Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia Journal Article

   

Authors:	Boutzen, H.; Saland, E.; Larrue, C.; de Toni, F.; Gales, L.; Castelli, F. A.; Cathebas, M.; Zaghdoudi, S.; Stuani, L.; Kaoma, T.; Riscal, R.; Yang, G.; Hirsch, P.; David, M.; De Mas-Mansat, V.; Delabesse, E.; Vallar, L.; Delhommeau, F.; Jouanin, I.; Ouerfelli, O.; Le Cam, L.; Linares, L. K.; Junot, C.; Portais, J. C.; Vergez, F.; Recher, C.; Sarry, J. E.
Article Title:	Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia
Abstract:	Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired differentiation programs caused by recurrent mutations, such as the isocitrate dehydrogenase (IDH) mutations found in 15% of AML patients. These mutations result in the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG), leading to a hypermethylation phenotype that dysregulates hematopoietic differentiation. In this study, we identified mutant R132H IDH1-specific gene signatures regulated by key transcription factors, particularly CEBP alpha, involved in myeloid differentiation and retinoid responsiveness. We show that treatment with all-trans retinoic acid (ATRA) at clinically achievable doses markedly enhanced terminal granulocytic differentiation in AML cell lines, primary patient samples, and a xenograft mouse model carrying mutant IDH1. Moreover, treatment with a cell-permeable form of 2-HG sensitized wild-type IDH1 AML cells to ATRA-induced myeloid differentiation, whereas inhibition of 2-HG production significantly reduced ATRA effects in mutant IDH1 cells. ATRA treatment specifically decreased cell viability and induced apoptosis of mutant IDH1 blasts in vitro. ATRA also reduced tumor burden of mutant IDH1 AML cells xenografted in NOD-Scid-IL2r gamma(null) mice and markedly increased overall survival, revealing a potent antileukemic effect of ATRA in the presence of IDH1 mutation. This therapeutic strategy holds promise for this AML patient subgroup in future clinical studies.
Keywords:	leukemogenesis; serum; prognostic-significance; cells; hypermethylation; idh2 mutations; sufficient; c/ebp-alpha; 2-hydroxyglutarate levels; mutant idh2
Journal Title:	Journal of Experimental Medicine
Volume:	213
Issue:	4
ISSN:	0022-1007
Publisher:	Rockefeller University Press
Date Published:	2016-04-04
Start Page:	483
End Page:	497
Language:	English
ACCESSION:	WOS:000373394100004
DOI:	10.1084/jem.20150736
PROVIDER:	wos
PMCID:	PMC4821643
PUBMED:	26951332
Notes:	Article -- Source: Wos

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