title: Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia.
abstract: Differentiating agents have been proposed to overcome the impaired cellular differentiation in acute myeloid leukemia (AML). However, only the combinations of all-trans retinoic acid or arsenic trioxide with chemotherapy have been successful, and only in treating acute promyelocytic leukemia (also called AML3). We show that iron homeostasis is an effective target in the treatment of AML. Iron chelating therapy induces the differentiation of leukemia blasts and normal bone marrow precursors into monocytes/macrophages in a manner involving modulation of reactive oxygen species expression and the activation of mitogen-activated protein kinases (MAPKs). 30% of the genes most strongly induced by iron deprivation are also targeted by vitamin D3 (VD), a well known differentiating agent. Iron chelating agents induce expression and phosphorylation of the VD receptor (VDR), and iron deprivation and VD act synergistically. VD magnifies activation of MAPK JNK and the induction of VDR target genes. When used to treat one AML patient refractory to chemotherapy, the combination of iron-chelating agents and VD resulted in reversal of pancytopenia and in blast differentiation. We propose that iron availability modulates myeloid cell commitment and that targeting this cellular differentiation pathway together with conventional differentiating agents provides new therapeutic modalities for AML.
authors.affiliation: Centre National de la Recherche Scientifique UMR 8147, Paris 75015, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Callens
authors.forename: Séverine
authors.initials: S
authors.lastname: Coulon
authors.forename: Jerome
authors.initials: J
authors.lastname: Naudin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Radford-Weiss
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boissel
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffoux
authors.forename: Pamella Huey Mei
authors.initials: PH
authors.lastname: Wang
authors.forename: Saurabh
authors.initials: S
authors.lastname: Agarwal
authors.forename: Houda
authors.initials: H
authors.lastname: Tamouza
authors.forename: Etienne
authors.initials: E
authors.lastname: Paubelle
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Ribeil
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.forename: Danielle
authors.initials: D
authors.lastname: Canioni
authors.forename: Olivia
authors.initials: O
authors.lastname: Chandesris
authors.forename: Marie Therese
authors.initials: MT
authors.lastname: Rubio
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
authors.forename: Marc
authors.initials: M
authors.lastname: Benhamou
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
authors.forename: Renato C
authors.initials: RC
authors.lastname: Monteiro
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Moura
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
mesh_terms: D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D001772:Blood Cell Count; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002762:Cholecalciferol / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D006098:Granulocytes / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D006887:Hydroxycholecalciferols / Q000627:therapeutic use; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000090463:Iron Deficiencies; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D011990:Receptors, Transferrin / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D039481:CD11b Antigen; C068126:CD71 antigen; D006887:Hydroxycholecalciferols; C509295:ITGAM protein, human; D007502:Iron Chelating Agents; D018950:Lipopolysaccharide Receptors; D017382:Reactive Oxygen Species; D018167:Receptors, Calcitriol; D011990:Receptors, Transferrin; D002762:Cholecalciferol; D007501:Iron; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases