Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia.
Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia.
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DOI：
10.1084/jem.20091488
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发表时间：
2010-04-12
期刊：
影响因子：
--
通讯作者：
Hermine O
中科院分区：
文献类型：
--
作者：
Callens C;Coulon S;Naudin J;Radford-Weiss I;Boissel N;Raffoux E;Wang PH;Agarwal S;Tamouza H;Paubelle E;Asnafi V;Ribeil JA;Dessen P;Canioni D;Chandesris O;Rubio MT;Beaumont C;Benhamou M;Dombret H;Macintyre E;Monteiro RC;Moura IC;Hermine O
已提出分化剂来克服急性髓系白血病（AML）中受损的细胞分化。然而，只有全反式视黄酸或三氧化二砷与化疗的组合取得了成功，并且仅在治疗急性早幼粒细胞白血病（也称为 AML3）方面取得了成功。我们证明铁稳态是治疗 AML 的有效目标。铁螯合疗法通过调节活性氧表达和激活丝裂原激活蛋白激酶（MAPK）的方式诱导白血病母细胞和正常骨髓前体细胞分化为单核细胞/巨噬细胞。 30% 受铁缺乏强烈诱导的基因也是维生素 D3 (VD)（一种众所周知的分化剂）的靶标。铁螯合剂诱导 VD 受体 (VDR) 的表达和磷酸化，缺铁和 VD 具有协同作用。 VD 放大 MAPK JNK 的激活和 VDR 靶基因的诱导。当铁螯合剂与 VD 联合用于治疗一名化疗难治性 AML 患者时，可逆转全血细胞减少症并促进原始细胞分化。我们提出，铁的可用性调节骨髓细胞的定向，并且针对该细胞分化途径与常规分化剂一起为 AML 提供新的治疗方式。
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.
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影响因子：
15.3
作者：
Hmama, Z;Nandan, D;Sly, L;Knutson, K L;Herrera-Velit, P;Reiner, N E
通讯作者：
Reiner, N E
影响因子：
20.3
作者：
Fu, Dong;Richardson, Des R.
通讯作者：
Richardson, Des R.
影响因子：
3.2
作者：
FENTON, RH;JOHNSON, FB;ZIMMERMAN, LE
通讯作者：
ZIMMERMAN, LE
DOI：
10.1073/pnas.78.8.4990
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
ABE, E;MIYAURA, C;SUDA, T
通讯作者：
SUDA, T
影响因子：
4.8
作者：
Amir-Moazami, Omid;Alexia, Catherine;Benhamou, Marc
通讯作者：
Benhamou, Marc