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000179057 041__ $$aEnglish
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000179057 1001_ $$aHe, Lixiazi$$b0
000179057 245__ $$aCDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia.
000179057 260__ $$aHeidelberg$$bEMBO Press$$c2022
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000179057 520__ $$aThe 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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000179057 650_7 $$2Other$$aAML
000179057 650_7 $$2Other$$aCDK7 inhibition
000179057 650_7 $$2Other$$aGPR56
000179057 650_7 $$2Other$$aleukemia stem cell
000179057 650_7 $$2Other$$aself-renewal
000179057 7001_ $$aArnold, Christian$$b1
000179057 7001_ $$aThoma, Judith$$b2
000179057 7001_ $$aRohde, Christian$$b3
000179057 7001_ $$aKholmatov, Maksim$$b4
000179057 7001_ $$aGarg, Swati$$b5
000179057 7001_ $$aHsiao, Cheng-Chih$$b6
000179057 7001_ $$0P:(DE-He78)071caf37b84945360110e55dd31cbdf5$$aViol, Linda$$b7$$udkfz
000179057 7001_ $$0P:(DE-He78)784c543f0b1e62e5055c40c3d17b171d$$aZhang, Kaiqing$$b8$$udkfz
000179057 7001_ $$0P:(DE-He78)35066569c0f5ef6be060063a48919d6b$$aSun, Rui$$b9$$udkfz
000179057 7001_ $$aSchmidt, Christina$$b10
000179057 7001_ $$aJanssen, Maike$$b11
000179057 7001_ $$aMacRae, Tara$$b12
000179057 7001_ $$aHuber, Karin$$b13
000179057 7001_ $$00000-0003-1241-2048$$aThiede, Christian$$b14
000179057 7001_ $$aHébert, Josée$$b15
000179057 7001_ $$aSauvageau, Guy$$b16
000179057 7001_ $$aSpratte, Julia$$b17
000179057 7001_ $$aFluhr, Herbert$$b18
000179057 7001_ $$aAust, Gabriela$$b19
000179057 7001_ $$aMüller-Tidow, Carsten$$b20
000179057 7001_ $$0P:(DE-He78)483ad6be7d7fe19e48db9cce86efd70e$$aNiehrs, Christof$$b21$$udkfz
000179057 7001_ $$0P:(DE-He78)5138c10dcd0901d001d67a31423402b5$$aPereira, Gislene$$b22$$udkfz
000179057 7001_ $$00000-0002-9448-1727$$aHamann, Jörg$$b23
000179057 7001_ $$00000-0003-3663-9554$$aTanaka, Motomu$$b24
000179057 7001_ $$00000-0001-8324-4040$$aZaugg, Judith B$$b25
000179057 7001_ $$aPabst, Caroline$$b26
000179057 773__ $$0PERI:(DE-600)2485479-7$$a10.15252/emmm.202114990$$n4$$pe14990$$tEMBO molecular medicine$$v14$$x1715-4684$$y2022
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