Journal Article

DKFZ-2022-00435

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia.

He, L. ; Arnold, C. ; Thoma, J. ; Rohde, C. ; Kholmatov, M. ; Garg, S. ; Hsiao, C.-C. ; Viol, L.DKFZ* ; Zhang, K.DKFZ* ; Sun, R.DKFZ* ; Schmidt, C. ; Janssen, M. ; MacRae, T. ; Huber, K. ; Thiede, C. ; Hébert, J. ; Sauvageau, G. ; Spratte, J. ; Fluhr, H. ; Aust, G. ; Müller-Tidow, C. ; Niehrs, C.DKFZ* ; Pereira, G.DKFZ* ; Hamann, J. ; Tanaka, M. ; Zaugg, J. B. ; Pabst, C.

2022
EMBO Press Heidelberg

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Please use a persistent id in citations: doi:10.15252/emmm.202114990

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.

Keyword(s): AML ; CDK7 inhibition ; GPR56 ; leukemia stem cell ; self-renewal

Note: DKFZ-ZMBH Alliance / 2022 Apr 7;14(4):e14990

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Contributing Institute(s):

1. A180 Molecular Biology of Centrosomes (A180)
2. A050 Molekulare Embryologie (A050)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2022

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Database coverage:
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