Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations.
Marie SabatierEmeline BoetSonia ZaghdoudiNathan GuiraudAlexis HucteauNathaniel PolleyGuillaume CognetEstelle SalandLaura LautureThomas FargeAmbrine SahalVera PancaldiEmeline Chu-VanFlorence A CastelliSarah BertoliPierre BoriesChristian RecherHéléna BoutzenVéronique De MasLucille StuaniJean-Emmanuel SarryPublished in: Cancers (2021)
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 mutations and the vitamin D receptor pathway on differentiation in AML, revealing a novel therapeutic approach easily transferable/immediately applicable to this subgroup of AML patients.
Keyphrases
- acute myeloid leukemia
- wild type
- drug resistant
- allogeneic hematopoietic stem cell transplantation
- low grade
- induced apoptosis
- end stage renal disease
- stem cells
- cell cycle arrest
- chronic kidney disease
- ejection fraction
- newly diagnosed
- peritoneal dialysis
- prognostic factors
- endothelial cells
- gene expression
- transcription factor
- cell death
- clinical trial
- acute lymphoblastic leukemia
- cancer therapy
- bone marrow
- signaling pathway
- drug delivery
- type diabetes
- systemic lupus erythematosus
- case report
- study protocol
- heat shock protein
- combination therapy
- smoking cessation
- single molecule
- heat shock