Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 25 August 2021 / Approved: 27 August 2021 / Online: 27 August 2021 (16:32:33 CEST)

How to cite: 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. Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations. Preprints 2021, 2021080529 (doi: 10.20944/preprints202108.0529.v1). 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. Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations. Preprints 2021, 2021080529 (doi: 10.20944/preprints202108.0529.v1).

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

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