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000142895 1001_ $$aLee, Catherine$$b0
000142895 245__ $$aLsd1 as a therapeutic target in Gfi1-activated medulloblastoma.
000142895 260__ $$a[London]$$bNature Publishing Group UK$$c2019
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000142895 520__ $$aDrugs that modify the epigenome are powerful tools for treating cancer, but these drugs often have pleiotropic effects, and identifying patients who will benefit from them remains a major clinical challenge. Here we show that medulloblastomas driven by the transcription factor Gfi1 are exquisitely dependent on the enzyme lysine demethylase 1 (Kdm1a/Lsd1). We demonstrate that Lsd1 physically associates with Gfi1, and that these proteins cooperate to inhibit genes involved in neuronal commitment and differentiation. We also show that Lsd1 is essential for Gfi1-mediated transformation: Gfi1 proteins that cannot recruit Lsd1 are unable to drive tumorigenesis, and genetic ablation of Lsd1 markedly impairs tumor growth in vivo. Finally, pharmacological inhibitors of Lsd1 potently inhibit growth of Gfi1-driven tumors. These studies provide important insight into the mechanisms by which Gfi1 contributes to tumorigenesis, and identify Lsd1 inhibitors as promising therapeutic agents for Gfi1-driven medulloblastoma.
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000142895 650_7 $$2NLM Chemicals$$aAntibiotics, Antineoplastic
000142895 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000142895 650_7 $$2NLM Chemicals$$aGFI1 protein, human
000142895 650_7 $$2NLM Chemicals$$aTranscription Factors
000142895 650_7 $$080168379AG$$2NLM Chemicals$$aDoxorubicin
000142895 650_7 $$0EC 1.14.11.-$$2NLM Chemicals$$aAof2 protein, mouse
000142895 650_7 $$0EC 1.14.11.-$$2NLM Chemicals$$aHistone Demethylases
000142895 7001_ $$00000-0002-4340-9311$$aRudneva, Vasilisa A$$b1
000142895 7001_ $$0P:(DE-He78)df8660bc5aba525f7fb6dba4aac15c1c$$aErkek, Serap$$b2$$udkfz
000142895 7001_ $$0P:(DE-He78)1beba8f953e7ae7e96e8d3e9a48f10f7$$aZapatka, Marc$$b3$$udkfz
000142895 7001_ $$aChau, Lianne Q$$b4
000142895 7001_ $$aTacheva-Grigorova, Silvia K$$b5
000142895 7001_ $$aGarancher, Alexandra$$b6
000142895 7001_ $$aRusert, Jessica M$$b7
000142895 7001_ $$aAksoy, Ozlem$$b8
000142895 7001_ $$aLea, Robin$$b9
000142895 7001_ $$aMohammad, Helai P$$b10
000142895 7001_ $$aWang, Jianxun$$b11
000142895 7001_ $$aWeiss, William A$$b12
000142895 7001_ $$00000-0001-8162-6758$$aGrimes, H Leighton$$b13
000142895 7001_ $$aPfister, Stefan M$$b14
000142895 7001_ $$aNorthcott, Paul A$$b15
000142895 7001_ $$aWechsler-Reya, Robert J$$b16
000142895 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-018-08269-5$$gVol. 10, no. 1, p. 332$$n1$$p332$$tNature Communications$$v10$$x2041-1723$$y2019
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