFB873 (project A14) and Heisenberg (PE1883‐3/4) programs of the DFG. This work was supported by Deutsche Forschungsgemeinschaft (DFG) FOR2149 grants PA 2815/2‐1 and HA‐4663/1‐1 to C.P. and J.H., respectively and by SFB1324 (project 331351713). C.P. is supported by a Max‐Eder‐Grant of German Cancer Aid (70111531) and by the Olympia‐Morata‐Program of the Medical Faculty of Heidelberg. The authors gratefully acknowledge the data storage service SDS@hd supported by the Ministry of Science, Research and the Arts Baden‐Württemberg (MWK) and the German Research Foundation (DFG) through grant INST 35/1314‐1 FUGG and INST 35/1503‐1 FUGG. Open Access funding enabled and organized by Projekt DEAL. in vivo Funding Information: We thank V. Eckstein for support with cell sorting, R. Schneider for helping with cell culture experiments, and M. Frechette for assistance with in vivo experiments. We thank the teams of the Banque de Cellules Leucémiques du Québec (BCLQ), the Biomaterial banks of Medical Department V, Heidelberg University Hospital, the Department of Internal Medicine I, University Hospital of Dresden Carl Gustav Carus, Germany, the Department of Internal Medicine III, Ludwig-Maximilians-University, Munich, Germany, the Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montreal, Canada, the CHU Sainte-Justine, Montreal, Canada, the Department of Obstetrics at University Hospital Heidelberg, Germany, and all donors for providing primary human cells. We thank G. Posern for providing the SRF reporter system and positive control plasmids. We thank I. Jeremias and B. Vick, Helmholtz Zentrum München, for providing PDX AML-491 cells. The work of G.P. and L.V. was supported by the collaborative SFB873 (project A14) and Heisenberg (PE1883-3/4) programs of the DFG. This work was supported by Deutsche Forschungsgemeinschaft (DFG) FOR2149 grants PA 2815/2-1 and HA-4663/1-1 to C.P. and J.H., respectively and by SFB1324 (project 331351713). C.P. is supported by a Max-Eder-Grant of German Cancer Aid (70111531) and by the Olympia-Morata-Program of the Medical Faculty of Heidelberg. The authors gratefully acknowledge the data storage service SDS@hd supported by the Ministry of Science, Research and the Arts Baden-Württemberg (MWK) and the German Research Foundation (DFG) through grant INST 35/1314-1 FUGG and INST 35/1503-1 FUGG. Open Access funding enabled and organized by Projekt DEAL. Publisher Copyright: ©2022 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2022/4/7
Y1 - 2022/4/7
N2 - 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.
AB - 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.
KW - AML
KW - CDK7 inhibition
KW - GPR56
KW - leukemia stem cell
KW - self-renewal
UR - http://www.scopus.com/inward/record.url?scp=85125631918&partnerID=8YFLogxK
U2 - https://doi.org/10.15252/emmm.202114990
DO - https://doi.org/10.15252/emmm.202114990
M3 - Article
C2 - 35253392
SN - 1757-4676
VL - 14
JO - EMBO molecular medicine
JF - EMBO molecular medicine
IS - 4
M1 - e14990
ER -