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000130701 0247_ $$2ISSN$$a1528-0020
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000130701 037__ $$aDKFZ-2017-05779
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000130701 1001_ $$aUras, Iris Z$$b0
000130701 245__ $$aPalbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6.
000130701 260__ $$aStanford, Calif.$$bHighWire Press$$c2016
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000130701 520__ $$aUp to 30% of patients with acute myeloid leukemia have constitutively activating internal tandem duplications (ITDs) of the FLT3 receptor tyrosine kinase. Such mutations are associated with a poor prognosis and a high propensity to relapse after remission. FLT3 inhibitors are being developed as targeted therapy for FLT3-ITD(+) acute myeloid leukemia; however, their use is complicated by rapid development of resistance, which illustrates the need for additional therapeutic targets. We show that the US Food and Drug Administration-approved CDK4/6 kinase inhibitor palbociclib induces apoptosis of FLT3-ITD leukemic cells. The effect is specific for FLT3-mutant cells and is ascribed to the transcriptional activity of CDK6: CDK6 but not its functional homolog CDK4 is found at the promoters of the FLT3 and PIM1 genes, another important leukemogenic driver. There CDK6 regulates transcription in a kinase-dependent manner. Of potential clinical relevance, combined treatment with palbociclib and FLT3 inhibitors results in synergistic cytotoxicity. Simultaneously targeting two critical signaling nodes in leukemogenesis could represent a therapeutic breakthrough, leading to complete remission and overcoming resistance to FLT3 inhibitors.
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000130701 650_7 $$2NLM Chemicals$$aMutant Proteins
000130701 650_7 $$2NLM Chemicals$$aPiperazines
000130701 650_7 $$2NLM Chemicals$$aProtein Kinase Inhibitors
000130701 650_7 $$2NLM Chemicals$$aProto-Oncogene Proteins
000130701 650_7 $$2NLM Chemicals$$aPyridines
000130701 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aFLT3 protein, human
000130701 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$afms-Like Tyrosine Kinase 3
000130701 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aPIM3 protein, human
000130701 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aProtein-Serine-Threonine Kinases
000130701 650_7 $$0EC 2.7.11.22$$2NLM Chemicals$$aCDK6 protein, human
000130701 650_7 $$0EC 2.7.11.22$$2NLM Chemicals$$aCyclin-Dependent Kinase 6
000130701 650_7 $$0G9ZF61LE7G$$2NLM Chemicals$$apalbociclib
000130701 7001_ $$0P:(DE-He78)8d1407b71d2891f2a088c1c5b20062e8$$aWalter, Gina$$b1$$eFirst author$$udkfz
000130701 7001_ $$aScheicher, Ruth$$b2
000130701 7001_ $$aBellutti, Florian$$b3
000130701 7001_ $$aPrchal-Murphy, Michaela$$b4
000130701 7001_ $$aTigan, Anca S$$b5
000130701 7001_ $$aValent, Peter$$b6
000130701 7001_ $$aHeidel, Florian H$$b7
000130701 7001_ $$aKubicek, Stefan$$b8
000130701 7001_ $$0P:(DE-He78)2c1a21d1cf5fdc9e297512c9d1354250$$aScholl, Claudia$$b9$$udkfz
000130701 7001_ $$0P:(DE-He78)f0144d171d26dbedb67c9db1df35629d$$aFröhling, Stefan$$b10$$udkfz
000130701 7001_ $$aSexl, Veronika$$b11
000130701 773__ $$0PERI:(DE-600)1468538-3$$a10.1182/blood-2015-11-683581$$gVol. 127, no. 23, p. 2890 - 2902$$n23$$p2890 - 2902$$tBlood$$v127$$x1528-0020$$y2016
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