Cancers, Vol. 13, Pages 5243: Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations

Cancers, Vol. 13, Pages 5243: Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations Cancers doi: 10.3390/cancers13205243 Authors: Marie Sabatier Emeline Boet Sonia Zaghdoudi Nathan Guiraud Alexis Hucteau Nathaniel Polley Guillaume Cognet Estelle Saland Laura Lauture Thomas Farge Ambrine Sahal Vera Pancaldi Emeline Chu-Van Florence Castelli Sarah Bertoli Pierre Bories Christian Récher Héléna Boutzen Véronique Mansat-De Mas Lucille Stuani Jean-Emmanuel Sarry Relapses and resistance to therapeutic agents are major barriers in the treatment of acute myeloid leukemia (AML) patients. These unfavorable outcomes emphasize the need for new strategies targeting drug-resistant cells. As IDH mutations are present in the preleukemic stem cells and systematically conserved at relapse, targeting IDH mutant cells could be essential to achieve a long-term remission in the IDH mutant AML subgroup. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutations, we showed that the production of an oncometabolite (R)-2-HG by IDH mutant enzymes induces vitamin D receptor-related transcriptional changes, priming these AML cells to differentiate with pharmacological doses of ATRA and/or VD. This activation occurs in a CEBPα-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutation...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research