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| Home > Publications database > CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia. > print |
| Home > Publications database > CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia. > print |
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| 005 | 20240229145530.0 | ||
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| 100 | 1 | _ | |a He, Lixiazi |b 0 |
| 245 | _ | _ | |a CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia. |
| 260 | _ | _ | |a Heidelberg |c 2022 |b EMBO Press |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 500 | _ | _ | |a DKFZ-ZMBH Alliance / 2022 Apr 7;14(4):e14990 |
| 520 | _ | _ | |a 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. |
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| 650 | _ | 7 | |a AML |2 Other |
| 650 | _ | 7 | |a CDK7 inhibition |2 Other |
| 650 | _ | 7 | |a GPR56 |2 Other |
| 650 | _ | 7 | |a leukemia stem cell |2 Other |
| 650 | _ | 7 | |a self-renewal |2 Other |
| 700 | 1 | _ | |a Arnold, Christian |b 1 |
| 700 | 1 | _ | |a Thoma, Judith |b 2 |
| 700 | 1 | _ | |a Rohde, Christian |b 3 |
| 700 | 1 | _ | |a Kholmatov, Maksim |b 4 |
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| 700 | 1 | _ | |a Hsiao, Cheng-Chih |b 6 |
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| 700 | 1 | _ | |a Sun, Rui |0 P:(DE-He78)35066569c0f5ef6be060063a48919d6b |b 9 |u dkfz |
| 700 | 1 | _ | |a Schmidt, Christina |b 10 |
| 700 | 1 | _ | |a Janssen, Maike |b 11 |
| 700 | 1 | _ | |a MacRae, Tara |b 12 |
| 700 | 1 | _ | |a Huber, Karin |b 13 |
| 700 | 1 | _ | |a Thiede, Christian |0 0000-0003-1241-2048 |b 14 |
| 700 | 1 | _ | |a Hébert, Josée |b 15 |
| 700 | 1 | _ | |a Sauvageau, Guy |b 16 |
| 700 | 1 | _ | |a Spratte, Julia |b 17 |
| 700 | 1 | _ | |a Fluhr, Herbert |b 18 |
| 700 | 1 | _ | |a Aust, Gabriela |b 19 |
| 700 | 1 | _ | |a Müller-Tidow, Carsten |b 20 |
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| 700 | 1 | _ | |a Hamann, Jörg |0 0000-0002-9448-1727 |b 23 |
| 700 | 1 | _ | |a Tanaka, Motomu |0 0000-0003-3663-9554 |b 24 |
| 700 | 1 | _ | |a Zaugg, Judith B |0 0000-0001-8324-4040 |b 25 |
| 700 | 1 | _ | |a Pabst, Caroline |b 26 |
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