All-trans retinoic acid and arsenic trioxide fail to derepress the monocytic differentiation driver Irf8 in acute promyelocytic leukemia cells.
All-trans retinoic acid and arsenic trioxide fail to derepress the monocytic differentiation driver Irf8 in acute promyelocytic leukemia cells.
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全反式视黄酸和三氧化二砷未能抑制急性早幼粒细胞白血病细胞中的单核细胞分化驱动因子 Irf8
DOI：
10.1038/cddis.2017.197
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发表时间：
2017-05-11
影响因子：
9
通讯作者：
Zhu J
中科院分区：
文献类型：
--
作者：
Liu X;Chen J;Yu S;Yan L;Guo H;Dai J;Zhang W;Zhu J
全反式视黄酸（ATRA）和/或三氧化二砷（ATO）主要通过靶向早幼粒细胞白血病/视黄酸受体α（PML/RARα）导致急性早幼粒细胞白血病（APL）细胞的粒细胞成熟和/或凋亡。然而，约 10-15% 的 APL 患者无法通过基于 ATRA 和 ATO 的疗法治愈，并且 ATRA 和 ATO 在完全逆转 PML/RARα 驱动的致癌改变方面的潜在失败尚未得到全面检查。在这里，我们使用 GFP 标记的 APL 模型描述了经 ATRA 和 ATO 处理的 APL 细胞中失调基因的体内初级反应。尽管 ATRA 或 ATO 给药后 APL 细胞的诱导粒细胞分化很明显，但 c-Kit+ APL 祖细胞中大多数失调基因的表达并未得到一致纠正。 Irf8 的表达随着体内 APL 祖细胞的自发分化而增加，代表了一种对 ATRA/ATO 信号传导无效的 PML/RARα 失调基因。有趣的是，Irf8 诱导（而非其敲除）通过驱动单核细胞成熟降低了 APL 致白血病潜力。因此，我们揭示了某些对 ATRA/ATO 信号传导无效的 PML/RARα 失调基因可能是 APL 细胞的不成熟状态和致白血病潜力的关键调节因子，可用于开发 ATRA/ATO 耐药 APL 病例的新治疗策略。
All-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) administration leads to granulocytic maturation and/or apoptosis of acute promyelocytic leukemia (APL) cells mainly by targeting promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα). Yet, ~10–15% of APL patients are not cured by ATRA- and ATO-based therapies, and a potential failure of ATRA and ATO in completely reversing PML/RARα-driven oncogenic alterations has not been comprehensively examined. Here we characterized the in vivo primary responses of dysregulated genes in APL cells treated with ATRA and ATO using a GFP-labeled APL model. Although induced granulocytic differentiation of APL cells was evident after ATRA or ATO administration, the expression of the majority of dysregulated genes in the c-Kit+ APL progenitors was not consistently corrected. Irf8, whose expression increased along with spontaneous differentiation of the APL progenitors in vivo, represented such a PML/RARα-dysregulated gene that was refractory to ATRA/ATO signaling. Interestingly, Irf8 induction, but not its knockdown, decreased APL leukemogenic potential through driving monocytic maturation. Thus, we reveal that certain PML/RARα-dysregulated genes that are refractory to ATRA/ATO signaling are potentially crucial regulators of the immature status and leukemogenic potential of APL cells, which can be exploited for the development of new therapeutic strategies for ATRA/ATO-resistant APL cases.
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通过将 PML-RARA 转导的人类共同骨髓祖细胞移植到免疫缺陷小鼠体内，建立人源化 APL 模型。
影响因子：
3.7
作者：
Matsushita H;Yahata T;Sheng Y;Nakamura Y;Muguruma Y;Matsuzawa H;Tanaka M;Hayashi H;Sato T;Damdinsuren A;Onizuka M;Ito M;Miyachi H;Pandolfi PP;Ando K
通讯作者：
Ando K
影响因子：
8.8
作者：
Arteaga, M. F.;Mikesch, J-H;Fung, T-K;So, C. W. E.
通讯作者：
So, C. W. E.
影响因子：
8.8
作者：
Nichol JN;Galbraith MD;Kleinman CL;Espinosa JM;Miller WH Jr
通讯作者：
Miller WH Jr
影响因子：
25.7
作者：
Teufel A;Maass T;Strand S;Kanzler S;Galante T;Becker K;Strand D;Biesterfeld S;Westphal H;Galle PR
通讯作者：
Galle PR
影响因子：
82.9
作者：
Ablain, Julien;Rice, Kim;de The, Hugues
通讯作者：
de The, Hugues