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000294574 1001_ $$aLaemmerer, Anna$$b0
000294574 245__ $$aAlternative lengthening of telomere-based immortalization renders H3G34R -mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens.
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000294574 500__ $$a2025 Mar 7;27(3):811-827
000294574 520__ $$aDiffuse hemispheric glioma, H3G34R/V-mutant (DHG-H3G34) is characterized by poor prognosis and lack of effective treatment options. DHG-H3G34R further harbor deactivation of Alpha-Thalassemia/Mental Retardation Syndrome X-linked protein (ATRX; DHG-H3G34R_ATRX) suggesting a unique interaction of these two oncogenic alterations. In this study, we dissect their cell biological interplay, investigate the impact on telomere stabilization and, consequently, validate a targeted therapy approach.We characterized patient-derived primary pediatric high-grade glioma (pHGG) models for telomere-maintenance mechanisms, DNA damage stress (including protein expression, pH2AX/Rad51 foci, cell-cycle arrest) and their sensitivity towards poly-ADP polymerase inhibitor (PARPi) combinations. Human induced pluripotent stem cells (iPSCs) were used for modelling the disease. The anticancer activity of PARPi combinations in vivo was studied in Chorioallantoic Membrane (CAM) and orthotopic in vivo experiments. Finally, we treated a DHG-H3G34R_ATRX patient with a PARPi combination therapy.We elaborate that alternative lengthening of telomeres (ALT) is a key characteristic of DHG-H3G34R_ATRX. A dominant cooperative effect between H3G34R and ATRX loss in ALT activation also became apparent in iPSCs, which endogenously exert telomerase activity. In both, patient-derived DHG-H3G34R_ATRX models and H3G34R+/ATRX- iPSCs, the ALT phenotype was associated with increased basal DNA damage stress, mediating synergistic susceptibility towards PARPi (talazoparib, niraparib) combinations with topoisomerase-I inhibitors (topotecan, irinotecan). In a first-of-its-kind case, treatment of a DHG-H3G34R_ATRX patient with the brain-penetrant PARP inhibitor niraparib and topotecan resulted in a significant tumor reduction.Our preclinical and clinical data strongly support the further development of PARPis together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX.
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000294574 650_7 $$2Other$$aATRX
000294574 650_7 $$2Other$$aDNA damage
000294574 650_7 $$2Other$$aDiffuse hemispheric glioma
000294574 650_7 $$2Other$$aH3G34R
000294574 650_7 $$2Other$$aPARP inhibitor
000294574 7001_ $$aLehmann, Christian$$b1
000294574 7001_ $$aMayr, Lisa$$b2
000294574 7001_ $$aBruckner, Katharina$$b3
000294574 7001_ $$aGabler, Lisa$$b4
000294574 7001_ $$aSenfter, Daniel$$b5
000294574 7001_ $$aMeyer, Philipp$$b6
000294574 7001_ $$aBalber, Theresa$$b7
000294574 7001_ $$aPirker, Christine$$b8
000294574 7001_ $$aJaunecker, Carola N$$b9
000294574 7001_ $$aKirchhofer, Dominik$$b10
000294574 7001_ $$aVician, Petra$$b11
000294574 7001_ $$aGriesser, Michelle$$b12
000294574 7001_ $$aSpiegl-Kreinecker, Sabine$$b13
000294574 7001_ $$aSchmook, Maria T$$b14
000294574 7001_ $$aTraub-Weidinger, Tatjana$$b15
000294574 7001_ $$aKuess, Peter$$b16
000294574 7001_ $$aEckert, Franziska$$b17
000294574 7001_ $$0P:(DE-He78)32c5110cd42ee8a96b18a3e8909bd0a9$$aFederico, Aniello$$b18$$udkfz
000294574 7001_ $$aMadlener, Sibylle$$b19
000294574 7001_ $$aStepien, Natalia$$b20
000294574 7001_ $$aRobl, Bernhard$$b21
000294574 7001_ $$aBaumgartner, Alicia$$b22
000294574 7001_ $$aHainfellner, Johannes A$$b23
000294574 7001_ $$aDieckmann, Karin$$b24
000294574 7001_ $$00000-0002-1843-7732$$aDorfer, Christian$$b25
000294574 7001_ $$aRoessler, Karl$$b26
000294574 7001_ $$aCorsini, Nina S$$b27
000294574 7001_ $$00000-0003-4077-3377$$aHolzmann, Klaus$$b28
000294574 7001_ $$aSchmidt, Wolfgang M$$b29
000294574 7001_ $$00000-0002-5736-8231$$aPeyrl, Andreas$$b30
000294574 7001_ $$00000-0002-1347-6644$$aAzizi, Amedeo A$$b31
000294574 7001_ $$00000-0003-1016-0545$$aHaberler, Christine$$b32
000294574 7001_ $$aBeck, Alexander$$b33
000294574 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b34$$udkfz
000294574 7001_ $$aSchueler, Julia$$b35
000294574 7001_ $$aLoetsch-Gojo, Daniela$$b36
000294574 7001_ $$aKnoblich, Jürgen A$$b37
000294574 7001_ $$aBerger, Walter$$b38
000294574 7001_ $$aGojo, Johannes$$b39
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