Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations

Sabatier, M.; Boet, E.; Zaghdoudi, S.; Guiraud, N.; Hucteau, A.; Polley, N.; Cognet, G.; Saland, E.; Lauture, L.; Farge, T.; Sahal, A.; Pancaldi, V.; Chu-Van, E.; Castelli, F.; Bertoli, S.; Bories, P.; Récher, C.; Boutzen, H.; Mansat-De Mas, V.; Stuani, L.; Sarry, J.-E. Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations. Cancers 2021, 13, 5243. Sabatier, M.; Boet, E.; Zaghdoudi, S.; Guiraud, N.; Hucteau, A.; Polley, N.; Cognet, G.; Saland, E.; Lauture, L.; Farge, T.; Sahal, A.; Pancaldi, V.; Chu-Van, E.; Castelli, F.; Bertoli, S.; Bories, P.; Récher, C.; Boutzen, H.; Mansat-De Mas, V.; Stuani, L.; Sarry, J.-E. Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations. Cancers 2021, 13, 5243.

Abstract

Relapses and resistance to therapeutic agents are major barriers for treatment of acute myeloid leukemia (AML) patients. This unfavorable circumstance emphasizes the need for new strategies targeting drug-resistant cells. As IDH mutation is present in the preleukemic stem cells and systematically conserved at relapse, targeting mutant IDH cells would be essential to achieve a long-term remission in the AML subgroup with IDH mutation. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutation, we showed that the presence of IDH mutation through the production of an oncometabolite (R)-2-HG induces vitamin D receptor related transcriptional programs, priming these AML cells to differentiate with pharmacological doses of ATRA or/and VD. This activation occurs in a CEBP-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutation and vitamin D pathway to differentiate in AML, revealing a novel therapeutic approach easily transferable/immediately applicable in clinics for this subgroup of AML patients.

Keywords

AML; IDH; Vitamin D; VDR; ATRA; CEBPa; Differentiation

Subject

Medicine and Pharmacology, Medicine and Pharmacology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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