Induced differentiation of acute myeloid leukemia cells by activation of retinoid X and liver X receptors.
Induced differentiation of acute myeloid leukemia cells by activation of retinoid X and liver X receptors.
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DOI：
10.1038/leu.2013.202
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发表时间：
2014-04
期刊：
影响因子：
11.4
通讯作者：
Carroll M
中科院分区：
文献类型：
--
作者：
Sanchez PV;Glantz ST;Scotland S;Kasner MT;Carroll M
全反式维甲酸（ATRA）作为分化剂的使用仅限于急性早幼粒细胞白血病（APL），因为非APL白血病对ATRA不敏感。我们最近证明了rexinoid， bexarotene，诱导难治性AML患者的分化和治疗反应。Rexinoids结合并激活视黄酸X受体（RXR），但单独的Rexinoids不能激活视黄酸受体(RAR)/RXR复合物，提示髓细胞分化可以独立于RAR发生。在本研究中，我们证明AML细胞的类维生素a分化是不依赖于RAR的，并且需要PU.1的表达。由于RXR与其他核受体的混杂性，贝沙罗汀与其他核受体配体的髓细胞分化被探索。在一些AML细胞系中，贝沙罗汀与ATRA联合作用可增强分化，而贝沙罗汀与PPARγ激动剂罗格列酮联合作用则无此作用。相比之下，贝沙罗汀联合肝X受体（LXR）激动剂T0901317或GW3965在AML细胞系和原代人AML细胞中诱导了强有力的分化和细胞毒性，但在正常祖细胞中没有作用。这些结果表明，正常细胞中RXR/LXR调控的基因表达在AML细胞中被解除调控，并确定了这些激动剂在非apl白血病的分化治疗中的潜在作用。
Use of all-trans-retinoic acid (ATRA) as a differentiation agent has been limited to acute promyelocytic leukemia (APL) as non-APL leukemias are insensitive to ATRA. We recently demonstrated that the rexinoid, bexarotene, induces differentiation and therapeutic responses in patients with refractory AML. Rexinoids bind and activate retinoid X receptors (RXR), however rexinoids alone are incapable of activating retinoic acid receptor (RAR)/RXR complexes, suggesting that myeloid differentiation can occur independent of RAR. In this study we demonstrate that rexinoid differentiation of AML cells is RAR independent and requires the expression of PU.1. Because of the promiscuousness of RXR with other nuclear receptors, myeloid differentiation by bexarotene with other nuclear receptor ligands was explored. Bexarotene cooperated with ATRA to enhance differentiation in some AML cell lines, however the combination of bexarotene with the PPARγ agonist rosiglitazone did not. In contrast, bexarotene combined with Liver X Receptor (LXR) agonists T0901317 or GW3965 induced potent differentiation and cytotoxicity in AML cell lines and primary human AML cells, but not in normal progenitor cells. These results suggest that RXR/LXR regulated gene expression in normal cells is deregulated in AML cells and identifies a potential role for these agonists in differentiation therapy of non-APL leukemias.
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影响因子：
20.3
作者：
Mueller, BU;Pabst, T;Tenen, DG
通讯作者：
Tenen, DG
DOI：
10.1073/pnas.88.5.1977
发表时间：
1991-03-01
影响因子：
11.1
作者：
ALCALAY, M;ZANGRILLI, D;PELICCI, PG
通讯作者：
PELICCI, PG
影响因子：
3.6
作者：
Kumar, Naresh;Solt, Laura A.;Griffin, Patrick R.
通讯作者：
Griffin, Patrick R.
影响因子：
5.5
作者：
Ricote, Mercedes;Snyder, Cynthia S.;Glass, Christopher K.
通讯作者：
Glass, Christopher K.
影响因子：
64.5
作者：
Novershtern N;Subramanian A;Lawton LN;Mak RH;Haining WN;McConkey ME;Habib N;Yosef N;Chang CY;Shay T;Frampton GM;Drake AC;Leskov I;Nilsson B;Preffer F;Dombkowski D;Evans JW;Liefeld T;Smutko JS;Chen J;Friedman N;Young RA;Golub TR;Regev A;Ebert BL
通讯作者：
Ebert BL