Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia.
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.
Callens
Celine
C
Centre National de la Recherche Scientifique UMR 8147, Paris 75015, France.
Coulon
Séverine
S
Naudin
Jerome
J
Radford-Weiss
Isabelle
I
Boissel
Nicolas
N
Raffoux
Emmanuel
E
Wang
Pamella Huey Mei
PH
Agarwal
Saurabh
S
Tamouza
Houda
H
Paubelle
Etienne
E
Asnafi
Vahid
V
Ribeil
Jean-Antoine
JA
Dessen
Philippe
P
Canioni
Danielle
D
Chandesris
Olivia
O
Rubio
Marie Therese
MT
Beaumont
Carole
C
Benhamou
Marc
M
Dombret
Hervé
H
Macintyre
Elizabeth
E
Monteiro
Renato C
RC
Moura
Ivan C
IC
Hermine
Olivier
O
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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