Vitamin C-induzierte DNA-Demethylierung als Präventivtherapie für Leukämie
Final Report Abstract
Despite overall improved diagnostics, standard of care, and therapeutic options, most acute myeloid leukemia (AML) patients suffer from severe therapy-related side effects and only every third patient reaches 5-year overall survival. An observation that formed the foundation for this project is the frequent occurrence of mutations in AML cells which affect enzymes that contribute to a special control mechanism that regulates if and how much of a gene is read from our DNA to produce functional proteins. This control mechanism involves the precise placement and removal of “methylation marks” - either directly on top of the DNA strands or at proteins that help to organize the DNA into chromatin. If the placement or removal of these methylation marks is altered, protein production and cell survival mechanisms are disturbed – a characteristic which is often observed in cancer cells. In the past, the Hirst laboratory contributed to the discovery that vitamin C acts as a co-factor that helps to re-activate the enzymes that remove methylation marks, even in the presence of inactivating mutations. These enzymes are called the Ten-eleven-translocation or TET family, with TET2 being the family member that is most frequently mutated or otherwise inhibited in AML. Treating TET2 loss-of-function AML cells with vitamin C was shown to revert their DNA hypermethylation defect and to slowly eliminate these cells under controlled laboratory conditions (“ex vivo”) in multiple preclinical studies. Therefore, this effect is currently investigated in AML clinical trials. As vitamin C is a non-toxic, well-tolerated, widely available, and cost-effective substance, its potential anti-cancer effect provided us with a unique opportunity to test whether this knowledge could be translated into effective but less toxic alternative treatment strategies for AML patients who harbour these mutations, especially those who are not fit for chemotherapy.
Publications
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Invited Talk: “Revisiting the ‘Pauling controversy’ - Studying sensitivity of acute myeloid leukemia cells to vitamin C”. Clinical Noon Research Rounds, seminar for physicians at BC Cancer Hospital, April 20, 2022
Grasedieck, Sarah
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Selected Abstract / Talk: “Sensitivity of myeloid leukemia cells to vitamin C is encoded in their regulatory DNA and chromatin topology”. 8th Canadian Conference on Epigenetics, Oct 2022, Quebec, Canada
Grasedieck, Sarah
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Cellular context determines sensitivity to ascorbic acid in an IDH1-mutant Acute Myeloid Leukemia model. EHA Library. 2024;420591;P527
Grasedieck, Sarah; MacPhee, Liam; MacPherson, Kyle; Bilenky, Misha; Stephenson, Maria; Cao, Rachelle; Moksa, Michelle; Edin, Glenn; Hale, Margaret; Kuchenbauer, Florian; Rouhi, Arefeh; Eaves, Connie & Hirst, Martin
